JPH06128219A - Production of o-substituted aminobenzenetiols - Google Patents

Abstract

PURPOSE:To efficiently obtain the subject compound useful as a synthetic intermediate for medicine, photographic additive and agrichemical by hydrolyzing a benzothiazolium salt replaced at the 3-position obtained from inexpensive benzothiazole as a starting raw material. CONSTITUTION:Benzothiazole is reacted with an alkylating agent of the formula R-X [R is alkyl, (substituted) allyl, benzyl or phenethyl; X is atom or atomic group convertible to counter ion of quaternary ammonium] to readily give a benzothiazolium salt-replaced at the 3-position of formula I (e.g. 3methylbenzothiazolium iodide) as a starting substance. The benzothiazolium salt is hydrolyzed in the presence of an alkali to give an o-substituted aminobenzenethiol of formula II (e.g. o-methylaminobenzenethiol). This method does not use a specific chemical, simply provides o-substituted aminobenzenetiols in high yield and is industrially advantageous. The o-substituted aminobenzenetiols are useful as a synthetic raw material for middle-membered ring ketone, an intermediate for various natural substances and a raw material for medicines.

Description

Detailed Description of the Invention

[0001]

The present invention relates to the general formula [I]

[Chemical 3] [In the formula, R represents an alkyl group, a substituted or unsubstituted allyl group, a benzyl group, or a phenethyl group, and X represents an atom or an atomic group which can be a counterion of the quaternary ammonium salt. ] The 3-position-substituted benzothiazolium salt represented by the general formula [II]

[Chemical 4] [In the formula, R represents an alkyl group, a substituted or unsubstituted allyl group, a benzyl group, or a phenethyl group. ] It is related with the novel manufacturing method of o- substituted aminobenzene thiols represented by these.

[0002]

The o-substituted aminobenzenethiols represented by the general formula [II] are useful as synthetic intermediates for pharmaceuticals, photographic additives and agricultural chemicals.

[Chemical 5] O-methylaminobenzenethiol is used as a protecting group for aldehydes and ketones, and is a synthetic raw material for medium-ring ketones that can be useful intermediates for various natural products containing a medium-ring, and at the same time as a medicinal raw material. Is also considered important.

As a method for producing o-methylaminobenzenethiol, the following method has already been disclosed [A. I.
Kiprianov, and Z. N. Pazenk
o, Zhurnal Obshchej Khimi
i, 19 , 1523 (1949)]. That is,

[Chemical 6] The o-methylaminobenzenethiol of the above formula [III] obtained by hydrolyzing a 3-methylbenzothiazoline derivative in which the 2-position is substituted with a hetero atom represented by To 8
4%, [IVb] to 76% and [IVc] to 63
It is described that it can be produced with a yield of%.

However, 3-methyl-2 (3H)-
In the production method from benzothiazolone [IVa], although the yield is good, [IVa] is produced by methylation of the mercapto group of 2-mercaptobenzothiazole, methylation at the 3-position, and then hydrolysis of the obtained quaternary salt. 3 processes are required, and the work process is complicated. 3-methyl-2 (3
H) -Benzothiazolethione [IVb] is produced by heating 2-methylmercaptobenzothiazole at 200 ° C. or higher in a sealed tube, but the reaction conditions are strict and it is difficult as an industrial production method. Further, the production method from 2-imino-3-methylbenzothiazoline [IVc] has a low hydrolysis yield. Therefore, these manufacturing methods are industrially disadvantageous methods. Therefore, there is a strong demand in the industry for a method that can easily and inexpensively produce o-substituted aminobenzenethiols.

[0005]

SUMMARY OF THE INVENTION It is an object of the present invention to provide a method for easily producing o-substituted aminobenzenethiols from inexpensive raw materials with a high yield.

[0006]

DISCLOSURE OF THE INVENTION As a result of intensive studies made by the present inventors in view of the above problems, the general formula [I]

[Chemical 7] [In the formula, R represents an alkyl group, a substituted or unsubstituted allyl group, a benzyl group, or a phenethyl group, and X represents an atom or an atomic group which can be a counterion of the quaternary ammonium salt. ] When the 3-position-substituted benzothiazolium salt represented by the formula is hydrolyzed in the presence of an alkali, a compound of the general formula [II]

[Chemical 8] [In the formula, R represents an alkyl group, a substituted or unsubstituted allyl group, a benzyl group, or a phenethyl group. ] It was found that o-substituted aminobenzenethiols represented by the following formula can be obtained, and the present invention has been completed based on this finding. The 3-position-substituted benzothiazolium salt of the general formula [I] according to the present invention is a compound of the general formula [V] with benzothiazole.

[Chemical 9] [In formula, R and X show the same thing as the said General formula [I]. ] It is easily obtained in a high yield by the reaction with an alkylating agent (see the Examples section as a reference example). Therefore, it is considered that the production method of the present invention can be industrialized because it uses an inexpensive compound such as benzothiazole as a starting material, has a high yield, and has a relatively easy reaction operation.

The above general formulas [I] and [I
R in [I] and [V] reacts with benzothiazole to form a 3-substituted benzothiazolium salt of general formula [I],
In addition, any compound which does not undergo decomposition under the hydrolysis conditions of the 3-substituted benzothiazolium salt according to the present invention may be used,
For example, methyl group, ethyl group, n-propyl group, iso-
Propyl group, n-butyl group, iso-butyl group, sec
-Butyl group, tert-butyl group, n-pentyl group, i
so-pentyl group, sec-pentyl group, tert-pentyl group, n-hexyl group, 1-methylpentyl group, 1
Examples thereof include an alkyl group such as an ethylbutyl group, a substituted or unsubstituted allyl group, a benzyl group, and a phenethyl group.

X in the above general formulas [I] and [V] according to the present invention may be any atom or atomic group forming a counterion of the quaternary ammonium salt, for example, halogen such as chlorine, bromine or iodine. , CH ₃ SO ₄ , p-CH ₃ C ₆
H ₄ SO _3, BF _4, and the like.

In the reaction of the above 3-substituted benzothiazolium salt of the general formula [I] with the o-substituted aminobenzenethiols of the general formula [II] according to the present invention, the compound 1 of the general formula [I] is used. It can be carried out by adding 1 equivalent or more, preferably 3 to 5 equivalents of alkali per equivalent and stirring in a solvent at 25 ° C. or higher, preferably 100 to 120 ° C. The obtained reaction mixture is neutralized with a mineral acid such as hydrochloric acid, sulfuric acid and phosphoric acid to obtain the compound of general formula [II] in high yield. This reaction (from general formula [I] to general formula [II]
Examples of the alkali used in (reaction to) include inorganic bases such as sodium hydroxide and potassium hydroxide,
Any alkali that achieves the object of the present invention is included in the scope of the present invention.

The reaction solvent used in this reaction is
Water, alcohols such as methyl alcohol, ethyl alcohol, n-propyl alcohol and iso-propyl alcohol, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, tetrahydrofuran,
Cyclic ethers such as dioxane, further, a bilayer solvent of aromatic hydrocarbons such as benzene, toluene and xylene and water, and a bilayer solvent of aromatic halides such as chlorobenzene and dichlorobenzene and a water layer. However, the invention is not limited to these. The effects of the present invention will be shown in the following examples, but the scope of the claims of the present invention is not limited to the embodiments.

[0011]

EXAMPLES Reference Example 1. Combination of 3-methylbenzothiazolium iodide
135 g (1.00 mol) of adult benzothiazole and 284 g (2.00 mol) of methyl iodide were added to 150 ml of toluene, and the mixture was stirred at 50 to 55 ° C for 14 hours. The obtained reaction mixture was filtered to separate crystals, which were washed with toluene to give 223.68 g of 3-methylbenzothiazolium iodide.
(Yield: 81%) was obtained. Melting point: 203.1 to 203.8 ° C. [after recrystallization from ethyl alcohol] ¹ H-NMR (DMSO-d ₆ ) δ: 4.42 (3
_{H, s, -CH 3),} 7.85~8.56 (4H, m,
Ar-H), 10.55 (1H, s, Ar-H)

Reference Example 2.3 3-Benzylbenzothiazoliu
Synthesis of Mubromide 27.80 g (0.206 mol) of benzothiazole and 105.56 g (0.617 mol) of benzyl bromide were added to 50 ml of toluene and heated under reflux for 5 hours. The precipitated crystals were filtered and washed with toluene to give 56.77 g of 3-benzylbenzothiazolium bromide (yield: 90
%)was gotten. Melting point: 184.8-186.0 ° C. (ethyl alcohol /
After recrystallization from ethyl acetate) ¹ H-NMR (DMSO-d ₆ ) δ: 6.23 (2
_{H, s, -CH 2 -)} , 7.39~8.63 (9H,
m, Ar-H), 10.92 (1H, s, Ar-H)

Reference Example 3.3-Allylbenzothiazolium
Synthesis of bromide 13.52 g (0.10 mol) of benzothiazole and 36.29 g (0.30 mol) of allyl bromide were dissolved in 25 ml of toluene, and heated and stirred at 70 ° C for 20 hours under a nitrogen stream. The precipitated crystals were collected by filtration and washed with toluene to give 3-allylbenzothiazolium bromide 1
5.83 g (yield: 62%) was obtained. Melting point: 145.5-146.7 ° C. (after recrystallization from isopropyl alcohol) ¹ H-NMR (DMSO-d ₆ ) δ: 5.44-5.
_{64 (4H, m, -CH 2} - and ₌ CH 2), 6.12
-6.26 (1H, m, -CH =), 7.84-8.6
4 (4H, m, Ar-H), 10.78 (1H, s, A
r-H)

Example 1. o-methylaminobenzenethio
Synthesis of sodium hydroxide 4.30 g (0.10 mol) 93%
Was dissolved in 5 ml of water, 5.549 (0.020 mol) of 3-methylbenzothiazolium iodide was added, and the mixture was heated under reflux for 10 hours under a nitrogen stream. The reaction mixture obtained is water 5
It was diluted with 0 ml and neutralized with dilute sulfuric acid under ice cooling. The released oil was extracted with 50 ml of toluene, and the toluene layer was washed with water,
Then, it was dried over anhydrous sodium sulfate. Toluene was distilled off from the obtained organic layer under reduced pressure, and the residue was distilled under reduced pressure.
-Methylaminobenzenethiol 2.53 g (yield: 9
1%) was obtained. Boiling point: 54.0-56.7 ° C / 0.11 mmHg MS (EI) m / z: 139 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ: 2.93 (3H,
_{s, -CH 3), 6.49~7.40 (} 4H, m, Ar
-H) IR (neat) 3404 cm ^-1 (-NH- and-)
SH)

Example 2. o-benzylaminobenzene
Synthesis of All 6.33 g (0.147 mol) of 93% sodium hydroxide was dissolved in 7 ml of water, and 9.00 g (0.0294 mol) of 3-benzylbenzothiazolium bromide was added to the solution. Heated to reflux for hours. The obtained reaction mixture was diluted with 100 ml of water and then neutralized with dilute sulfuric acid. The liberated oil was extracted with 100 ml of toluene, the toluene layer was washed with water, and then dried over anhydrous sodium sulfate. Toluene was distilled off from the obtained organic layer under reduced pressure, and the residue was distilled under reduced pressure to give o-benzylaminobenzenethiol 5.58.
g (yield: 88%) was obtained. Boiling ^{point: 143 ℃ / 0.25mmHg MS (EI} ) m / z: 215 (M +) 1 H-NMR (CDCl 3) δ: 2.83 (1H, b
rs, -NH- or -SH), 4.37 (2H, s,-
_{CH 2 -), 5.01 (1H} , brs, -NH- or -
SH), 6.52 to 7.46 (9H, m, Ar-H) IR (neat) 3396 cm ^-1 (-NH- and-).
SH)

Embodiment 3. o-allylaminobenzenethio
Lumpur synthesis 93% sodium hydroxide 10.11g of (0.235 mol) was dissolved in water 11 ml, 3- allyl benzothiazolium bromide 12.04g of (0.047 mol) was added, under a nitrogen stream, The mixture was heated under reflux for 12.5 hours. The resulting reaction mixture was diluted with 120 ml of water and neutralized with dilute sulfuric acid. The liberated oil was extracted with 120 ml of toluene, washed with water, and dried over anhydrous sodium sulfate. The obtained organic layer was concentrated, and the residue was distilled under reduced pressure to obtain o-allylaminobenzenethiol (6.41 g, yield: 82%). Boiling point: 68.0 ° C./0.10 mmHg MS (EI) m / z: 165 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ: 2.91 (1H, b
rs, -NH- or -SH), 3.82 (2H, d, J
_{= 6Hz, = CH 2),} 4.08 (1H, brs, -N
H- or -SH), 5.15 to 5.32 (2H, m,-)
_{CH 2 -), 5.89~6.03 (1H} , m, -CH
=), 6.58 to 7.41 (4H, m, Ar-H) IR (Neat) 3392 cm ^-1 (-NH- and-).
SH)

[0017]

[Effect] The reaction for obtaining o-substituted aminobenzenethiols through a 3-position-substituted benzothiazolium salt obtained by substituting the 3-position of benzothiazole, which is inexpensive and easy to obtain industrially, has no effect. It is a method that can be industrialized because it does not require the use of special chemicals and is simple in high yield.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Yoshiko Yamamoto 7-4 Oofune, Kobunecho, Nihonbashi, Chuo-ku, Tokyo Inside Shinko Chemical Industry Co., Ltd.

Claims (1)

[Claims] 1. When producing o-substituted aminobenzenethiols, a compound of the general formula [I]: [In the formula, R represents an alkyl group, a substituted or unsubstituted allyl group, a benzyl group, or a phenethyl group, and X represents an atom or an atomic group which can be a counterion of the quaternary ammonium salt. ] The 3-substituted benzothiazolium salt represented by the formula [II] is characterized by being hydrolyzed in the presence of an alkali. [In the formula, R represents an alkyl group, a substituted or unsubstituted allyl group, a benzyl group, or a phenethyl group. ] The manufacturing method of o- substituted aminobenzene thiol represented by these.