JP5581927B2 - Process for producing 4-amino-m-cresol - Google Patents

Description

  The present invention relates to a process for producing 4-amino-m-cresol.

を有する化合物（別名：４−アミノ−３−メチルフェノール）であり、アミノ基とヒドロキシル基とを有することから、樹脂、染料、酸化防止剤、化学品、化学薬品、農薬、医薬などの合成中間体として、非常に工業的に有用な化合物である。 4-Amino-m-cresol has the following structure:

Compound (also known as: 4-amino-3-methylphenol) having an amino group and a hydroxyl group, it is a synthetic intermediate for resins, dyes, antioxidants, chemicals, chemicals, agricultural chemicals, pharmaceuticals, etc. It is a very industrially useful compound as a body.

Further, 4-amino-m-cresol itself can be directly blended into hair dyes, cosmetics, medicines and the like.
For example, patent document 1 (Unexamined-Japanese-Patent No. 2003-238369) discloses the hair dye containing 4-amino-m-cresol. More specifically, Patent Document 1 discloses the following components A to C:
As the component A, one or more selected from p-phenylenediamine, toluene-2,5-diamine, 2-chloro-p-phenylenediamine and salts thereof;
As the component B, one or more selected from “4-amino-3-methylphenol” and salts thereof,
As C component, it contains at least one selected from 5-amino-2-methylphenol, 5- (2-hydroxyethylamino) -2-methylphenol, and salts thereof,
Disclosed is a hair dye characterized in that the dosage form is a powder.
Patent Document 1 discloses “4-amino-3-methylphenol” (that is, 4-amino-m-cresol) as the component B. However, the source, manufacturer and synthesis of 4-amino-m-cresol are disclosed. No method is disclosed.

  Patent Document 2 (Japanese Patent Publication No. 6-89115) is characterized by containing a triglycidyl derivative of 4-amino-m-cresol having a viscosity at 25 ° C. of 15 poise or less and a curing agent. An “epoxy resin composition” is disclosed. The epoxy resin composition containing the triglycidyl derivative of 4-amino-m-cresol disclosed in Patent Document 2 is excellent in heat resistance and low in viscosity, and therefore has excellent workability. However, even in Patent Document 2, the source, manufacturer and synthesis method of 4-amino-m-cresol are not disclosed at all.

  Patent Document 3 (US Pat. No. 2,765,342) discloses a method for producing 4-amino-m-cresol from o-nitrotoluene. In this production method, the nitro group of o-nitrotoluene is converted to an amino group. Simultaneously with the reduction, 4-amino-m-cresol is produced by introducing a hydroxyl group at the para-position of the amino group derived from the nitro group by the Bamberger rearrangement reaction (see the following reaction formula) ) However, in this method, the yield of 4-amino-m-cresol is low, and o-toluidine, which is difficult to remove as an impurity, is produced as a by-product, so that the purity of 4-amino-m-cresol is also reduced. . Therefore, in the production method disclosed in Patent Document 3, high-purity 4-amino-m-cresol, particularly high-purity 4-amino-m-cresol, which is desirable as an intermediate of an epoxy resin used for electronic parts, is obtained. I can't.

Furthermore, Non-Patent Document 1 (Yanqing Peng et al., Indian Journal of Chemistry, Vol. 43B, September 2004, pp. 2021-2023) uses an excessive amount of sodium dithionite (Na ₂ S ₂ O as a reducing agent). ₄ ) Disclosed is a method for producing 4-amino-m-cresol from sodium salt of p- (4-hydroxy-o-tolylazo) benzenesulfonic acid by irradiation with microwave (MW) in the presence of ( See the reaction equation below).

  Furthermore, in the production method disclosed in Non-Patent Document 1, sodium dithionite, which is a reducing agent, is not reusable, and there is no problem with the treatment of the sulfur-containing waste liquid and the recovery of sulfanilic acid used as a raw material. Since it is possible, the production cost of 4-amino-m-cresol is very high.

JP 2003-238369 A Japanese Patent Publication No. 6-89115 U.S. Pat. No. 2,765,342

Yanqing Peng et al. , Indian Journal of Chemistry, Vol. 43B, September 2004, pp. 2021-2023

  An object of the present invention is to produce 4-amino-m-cresol inexpensively and easily with high yield and high purity.

  As a result of intensive studies, the present inventors have determined that the azo group (—N═N—) of p- (4-hydroxy-o-tolylazo) benzenesulfonic acid is obtained by catalytic reduction in the presence of hydrogen and a transition metal catalyst. The inventors have found a method for selectively producing only 4-amino-m-cresol in a high yield and high purity, thereby completing the present invention. Accordingly, the present invention provides the following.

[1]
P- (4-Hydroxy-o-tolylazo) benzenesulfonic acid by catalytic reduction in the presence of hydrogen and a transition metal catalyst at a reaction temperature in the range of 0 to 90 ° C. and a reaction pressure in the range of 0.1 to 3.0 MPa. Or a method for producing 4-amino-m-cresol from a salt thereof ,
The transition metal catalyst is Pd / C, Pt / C, Pd (II) X ¹ ₂ , Pt (0) L ¹ ₂ , Pt (II) X ² ₂ , Pt (0) L ² ₂ , Raney nickel, NiX ³ Selected from the group consisting of ₂ and Ni (0) L ³ ₂
Wherein X ¹ , X ² and X ³ are each independently selected from the group consisting of chlorine, bromine and iodine atoms;
L ¹ , L ² and L ³ are each independently dba (dibenzylideneacetone), dppf (1,1′-bis (diphenylphosphino) ferrocene), dppp (1,3-bis (diphenylphosphino)) Propane), acac (acetylacetonate), dppb (o-diphenylphosphinobenzoyl), cod (1,5-cyclooctadiene), TPP (triphenylphosphine), TPB (tetraphenylborate) and BINAP (2,2 Selected from the group consisting of '-bis (diphenylphosphino) -1,1'-binaphthyl.]
A process for producing 4-amino-m-cresol, which is a transition metal catalyst selected from the group consisting of:

[2]
After the catalytic reduction, further comprising the step of adjusting the pH of the reaction solution to 4.0 to 8.0 to precipitate 4-amino-m-cresol, and then separating the precipitate and the filtrate by filtration. The method according to [1] above.

[3]
The method according to [2] above , further comprising a step of obtaining crystals of 4-amino-m-cresol from the precipitate by recrystallization.

[4]
The method according to any one of [1] to [3], further comprising a step of recovering sulfanilic acid from the filtrate.

[5]
Prior to the catalytic reduction, comprising diazotizing sulfanilic acid and further reacting with m-cresol to prepare the p- (4-hydroxy-o-tolylazo) benzenesulfonic acid or a salt thereof. The method according to any one of [1] to [4] above.

[ 6 ]
The method according to any one of [1] to [5] above, wherein the catalytic reduction is performed in an alkaline aqueous solution.

[7]
A step of preparing p- (4-hydroxy-o-tolylazo) benzenesulfonic acid or a salt thereof by diazotizing sulfanilic acid and further reacting with m-cresol;
Hydrogen ; and Pd / C, Pt / C, Pd (II) X ¹ ₂ , Pt (0) L ¹ ₂ , Pt (II) X ² ₂ , Pt (0) L ² ₂ , Raney nickel, NiX ³ ₂ and Ni (0) L ³ ₂
Wherein X ¹ , X ² and X ³ are each independently selected from the group consisting of chlorine, bromine and iodine atoms;
L ¹ , L ² and L ³ are each independently dba (dibenzylideneacetone), dppf (1,1′-bis (diphenylphosphino) ferrocene), dppp (1,3-bis (diphenylphosphino)) Propane), acac (acetylacetonate), dppb (o-diphenylphosphinobenzoyl), cod (1,5-cyclooctadiene), TPP (triphenylphosphine), TPB (tetraphenylborate) and BINAP (2,2 Selected from the group consisting of '-bis (diphenylphosphino) -1,1'-binaphthyl.]
In the presence of a transition metal catalyst selected from the group consisting of : a reaction temperature in the range of 0 to 90 ° C. and a reaction pressure in the range of 0.1 to 3.0 MPa by catalytic reduction in an aqueous alkaline solution. A step of preparing 4-amino-m-cresol from (4-hydroxy-o-tolylazo) benzenesulfonic acid or a salt thereof;
After the catalytic reduction, the pH of the reaction solution is adjusted to 4.0 to 8.0 to precipitate 4-amino-m-cresol, and then the precipitate and the filtrate are separated by filtration;
Obtaining crystals of 4-amino-m-cresol from the precipitate by recrystallization, and
Recovering sulfanilic acid from the filtrate,
In the production of 4-amino-m-cresol, comprising: sulfanilic acid as a raw material.

[8]
The sulfanilic acid recovered by the method according to any one of the above [7] is diazotized and further reacted with m-cresol to obtain p- (4-hydroxy-o-tolylazo) benzenesulfonic acid or a salt thereof. How to manufacture.

  According to the present invention, 4-amino-m in high yield and purity is obtained from p- (4-hydroxy-o-tolylazo) benzenesulfonic acid or a salt thereof by catalytic reduction in the presence of hydrogen and a transition metal catalyst. -Only cresol can be produced selectively and inexpensively. In the present invention, sulfanilic acid by-produced by catalytic reduction can be recovered from the waste liquid after catalytic reduction with high yield and high purity. By reusing the recovered sulfanilic acid, the above p- (4-hydroxy-o-tolylazo) benzenesulfonic acid or a salt thereof can be synthesized again from the recovered sulfanilic acid. -Since amino-m-cresol can be manufactured, the manufacturing cost of 4-amino-m-cresol can be reduced significantly and it is suitable for industrial production. In addition, the method of the present invention reuses the waste liquid, so it is environmentally friendly and very useful.

2 is an HPLC chart of 4-amino-m-cresol produced in Example 1. FIG. 2 is a ¹ H-NMR spectrum of 4-amino-m-cresol prepared in Example 1. FIG. 2 is a ¹³ C-NMR spectrum of 4-amino-m-cresol prepared in Example 1. FIG. 2 is an HPLC chart of 4-amino-m-cresol produced in Comparative Example 1.

  Although this invention relates to the manufacturing method of 4-amino-m-cresol, according to the following schemes, the form for implementing this invention is demonstrated in detail, This invention is not limited to these.

  As shown in the above scheme, the present invention relates to a process for producing 4-amino-m-cresol, and more specifically, in the present invention, by catalytic reduction in the presence of hydrogen and a transition metal catalyst, p- (4 It relates to a process for producing 4-amino-m-cresol from -hydroxy-o-tolylazo) benzenesulfonic acid.

  Moreover, the p- (4-hydroxy-o-tolylazo) benzenesulfonic acid used in the present invention may be in the form of a salt as represented by the following formula.

  (In the formula, X represents a hydrogen atom, lithium, sodium or potassium, but is not particularly limited thereto)

  In the present invention, p- (4-hydroxy-o-tolylazo) benzenesulfonic acid or a salt thereof is obtained by diazotizing sulfanilic acid and further coupling with m-cresol as shown in the above scheme, that is, “diazo It is preferable that it was obtained by the "coupling reaction".

Diazotization coupling reaction First, sulfanilic acid is added to water and then a base is added to completely dissolve the sulfanilic acid in water.

  The amount of water is 1.0 to 5.0 L, preferably 1.2 to 2.5 L, relative to 1 molar equivalent of sulfanilic acid. If it is less than 1.0 L, there is a risk of problems such as incomplete dissolution, and if it exceeds 5.0 L, there may be a problem that the yield of the final product decreases and the amount of waste liquid increases.

  Examples of the base include hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; carbonates of alkali metals such as sodium carbonate, potassium carbonate, and cesium carbonate; sodium bicarbonate, potassium bicarbonate, and the like And alkali metal hydrogen carbonates of the above.

  The addition amount of the base is 0.5 to 1.5 molar equivalents, preferably 0.5 to 1.2 molar equivalents, relative to 1 molar equivalent of sulfanilic acid. If the amount is less than 0.5 molar equivalent, there is a risk of problems such as incomplete dissolution. If the amount exceeds 1.5 molar equivalent, a large amount of acid is required at the time of acid precipitation and the amount of target product recovered is reduced. There is a fear.

  An aqueous sulfanilic acid solution is cooled to 0 to 10 ° C., preferably 0 to 5 ° C., and a nitrite such as sodium nitrite and potassium nitrite or an aqueous solution thereof is added to the aqueous solution, and then an acid such as hydrochloric acid and sulfuric acid is added. Diazotize the sulfanilic acid (ie, formation of a diazonium salt). When the acid is added, it is desirable to add, preferably add dropwise, so that the liquid temperature is 10 ° C. or lower, preferably 5 ° C. or lower.

  If the temperature of the aqueous sulfanilic acid solution is less than 0 ° C, the solvent may freeze or become a sherbet, and if it exceeds 10 ° C, the diazonium salt may be decomposed. is there.

  The amount of nitrite added is 1.01 to 2.0 molar equivalents, preferably 1.05 to 1.2 molar equivalents, relative to 1 molar equivalent of sulfanilic acid. If it is less than 1.01 molar equivalent, there is a risk of problems such as incomplete diazotization reaction. If it exceeds 2.0 molar equivalent, side reactions may occur due to excess nitrite, or denitrification. There is a risk of problems such as the need for large amounts of sulfamic acid.

  The amount of acid added is 2.0 to 5.0 molar equivalents, preferably 2.5 to 4.0 molar equivalents, relative to 1 molar equivalent of sulfanilic acid. If the amount is less than 2.0 molar equivalents, the diazotization reaction may be incomplete, and if it exceeds 5.0 molar equivalents, a side reaction may occur.

  Stirring is continued at this temperature for 10 minutes to 1 hour, preferably 20 minutes to 40 minutes to diazotize sulfanilic acid to obtain a solution containing a diazonium salt of sulfanilic acid (hereinafter referred to as diazo-containing solution). Since an excessive amount of nitrite is present in the diazo-containing solution, for example, sulfamic acid is added to decompose (denitrify) the nitrite. At this time, sulfamic acid is added to the diazo-containing solution little by little, the diazo-containing solution squeezed with a glass rod is applied to KI starch paper, and sulfamic acid is added to the diazo-containing solution until it does not change color.

  Next, in order to perform a coupling reaction with m-cresol, separately, m-cresol is added to water, and further, a base is added to completely dissolve m-cresol in water to prepare a coupler solution. To do.

  The amount of water added is 1.0 to 5.0 L, preferably 1.5 to 2.5 L, relative to 1 molar equivalent of m-cresol. If it is less than 1.0 L, there is a risk of problems such as incomplete dissolution, and if it exceeds 5.0 L, a large amount of acid is required at the time of acid precipitation and there is a risk that the amount of target product recovered will be reduced.

  Examples of the base include hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; carbonates of alkali metals such as sodium carbonate, potassium carbonate, and cesium carbonate; sodium bicarbonate, potassium bicarbonate, and the like And alkali metal hydrogen carbonates of the above.

  The addition amount of the base is 1.0 to 1.5 molar equivalents, preferably 1.0 to 1.1 molar equivalents with respect to 1 molar equivalent of m-cresol. If the amount is less than 1.0 molar equivalent, there is a risk of problems such as incomplete dissolution. If the amount exceeds 1.5 molar equivalent, a large amount of acid is required at the time of acid precipitation and the amount of recovered target product is reduced. There is a fear.

  The coupler solution is then cooled to 0-10 ° C, preferably 0-5 ° C. If it is lower than 0 ° C., there is a fear that the solvent water freezes or becomes a sherbet, and if it exceeds 10 ° C., there is a possibility that the diazonium salt decomposes.

  The diazo-containing solution of sulfanilic acid described above is added dropwise to the cooled coupler solution. In dropping, it is desirable to adjust the temperature of the reaction system to 0 to 10 ° C, preferably 0 to 5 ° C. If the temperature is less than 0 ° C, water as a solvent may freeze or become a sherbet, and if it exceeds 10 ° C, the diazonium salt decomposes and a side reaction occurs. There is a fear.

  Further, an aqueous solution of a base such as an alkali metal hydroxide (for example, sodium hydroxide, potassium hydroxide) or an alkali metal carbonate (for example, sodium carbonate, potassium carbonate) is appropriately added to the reaction solution, It is desirable to adjust the pH of the reaction system so that the pH of the reaction system is 8 to 14, preferably 9 to 11, more preferably pH 10. If the pH is less than 8, there may be problems such as side reactions (those with different coupling positions). If the pH exceeds 14, side reactions (two couplings occur) and a large amount during acid precipitation. This may cause problems such as reduced acid recovery due to the need for acid.

  In the diazotization coupling reaction, the amount of m-cresol used is 0.99 to 1.01 molar equivalent, preferably an equimolar amount, relative to 1 molar equivalent of sulfanilic acid.

  After completion of the dropwise addition, the mixture is stirred for 30 minutes to 5 hours, preferably 1 hour to 3 hours, and subjected to salting out and / or aciding out to obtain a diazotized coupling reaction product, that is, p- (4-hydroxy-o- Tolylazo) benzenesulfonic acid or a salt thereof.

  Examples of the salt used for salting out include lithium chloride, sodium chloride, potassium chloride, and the like. The amount of the salt added is 1 molar equivalent of p- (4-hydroxy-o-tolylazo) benzenesulfonic acid or a salt thereof. 1 to 20 molar equivalents, preferably 5 to 15 molar equivalents, more preferably 8 to 12 molar equivalents. If it is less than 1 molar equivalent, the product recovery rate may be low, and if it exceeds 20 molar equivalent, salt may be mixed into the product and the purity may be reduced.

  Examples of the acid used for acid precipitation include hydrochloric acid and sulfuric acid. These acids are added until the pH of the reaction solution becomes near neutral.

  The liquid temperature at the time of salting out and / or aciding out depends on the type of precipitate, but is not particularly limited, and is, for example, 0 to 30 ° C., preferably 5 to 15 ° C., and less than 0 ° C. If the temperature exceeds 30 ° C., the product may be decomposed.

  The pH at the time of salting out and / or aciding out depends on the type of precipitate, but is not particularly limited. For example, the pH is 3 to 9, preferably 6 to 9, and less than 3. There is a risk of problems such as precipitation of the product, and if it exceeds 9, there is a risk of problems such as no precipitation of the product.

（式中、Ｘは、水素原子、リチウム、ナトリウムまたはカリウムを表すが、特にこれらに限定されない）
で表され、遊離酸（Ｘ＝Ｈ）の形態であっても、塩（Ｘ＝Ｌｉ、ＮａまたはＫなど）の形態であっても、あるいは、これらの混合物であってもよい。析出したｐ−（４−ヒドロキシ−ｏ−トリルアゾ）ベンゼンスルホン酸またはその塩は、必要に応じて、濾取し、水で洗浄し、乾燥してもよく、あるいは、ウェットケーキの状態で次の反応に用いてもよい。 Accordingly, p- (4-hydroxy-o-tolylazo) benzenesulfonic acid or a salt thereof precipitated by such salting out and / or aciding out has the formula:

(In the formula, X represents a hydrogen atom, lithium, sodium or potassium, but is not particularly limited thereto)
And may be in the form of a free acid (X = H), a salt (such as X = Li, Na or K), or a mixture thereof. The precipitated p- (4-hydroxy-o-tolylazo) benzenesulfonic acid or a salt thereof may be collected by filtration, washed with water and dried, if necessary, or in the form of a wet cake. You may use for reaction.

Catalytic reduction Next, catalytic reduction of p- (4-hydroxy-o-tolylazo) benzenesulfonic acid or a salt thereof will be described.

  In the present invention, as shown in the above-mentioned scheme, an azo group (—N═N—) contained in p- (4-hydroxy-o-tolylazo) benzenesulfonic acid or a salt thereof is converted into hydrogen and a transition metal catalyst by catalytic reduction. Can be cleaved by reduction in the presence of and decomposed into “4-amino-m-cresol” and “sulfanilic acid”.

  More specifically, p- (4-hydroxy-o-tolylazo) benzenesulfonic acid or a salt thereof is charged into a pressure vessel such as an autoclave, and hydrogen is blown into the pressure vessel in an alkaline aqueous solution in the presence of a transition metal catalyst. Thus, the azo bond (—N═N—) can be cleaved reductively.

The transition metal catalyst is not particularly limited as long as it is a metal catalyst having a catalytic hydrogen reduction action. For example, Pd / C, Pt / C, Pd (II) X ¹ ₂ , Pt (0) L ¹ ₂ , Pt ( II) Those selected from the group consisting of X ² ₂ , Pt (0) L ² ₂ , Raney Nickel (Raney Ni), NiX ³ ₂ and Ni (0) L ³ ₂ are preferred. X ¹ , X ² and X ³ each independently represent a halogen atom, and are preferably selected from the group consisting of a chlorine atom, a bromine atom and an iodine atom. L ¹ , L ² and L ³ each independently represent a ligand, preferably dba (dibenzylideneacetone), dppf (1,1′-bis (diphenylphosphino) ferrocene), dppp (1 , 3-bis (diphenylphosphino) propane), acac (acetylacetonate), dppb (o-diphenylphosphinobenzoyl), cod (1,5-cyclooctadiene), TPP (triphenylphosphine), TPB (tetra Phenylborate) and BINAP (2,2′-bis (diphenylphosphino) -1,1′-binaphthyl) As the transition metal catalyst, Pd / C is particularly preferable from the viewpoint of yield improvement. preferable.

  The amount of the transition metal catalyst used is not particularly limited as long as catalytic reduction proceeds, and for example, with respect to 1 mol of p- (4-hydroxy-o-tolylazo) benzenesulfonic acid or a salt thereof, 0.001 mol% to 10.0 mol%, preferably 0.01 mol% to 5.0 mol%, more preferably 0.01 mol% to 1.0 mol%, and if it is less than 0.001 mol%, the reaction is not completed. There is a risk of problems such as possibility, and if it exceeds 10.0 mol%, there is a risk of problems such as high cost.

  The reaction temperature is 0 to 90 ° C, preferably 15 to 85 ° C, more preferably 20 to 80 ° C, particularly preferably 60 ° C, and the pressure is 0.1 to 3.0 MPa, preferably 0.25 to 0. .75 MPa, more preferably 0.4 to 0.6 MPa. It is desirable to carry out the reaction until no hydrogen is absorbed under these conditions.

  If the reaction temperature is less than 0 ° C., there is a fear that the reaction does not proceed, and if it exceeds 90 ° C., there is a risk that the reaction is dangerous or a side reaction occurs.

  Further, if the pressure is less than 0.1 MPa, there is a fear that the reaction does not proceed, and if it exceeds 3.0 MPa, there is a danger that a dangerous side reaction occurs.

  In the present invention, the catalytic reduction is preferably performed in an alkaline aqueous solution, preferably in an aqueous sodium hydroxide solution or an aqueous potassium hydroxide solution.

  The concentration of the alkaline aqueous solution used in the catalytic reduction is 1% by weight to 20% by weight, preferably 3% by weight to 17% by weight, and more preferably 5% by weight to 10% by weight. If the concentration is less than 1% by weight, the raw material may not be uniformly dissolved / dispersed, and the efficiency of the catalytic reduction reaction may be reduced. If the concentration exceeds 20% by weight, a large amount of acid is generated during acid precipitation. There is a risk of problems such as need.

  The addition amount of the alkaline aqueous solution is 0.3 L to 3.0 L, preferably 0.5 L to 1.5 L with respect to 1 molar equivalent of p- (4-hydroxy-o-tolylazo) benzenesulfonic acid or a salt thereof. is there. If it is less than 0.3 L, the raw material may not be uniformly dissolved / dispersed and the efficiency of the catalytic reduction reaction may be reduced. If it exceeds 3.0 L, a large amount of acid is required during acid precipitation. There is a risk of problems such as.

  In the catalytic reduction, the pH of the reaction solution is 7 to 12, preferably 8 to 12. If the pH is less than 7, the raw materials may not be uniformly dissolved and dispersed, which may cause problems such as reduced efficiency of the catalytic reduction reaction. If it exceeds 12, a large amount of acid is required during acid precipitation. There is a risk of problems.

  After completion of the catalytic reduction reaction, it is desirable to remove the catalyst from the reaction solution as necessary. For example, the catalyst can be removed from the reaction solution by an ordinary operation such as filtration. In addition, since the recovered catalyst can be reused, it is very economical.

  Further, after completion of the catalytic reduction reaction, only 4-amino-m-cresol is precipitated from the reaction solution by adjusting the pH of the reaction solution to 4.0 to 8.0, particularly preferably to pH 7.0. Can be made. If the pH is less than 4.0, sulfanilic acid may be co-deposited to lower the purity of the target compound and the recovery rate of sulfanilic acid may decrease, and if the pH exceeds 8.0, the target product yield may be reduced. There is a risk of problems such as lowering.

  Moreover, the temperature of the reaction liquid at this time is 0 degreeC-40 degreeC, Preferably it is 5 degreeC-20 degreeC. If the temperature is lower than 0 ° C, there is a risk of problems such as precipitation of impurities, and if it is higher than 40 ° C, there is a risk that the recovery rate of 4-amino-m-cresol is reduced.

  In order to adjust the pH of the reaction solution within the above range, an acid such as hydrochloric acid, sulfuric acid, and nitric acid can be used, but the amount and concentration of the acid used can be adjusted within the above range. There is no particular limitation.

  Thus, after completion of the catalytic reduction reaction, the target 4-amino-m-cresol is precipitated by adjusting the pH of the reaction solution to 4.0 to 8.0, and sulfanilic acid is used as a by-product in the solution ( In the filtrate).

  Accordingly, in the present invention, as shown in the above scheme, 4-amino-m-cresol can be recovered as a precipitate and sulfanilic acid can be recovered in the filtrate by filtration. In addition, there is no restriction | limiting in particular in filtration temperature, Usually, it is 10-30 degreeC. Further, the precipitate collected by filtration may be washed with water.

  After filtration, the precipitate is dried at 50-150 ° C., preferably 70-120 ° C., to give 4-amino-m-cresol.

  Furthermore, it is desirable that the 4-amino-m-cresol is further purified by further purification.

  First, dried 4-amino-m-cresol is dispersed in water to obtain a dispersion. The usage-amount of water is 300-3000 mL with respect to 1 molar equivalent of 4-amino-m-cresol, Preferably it is 500-2000 mL. If it is less than 300 mL, there is a fear that a sufficient purification effect cannot be obtained, and if it exceeds 3000 mL, there is a possibility that the recovery rate of 4-amino-m-cresol is lowered.

  Further, a small amount of reducing agent and activated carbon may be added and heated and stirred.

  This is because the reducing agent prevents coloring due to oxidation of the amino group of 4-amino-m-cresol and obtains the desired product as a white product. Examples of the reducing agent include sodium bisulfite and sodium dithionite. The amount of the reducing agent used is 0.5 to 5.0% by weight, preferably 1.0 to 3.0% by weight, based on the weight of 4-amino-m-cresol. If it is less than 0.5% by weight, there is a fear that a sufficient effect cannot be obtained, and if it exceeds 5.0% by weight, there is a possibility that it may be mixed into the product as an impurity.

  Activated carbon is used for removing colored substances and odorous substances in the reaction system, and the amount of activated carbon used is 0.5 to 5.0% by weight based on the weight of 4-amino-m-cresol. It is preferably 1.0 to 3.0% by weight. If it is less than 0.5% by weight, there may be a problem that a sufficient effect cannot be obtained, and if it exceeds 5.0% by weight, there may be a problem that it takes time to remove.

  Next, the aqueous dispersion of 4-amino-m-cresol is heated and stirred at 80 to 100 ° C., preferably 85 to 95 ° C. for 0.1 to 3 hours, preferably 0.5 to 2 hours. Filter while hot.

  The temperature during hot filtration is 60 to 100 ° C., preferably 70 to 80 ° C. If the temperature is less than 60 ° C., there is a possibility that a large amount of 4-amino-m-cresol may be precipitated. If it exceeds 1, 4-amino-m-cresol may be decomposed or may react with other substrates.

  After hot filtration, the filtrate is cooled to 0 to 40 ° C., preferably 10 to 25 ° C., and desirably allowed to cool for 1 to 24 hours, preferably 6 to 16 hours until reaching the above temperature. 4-amino-m-cresol can be obtained as crystals (ie, recrystallization purification). The precipitated crystals can be further filtered, washed and dried as necessary to obtain 4-amino-m-cresol crystals having a purity of 95 to 100%.

  Thus, in the present invention, 4-amino-m-cresol can be produced from p- (4-hydroxy-o-tolylazo) benzenesulfonic acid or a salt thereof with high yield and high purity. Further, according to the present invention, as described above, only 4-amino-m-cresol can be easily and selectively produced.

  Furthermore, in the present invention, only 4-amino-m-cresol can be selectively produced in high yield and high purity from p- (4-hydroxy-o-tolylazo) benzenesulfonic acid or a salt thereof. In addition, since sulfanilic acid as a raw material can be recovered as a by-product of the above catalytic reduction reaction, 4-amino-m-cresol can be produced at a very low cost.

Recovery of sulfanilic acid As shown in the above scheme, sulfanilic acid can be recovered from the filtrate obtained by filtering off 4-amino-m-cresol precipitated from the reaction solution for catalytic reduction.

  First, the filtrate containing sulfanilic acid is heated to 70 to 150 ° C., preferably 90 to 120 ° C., and concentrated.

  Next, the temperature of the concentrate is adjusted to 50 to 70 ° C., particularly preferably 60 ° C., and an acid is added to adjust the pH to 0.1 to 2.0, preferably 0.3 to 1.0, particularly preferably 0. Adjust to .5. The acid is not particularly limited as long as it is stronger than sulfanilic acid. For example, acids such as hydrochloric acid, sulfuric acid, and nitric acid can be used. The concentration and amount of the acid used are not particularly limited as long as the pH in the above range can be achieved.

  Then, it cools to 20-30 degreeC, Most preferably, it is 25 degreeC, and sulfanilic acid is precipitated.

  Finally, the precipitated sulfanilic acid is collected by filtration and, if necessary, washed and dried to recover the sulfanilic acid with high purity and high yield.

  For washing sulfanilic acid, inorganic acids such as water, hydrochloric acid, sulfuric acid, nitric acid and aqueous solutions thereof, alcohols such as methanol, ethanol, isopropyl alcohol, etc. can be used. However, impurities cannot be dissolved without dissolving sulfanilic acid. It is preferable to use hydrochloric acid and methanol in combination from the viewpoint of dissolving the solvent.

  The drying temperature of sulfanilic acid is 40 to 120 ° C, preferably 60 to 100 ° C. If the temperature is lower than 40 ° C., there is a fear that it takes time for drying, and if it exceeds 120 ° C., there is a possibility that the sulfanilic acid is decomposed.

  In the present invention, sulfanilic acid can be recovered in this way, and further, the recovered sulfanilic acid can be reused as shown in the above scheme and used again for the diazotization coupling reaction with m-cresol, It is very economical.

  Hereinafter, the present invention will be described in more detail with reference to specific examples of the present invention, but these do not limit the present invention.

Example 1
1-1 Diazotization coupling reaction of sulfanilic acid and m-cresol 87.0 g (0.5 mol) of sulfanilic acid was added to 750 mL of water with stirring, and 29.0 g (0.27 mol) of sodium carbonate was gradually added thereto. And completely dissolved. The solution was cooled to 0 ° C., and 100 g (0.525 mol) of 36% aqueous sodium nitrite solution was added. To this solution, 180 g (1.75 mol) of 35% hydrochloric acid is gradually added dropwise so that the liquid temperature does not exceed 5 ° C., and the mixture is stirred for 30 minutes to diazotize sulfanilic acid, thereby containing diazonium salt of sulfanilic acid. A containing solution was obtained. Denitrification was performed using sulfamic acid.

  Separately, 55.0 g (0.5 mol) of m-cresol was suspended in 1.0 L of water while stirring, and 100 g (0.5 mol) of 20% aqueous sodium hydroxide solution was added to completely dissolve the solution. Upon cooling, a coupler solution of m-cresol was obtained. The diazo-containing solution was gradually added dropwise to the coupler solution so that the temperature did not exceed 5 ° C. At this time, in order to maintain pH 10.0, 204 g of a 20% aqueous sodium hydroxide solution was gradually added dropwise. After completion of the dropwise addition, the mixture was stirred for 2 hours, 300 g of sodium chloride was added, the temperature of the solution was raised to 10 ° C., and a precipitate was generated at pH 8.1 using hydrochloric acid. This precipitate was collected by filtration, washed with 500 mL of water, and as a wet cake of an azo compound, 326.0 g of a mixture of a free acid form of p- (4-hydroxy-o-tolylazo) benzenesulfonic acid and a sodium salt ( Water content 46.0%; conversion dry yield 111%).

1-2 Wet cake containing p- (4-hydroxy-o-tolylazo) benzenesulfonic acid obtained in Example 1-1 in a catalytic reduction reaction beaker of p- (4-hydroxy-o-tolylazo) benzenesulfonic acid 326.0 g was uniformly suspended in 250 mL of a 7.4% aqueous sodium hydroxide solution heated to 60 ° C., then transferred to an autoclave (volume: 1 L / SUS), and 2.96 g (0. 5% Pd / C). 25 mol%) was added and heated to 60 ° C. Thereafter, hydrogen was charged into the autoclave, and the reaction was continued at the same temperature until hydrogen absorption disappeared while maintaining a pressure of 0.4 to 0.6 MPa. Pd / C was separated from the reaction solution by filtration, cooled to about 10 ° C., and hydrochloric acid was added to adjust the pH to 7.0, and the resulting precipitate was collected by filtration (the filtrate at this time is referred to as “filtrate 1”). The obtained precipitate was washed with 500 mL of water and dried, and the solid obtained was again dispersed in 600 mL of water, 1.0 g of sodium bisulfite and 1.5 g of activated carbon were added, and the mixture was heated and stirred for 1 to 2 hours. The mixture was filtered while hot, and the filtrate was allowed to cool overnight, and recrystallized and purified. The resulting crystals were collected by filtration and dried to obtain 51.8 g of 4-amino-m-cresol as yellowish white needle crystals (yield 84.2%, HPLC purity: 98.7%). FIG. 1 shows a high performance liquid chromatography (HPLC) chart of 4-amino-m-cresol.

The measurement conditions of high performance liquid chromatography (HPLC) of 4-amino-m-cresol are as follows.
Column: L-column ODS 4.6 × 250 mm manufactured by Chemical Substances Evaluation Organization
Mobile phase: acetonitrile: water = 4: 6
Detection wavelength: 256 nm
Flow rate: 1.0 mL / min
Temperature: 40 ° C
Under this condition, 4-amino-m-cresol gives two peaks at retention times of 3.2 and 3.6 minutes as shown in FIG. It is considered that the hydroxyl group or amino group of cresol is ionized to give two peaks. Therefore, the purity of 4-amino-m-cresol was calculated as the sum of these two peak areas (HPLC purity: 98.7%). It should be noted that the 4-amino-m-cresol produced and isolated in the present invention is a single compound that the following ¹ H-NMR (300 MHz) and ¹³ C-NMR (75 MHz) measurement results, and It was clear from the results of elemental analysis.

^{Both 1} H-NMR (300 MHz) and ¹³ C-NMR (75 MHz) measurements were performed using JNM-AL300 manufactured by JEOL. The ¹ H-NMR and ¹³ C-NMR charts of the resulting 4-amino-m-cresol are shown in FIGS. 2 and 3, respectively.

  Elemental analysis was performed using a Series II CHNS / O Analyzer 2400 manufactured by Perkin Elmer. The results of elemental analysis of 4-amino-m-cresol produced in Example 1 of the present invention are shown below.

1-3 Recovery of Sulfanilic Acid “Filtration 1” (500 mL) obtained in 1-2 was heated and concentrated to 150 mL, and 23 g of hydrochloric acid was added at 60 ° C. to adjust the pH to 0.5, and then 25 ° C. The resulting precipitate was collected by filtration. The filtered product was washed with 75 mL of 3.5% hydrochloric acid, followed by 250 mL of methanol and dried to recover 64.4 g of sulfanilic acid having an HPLC purity of 99.5% (recovery from sulfanilic acid used as a raw material). 74.0%).

  The elemental analysis results of the recovered sulfanilic acid are shown in the following table.

Example 2
2-1 Diazotization coupling reaction of sulfanilic acid and m-cresol The diazotization coupling reaction was carried out according to the same procedure as 1-1 in Example 1 to obtain p- (4-hydroxy-o-tolylazo as an azo compound. ) A mixture of the free acid form of benzenesulfonic acid and the sodium salt was obtained.

2-2 Catalytic reduction reaction of p- (4-hydroxy-o-tolylazo) benzenesulfonic acid In Example 1-2, the transition metal catalyst was changed from Pd / C to Pt / C (0.25 mol%). Except for the above, 36.4 g of 4-amino-m-cresol (yield: 29.6%, HPLC purity: 99.7%) was obtained as white pink needle-like crystals. The HPLC chart was the same as that of Example 1.

Example 3
3-1 Diazotization coupling reaction of sulfanilic acid and m-cresol The diazotization coupling reaction was performed according to the same operation as 1-1 in Example 1, and p- (4-hydroxy-o-tolylazo) was used as the azo compound. ) A mixture of the free acid form of benzenesulfonic acid and the sodium salt was obtained.

3-2 Catalytic reduction reaction of p- (4-hydroxy-o-tolylazo) benzenesulfonic acid In Example 1-2, except that the transition metal catalyst was changed from Pd / C to 2.0 g of Raney nickel, The same operation was performed to obtain 59.3 g of 4-amino-m-cresol as a yellowish white needle crystal (yield: 48.2%, HPLC purity: 99.0%). The HPLC chart was the same as that of Example 1.

Comparative Example 1
A 2-nitrotoluene Bamberger rearrangement reaction autoclave was charged with 165 g (1.2 mol) of 2-nitrotoluene, 300 g of 52.6% sulfuric acid aqueous solution and 72 g of acetic acid, 1 drop of dimethyl sulfoxide and 2.0 g of 3% Pt / C. Was added. The mixture was heated to 60 ° C. and reacted for 7.5 hours while maintaining 0.3 to 0.5 MPa. Pt / C was removed by filtration and added dropwise to 200 mL of a 50% aqueous sodium hydroxide solution with stirring so as not to exceed 50 ° C. The organic matter was extracted from the mixed solution, the aqueous layer was kept at 40 ° C., 23 mL of 35% hydrochloric acid was dropped into the aqueous layer, and the resulting precipitate was collected by filtration and dried to obtain 136.9 g of crude 4-amino-m-cresol. Obtained. The crude product was recrystallized and purified in the same manner as in Example 1-2, and 30.0 g (yield 20) of 4-amino-m-cresol, which was a light brown needle crystal having an HPLC purity of 91.7%, was obtained. .3%). An HPLC chart is shown in FIG. In the HPLC chart of FIG. 4, many impurity peaks derived from by-products were detected over a retention time of 1 to 10 minutes. This shows that the purity of 4-amino-m-cresol produced in Comparative Example 1 is considerably low, even though the purification method is the same as Example 1 of the present invention shown in FIG. As a result, in Comparative Example 1, not only the purity but also the yield is significantly reduced.
Example 1: Yield 84.2%, purity 98.7%
Comparative Example 1: Yield 20.3%, Purity 91.7%

Comparative Example 2
Reduction reaction of p- (4-hydroxy-o-tolylazo) benzenesulfonic acid with dithionite 87.0 g (0.5 mol) of sulfanilic acid was added to 750 mL of water with stirring, and 29.0 g of sodium carbonate ( 0.27 mol) was gradually added and completely dissolved. The solution was cooled to 0 ° C., and 100 g (0.525 mol) of 36% aqueous sodium nitrite solution was added. To this solution, 180 g (1.75 mol) of 35% hydrochloric acid is gradually added dropwise so that the liquid temperature does not exceed 5 ° C., and the mixture is stirred for 30 minutes to diazotize sulfanilic acid, thereby containing diazonium salt of sulfanilic acid. A containing solution was obtained. Denitrification was performed using sulfamic acid.

Separately, 55.0 g (0.5 mol) of m-cresol was suspended in 1.0 L of water while stirring, and 100 g (0.5 mol) of 20% aqueous sodium hydroxide solution was added to completely dissolve the solution. Upon cooling, a coupler solution of m-cresol was obtained. The diazo-containing solution was gradually added dropwise to the coupler solution so that the temperature did not exceed 5 ° C. At this time, in order to maintain pH 10.0, 204 g of a 20% aqueous sodium hydroxide solution was gradually added dropwise. After completion of dropping, the mixture was stirred at 0 ° C. for 2 hours, heated to 45 ° C., 270 g (1.31 mol) of sodium dithionite (Na ₂ S ₂ O ₄ ) was added, and the mixture was stirred for 1 hour, and then 20% aqueous sodium hydroxide solution To pH 12. The mixture was further heated and stirred at 75 ° C. for 45 minutes, cooled in an ice bath, adjusted to pH 7 with 35% hydrochloric acid, and the resulting precipitate was collected by filtration (this filtrate is referred to as “filtrate 2”). The obtained precipitate was dried and recrystallized and purified in the same manner as in Example 1 to obtain 12.7 g of 4-amino-m-cresol (yield 20.6%, HPLC purity: 98.8%). . The results of elemental analysis of 4-amino-m-cresol produced in Comparative Example 2 are shown in the following table.

An attempt was made to recover sulfamic acid from “filtrate 2”, but an excessive amount of sodium dithionite (Na ₂ S ₂ O ₄ ) was used, and thus sulfanilic acid could not be recovered.

  The final product obtained by the Bamberger rearrangement reaction of Comparative Example 1 has more impurities and lower purity than Example 1 (FIG. 1) as shown in the HPLC chart of FIG. 4 (Example 1). Purity: 98.7%, purity in Comparative Example 1: 91.7%). Further, in the method of Comparative Example 1, since a by-product is generated, the selectivity of the reaction is poor, and the yield is about 20%, which is not suitable for industrial production (yield in Example 1: 84). 0.2%, yield in Comparative Example 1: 20.3%).

  In Comparative Example 2, the purity of HPLC is as high as 98.8%. However, when the result of elemental analysis is seen, sulfur is detected, and therefore, since an inorganic salt containing sulfur is mixed, Its purity is very low. Moreover, it is very difficult to remove such inorganic salts containing sulfur. Further, in Comparative Example 2, since 2 molar equivalents or more of sodium dithionite is required as the reducing agent, it is impossible to recover sulfanilic acid from the filtrate after the reduction (filtrate 2), and it is an inexpensive industrial product. This is not a typical production method (the recovery rate of sulfanilic acid in Example 1: 74.0%, the recovery rate of sulfanilic acid in Comparative Example 2: 0%). Moreover, in Comparative Example 2, a large amount of waste liquid containing sulfur is generated, so the load on the environment increases.

In the production method of the present invention, the desired 4-amino-m-cresol can be selectively produced with high yield and high purity. As shown in Comparative Example 1 (or Patent Document 3), in the method for producing 4-amino-m-cresol utilizing the Bamberger rearrangement reaction, a by-product is produced, and yield, purity and selectivity are increased. The production method of the present invention is very useful as an alternative to the production method of 4-amino-m-cresol utilizing a Bamberger rearrangement reaction because it is significantly reduced.
Moreover, since sulfur is not used as a reducing agent in the present invention, it is a production method that is friendly to the environment without producing a sulfur-containing waste liquid. For example, in Comparative Example 2 (or Non-Patent Document 1), sodium dithionite (Na ₂ S ₂ O ₄ ) is used in a large amount (2 molar equivalents or more) as a reducing agent. It is very difficult and undesirable for industrial production. Sodium dithionite (Na ₂ S ₂ O ₄ ) also causes a reduction in product purity. Furthermore, in Comparative Example 2 (or Non-Patent Document 1), as described above, it is impossible to recover the raw material sulfanilic acid. Therefore, the production method of the present invention is very useful as an alternative to the production method of 4-amino-m-cresol using a reducing agent containing sulfur.
Thus, in the present invention, only the target 4-amino-m-cresol can be selectively produced with high yield and high purity. Further, the production method is very simple, and the sulfamic acid as a raw material can be easily recovered with high yield and high purity, and can be reused as a raw material. According to the above, as a whole, 4-amino-m-cresol can be produced in a high yield at a very low cost.

Claims (8)

P- (4-Hydroxy-o-tolylazo) benzenesulfonic acid by catalytic reduction in the presence of hydrogen and a transition metal catalyst at a reaction temperature in the range of 0 to 90 ° C. and a reaction pressure in the range of 0.1 to 3.0 MPa. Or a method for producing 4-amino-m-cresol from a salt thereof,
The transition metal catalyst is Pd / C, Pt / C, Pd (II) X ¹ ₂ , Pt (0) L ¹ ₂ , Pt (II) X ² ₂ , Pt (0) L ² ₂ , Raney nickel, NiX ³ ₂ and Ni (0) L ³ ₂
Wherein X ¹ , X ² and X ³ are each independently selected from the group consisting of chlorine, bromine and iodine atoms;
L ¹ , L ² and L ³ are each independently dba (dibenzylideneacetone), dppf (1,1′-bis (diphenylphosphino) ferrocene), dppp (1,3-bis (diphenylphosphino)) Propane), acac (acetylacetonate), dppb (o-diphenylphosphinobenzoyl), cod (1,5-cyclooctadiene), TPP (triphenylphosphine), TPB (tetraphenylborate) and BINAP (2,2 Selected from the group consisting of '-bis (diphenylphosphino) -1,1'-binaphthyl.]
A process for producing 4-amino-m-cresol, which is a transition metal catalyst selected from the group consisting of:   After the catalytic reduction, further comprising the step of adjusting the pH of the reaction solution to 4.0 to 8.0 to precipitate 4-amino-m-cresol, and then separating the precipitate and the filtrate by filtration. The method of claim 1. The method according to claim 2 , further comprising the step of obtaining crystals of 4-amino-m-cresol from the precipitate by recrystallization.   The method according to claim 1, further comprising a step of recovering sulfanilic acid from the filtrate.   Prior to the catalytic reduction, comprising diazotizing sulfanilic acid and further reacting with m-cresol to prepare the p- (4-hydroxy-o-tolylazo) benzenesulfonic acid or a salt thereof. The method according to claim 1.   The method according to claim 1, wherein the catalytic reduction is performed in an alkaline aqueous solution. A step of preparing p- (4-hydroxy-o-tolylazo) benzenesulfonic acid or a salt thereof by diazotizing sulfanilic acid and further reacting with m-cresol;
Hydrogen; and Pd / C, Pt / C, Pd (II) X ¹ ₂ , Pt (0) L ¹ ₂ , Pt (II) X ² ₂ , Pt (0) L ² ₂ , Raney nickel, NiX ³ ₂ and Ni (0) L ³ ₂
Wherein X ¹ , X ² and X ³ are each independently selected from the group consisting of chlorine, bromine and iodine atoms;
L ¹ , L ² and L ³ are each independently dba (dibenzylideneacetone), dppf (1,1′-bis (diphenylphosphino) ferrocene), dppp (1,3-bis (diphenylphosphino)) Propane), acac (acetylacetonate), dppb (o-diphenylphosphinobenzoyl), cod (1,5-cyclooctadiene), TPP (triphenylphosphine), TPB (tetraphenylborate) and BINAP (2,2 Selected from the group consisting of '-bis (diphenylphosphino) -1,1'-binaphthyl.]
In the presence of a transition metal catalyst selected from the group consisting of: a reaction temperature in the range of 0 to 90 ° C. and a reaction pressure in the range of 0.1 to 3.0 MPa by catalytic reduction in an aqueous alkaline solution. A step of preparing 4-amino-m-cresol from (4-hydroxy-o-tolylazo) benzenesulfonic acid or a salt thereof;
After the catalytic reduction, the pH of the reaction solution is adjusted to 4.0 to 8.0 to precipitate 4-amino-m-cresol, and then the precipitate and the filtrate are separated by filtration;
Obtaining crystals of 4-amino-m-cresol from the precipitate by recrystallization, and
Recovering sulfanilic acid from the filtrate,
In the production of 4-amino-m-cresol, comprising: sulfanilic acid as a raw material.   A method for producing p- (4-hydroxy-o-tolylazo) benzenesulfonic acid or a salt thereof by diazotizing the sulfanilic acid recovered by the method according to claim 7 and further reacting with m-cresol.

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