JPS6354360A - Production of indolines - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as an intermediate raw material for medicines, agricultural chemicals, etc., in high selectivity and yield by ready operation, by reacting a 2-(2-aminophenyl)ethanols with sulfonyl chloride in the presence of a base in an organic solvent. CONSTITUTION:A compound expressed by formula I [R1 is H, 1-4C alkyl, hydroxymethyl, Cl, Br, CN or COOR (R is 1-4C alkyl); R2 is H, 1-7C alkyl or cycloalkyl; X and Y are H, halogen (substituted) 1-4C alkyl, 1-4C alkoxy, NH2 or OH] is reacted with a compound expressed by the formula Z-SO2Cl (Z is methyl, phenyl or p-toluyl) in the presence of a base in a solvent, e.g. a hydrocarbon based solvent, ether compound, etc., at -20-+50 deg.C, preferably -10-+20 deg.C temperature to afford the aimed compound expressed by formula II.

Description

[Detailed description of the invention] Industrial applications The present invention relates to a method for producing indolines.

More specifically, the present invention relates to a method for producing indolines from 2-(2-aminophenyl)ethanols.

BACKGROUND OF THE INVENTION Indolines are important intermediates as raw materials for pharmaceuticals, agricultural chemicals, and the like. Several methods have been reported for producing indolines using 2-(2-aminephenyl)ethanols as starting materials. German Patent No. 606027 describes a method of treatment in the gas phase, which involves dehydration or cavity 1 treatment.
A method for obtaining indolines by catalytic gas phase reaction with a hydrogen catalyst has been proposed. Also, J.

Bakl et al. reported that indoline is produced when 2-(2-aminophenyl)ethanol is brought into contact with silica gel in the gas phase.

(Aeta Chemica 5cand,, B 2
8, pp. 393-394 (1974)). There is also a method of producing indoline by reacting 2-(2-aminophenyl)ethanol with a catalyst in combination with a boron compound tosilica gel in a gas phase. (Unexamined Japanese Patent Publication No. 58-14656
No. 2) However, these methods are not industrially satisfactory because they have drawbacks such as the catalyst being easily deteriorated and the need for special equipment. On the other hand, as a liquid phase reaction, 2
-(2-aminophenyl)ethanol hydrochloride at 220
There is a method (Japanese Patent Laid-Open No. 86155/1983) in which indoline hydrochloride is obtained by thermal decomposition for 5 minutes at 0.degree. It's a bunch 2
(2-Aminophenyl) ethanol is heated to 200°C or higher in the presence of a solid acid catalyst (Unexamined Japanese Patent Publication No. 58-14).
No. 6563), but this method has problems such as corrosion of the reactor and deterioration of the catalyst. M* G, Ben
Nett et al.
It has been reported that a mixture of benzenesulfonyl indoline and indoline can be obtained by reacting them in a 1:1 medium. (J. Chem. Soe, 1941,
(287) However, when this reaction was actually conducted in supplementary test 1, both the selectivity and yield were not sufficient.

Problems to be Solved by the Invention There is a desire for the development of a method for producing indolines from 2-(2-aminophenyl)ethanols at low cost with simple operations.

Means for Solving the Problems The present inventors have improved the above-mentioned drawbacks of conventional production methods and improved the efficiency of producing indolines from 2-(2-aminophenyl)ethanols! f: The present invention was achieved as a result of intensive research on the manufacturing method. That is, the present invention relates to the general formula (1) cyan group or group C02R (R represents a C8-4 alkyl group), R2 represents hydrogen, a C8-1 alkyl group or a cycloalkyl group, and X and Y are Hydrogen,...rogen atom, substituted or unsubstituted C3-4 alkyl group, C1-
2-( represents the same or different group selected from the group consisting of 4 alkoxy groups, amine 7 groups, and hydroxyl groups)]
2-aminophenyl) ethanols Formula (2)% Formula% (
2) It is characterized by reacting the compound represented by [Formula (2), Z represents a methyl group, phenyl group or P-tolyl group] in an organic solvent in the presence of a base.

[In formula (3), R, , R, , X, Y and Z have the same meanings as above] A method for producing an indoline compound represented by the formula (3) is provided.

2-(2
Specific examples of -7minophenyl) ethanol are 2-
(2-aminophenyl)ethanol, 2-(2-aminophenyl)-1,3-propanediol, 2-(2-amino-6-chlorophenyl)-1,3-7'lovandiol, 2-(2- amino-5-promophenyl)-1,
3-propanediol, 2-(2-7mi/-6-7'romophenyl)ethanol, 2-(2-amino-6-bromophenyl)-1,3-propanediol, 2-(2-
Amino-6-iodophenyl)-1,,3-propanediol, 2-(2-amino-5-chlorophenyl)-1
, 3-7'ropanediol, 2-(2-amino-4,5
-dichlorophenyl)-1,3-propanediol, 2
-(2-amino-4-chloro-5-bromophenyl)-
1,3-propanediol, 2-(2-amino-4-chloro-5-fluorophenyl)-1,3-propanediol, 2-(2-amino-5-fluorophenyl) -
i.

3-propanediol, 2-(2-amino-3,5-dichlorophenyl)-1,3-propanediol, 2-
(2,4-diaminophenyl)-1,3-propanediol, 2-(2-amino-5-bromo-4-hydroxyphenyl)-1,3-propanediol, 2-(2-amino-4-hydroxyphenyl) )-1,3-propanediol, 2-(2-amino-6-methylphenyl)-ethanol, 2-(2-aminophenyl)-2-methylethanol, 2-(2,4-diaminophenyl)-2 −
Methylethanol, 2-(2-amino-4-hydroxyphenyl)-2-methylethanol, 2-(2-amino-4-chlorophenyl)-2-methylethanol, 2-
(2-amino-4,5-dichlorophenyl)-2-methylethanol, 2-(2-amino-6-chlorophenyl)-2-methyletha 7-/1/.

2-(2-amino-4-chloro-5-fluorophenyl)-2-methylethanol, 2-(2-7mi/phenyl)-2-ethylethanol, 2-(2-aminophenyl)-2-butyl Ethanol, 2-(2-aminophenyl)-2-chloroethanol, 2-(2-amino-4-chloromethylphenyl)-1,3-furopanediol, 2
-(2-amino-4-hydroxymethylphenyl)-1
, 3-7'ropanediol, 2-(2-amino-3,4
-dihydroxyphenyl)-1,3-7'ropanediol, 2-(2-aminophenyl)-2-bromoethanol, 2-(2-amino-4-methoxyphenyl)-1,
3-propanediol, 2-(2-amino-3,4-dimethoxyphenyl)-1,3-7''ropanediol.

2-(2-amino-4-butoxyphenyl)-1,3-
Propanediol, 2-(2-aminophenyl)-2-
Cyanethanol, 2-(2-amino-6-chlorophenyl)-2-cyanethanol, 2-(2-amino-5
-fluorophenyl)-2-cyanoethyl/ -l, 2-
(2-amino-4-10lophenyl)-2-cyanoethanol, 2-(2-amino-6-bromophenyl)-2
-cyanoethanol, 2-(2-amino-4,5-dichlorophenyl-2-cyanoethanol, 2-(2-amino-4-chloro-5-fluorophenyl)-2-cyanoethanol, 2-(2-amino phenyl)-1-cyclohexylethanol, 2-(2-aminophenyl)-2
-methoxycarbonylethanol, 2-(2-ami/-
6-10lophenyl)-2-ethoxycarbonylethanol, 2-(2-amino-4,5-dichlorophenyl)
-2-ethoxycarbonylethanol, 2-(2-amino-6-bromophenyl)-2-butoxycarbonylethanol, 2-(2-amino-3,5-dichlorophenyl)-2-methoxycarbonylethanol, 2-(2-amino-3,5-dichlorophenyl)-2-methoxycarbonylethanol, −
Amino-4-chloro-5-fluorophenyl)-2-ethoxycarbonylethanol, 2-(2-amino-6-
iodophenyl)-2-ethoxycarbonylethanol, 2-(2-aminophenyl)-1-isopropylethanol, 1-(2-7minophenyl)-3-ethyl-2
-Hydroxyhebutane, 1-(2-aminophene/+/
)-3-ethyl-2-hydroxypentane.

2-(2-A1)-6-chlorophenyl)-1-isopropylethanol, 2-(2-amino-4-butylphenyl)ethanol, 2-(2-amino-4-methylphenyl)-1゜3- Examples include propanediol.

Specific examples of the sulfonyl chloride represented by formula (2) include methanesulfonyl chloride, benzenesulfonyl chloride, and P-toluenesulfonyl chloride. The amount used is usually 2.0 to 3.0 mol based on the compound of formula (1) when one dihydroxy group of 2-(2-aminophenyl)ethanol of formula (1) is included as a raw material. , preferably 2.1 to 2.
5 mole range, and in formula (1), the hydroxy group is 2
If the compound of formula (1) contains 3.
In the range 0 to 5.0 mol, preferably 3.2 to 4.0 mol Li0H1Na2Co3, K, , CO3, Ca
C03, BaCO3, MgCO5, NaHCO,, K
Hydroxides of alkali gold or alkaline earth metals such as HCO3, MgO, CaO1BaO1Na20,
Carbonates, bicarbonates or oxides; organic amines such as diethylamine, triethylamine, tributylamine, triethylenediamine, 1,8-diazabicyclo(5°4.0)-7-undecene (DBU), pyridine, piperidine, piperazine, etc. can be mentioned. The amount of these bases to be used is usually 3.0 to 5.0 mol, preferably 3.0 to 5.0 mol based on the compound of formula (1) when the compound (reaction substrate) of formula (1) contains one hydroxy group. is in the range of 3.2 to 4.0 mol, and when the compound of formula (1) contains two hydroxy groups, it is usually 4.0 to 6.0 mol, preferably preferably ranges from 4.2 to 5.0 moles.

The method of the present invention is carried out in an organic solvent, and a solvent inert to the reaction is used as the organic solvent. Specific examples thereof include hexane, heptane, octane, dichloromethane, dichloroethane, trichloroethane, diphenyl, benzene, Examples include hydrocarbon solvents such as monochlorobenzene, dichlorobenzene, toluene, toluene, ispropylbenzene, and ethers such as tetrahydrofuran, dioxane, and diphenyl ether. The amount of these solvents to be used varies depending on the type of compound (reaction substrate) of formula (1), but it is preferable to use them in a weight ratio of usually 1 to 100 times, preferably 3 to 30 times. The reaction temperature is usually in the range of -20 to 50°C, preferably -10 to 20°C. The reaction time varies depending on the compound of formula (1), the solvent, the type of catalyst, etc., but it is usually 10 minutes to 20 hours, preferably 30 hours while checking the progress of the reaction with TLC etc.
The duration ranges from minutes to 10 hours.

The method of the present invention has a high yield of indolines, and the indolines obtained in this way can be used as pharmaceuticals.

It has sufficient purity to be converted into indole compounds useful as raw materials for dyes and pigments, agricultural chemicals, etc. If desired, it is also possible to purify by methods such as distillation, recrystallization, and column chromatography.

Example The present invention will be explained in more detail with reference to Examples.

Example 1゜Methylene chloride 2ml, triethylamine 0.6ml in a reactor
ml (4,3 mmol), and 180 mg of 2-(2-aminophenyl)-1,3-furopanediol
(1.1 mmol) and stir to make a homogeneous solution. Cool to -10°C [-0.18 ml (2.3 mmol) of methanesulfonyl chloride while stirring]
drip over 1 hour. Thereafter, the reaction temperature was gradually returned to room temperature. After further stirring for 2 hours, the mixture was cooled again to -10°C, and 0.08 ml of methanesulfonyl chloride was added.
(0.1 mmol) was added dropwise. After stirring for 1 hour, the reaction solution was dissolved in ethyl acetate and diluted with a saturated aqueous solution of 1.
Wash twice with saturated saline. After drying (mirabilite) the ethyl acetate phase containing the desired product, methylene chloride, the methylene chloride and ethyl acetate were distilled off to obtain a crude product. The obtained crude product was purified using a silica gel column to obtain 280 mg (85%) of 1-methanesulfonyl-3-methanesulfonyloxymethylindoline as white crystals.

Physical properties of 1-methanesulfonyl-3-methanesulfonyloxyindoline Melting point; 99-101°C DingR (CHCI3); 3070.1605.1485. 1460.1355
．． 1060.95 Q cm-''H-NMR (CDC
l5) δ 2.89 (s, 3H, NSO□-CH5) δ
2.95 (s, 3H,08Q2-CH3)δ 3.
6-4.1 (m, 3H, Ar-CH, CH, -N) δ 4.32
(d, d, 2H, J=6.0Hz.

J = 1.0 Hz, CH2O) δ 6.99~
7.35 (m, 4H, Ar, H) Examples 2 to 7 Table 1 shows the results of a reaction conducted in the same manner as in Example 1, but with different bases and solvents.

Table 1゜In the table, THF is tetrahydrofuran, DBU is 1,
It means 8-diazabicyclo(5,4,0)-7-undecene.

Example 8゜A reaction was carried out under almost the same conditions as in Example 1, except that p-toluenesulfonyl chloride was used instead of methanesulfonyl chloride in Example IK. As a result, 1-(
p-)luenesulfonyl)-3-(p-toluenesulfonyloxymethyl)indoline as white crystals in yield 8.
9% was obtained.

Physical properties of 1-(p-)luenesulfonyl)-3-(p-1luenesulfonyloxymethyl)indoline Melting point; 46-48°C IR (CHCI3); 3010.1600.1480.1460.1360.
1160.1090.970cm-'IH-NMR(C
DCl 3) δ 2.33 (s, 3H, N-802C6H Pudan,
) δ 2.42 (s, 3H, -0502C6H
, type, ) δ 3.30-4.10 (m, 5H, Ar-CHC, -0°Ar-N-form 2
-) δ 6.84-7.22 (m, 12H, ArH, -NSO2C6H4CH3,
-0-802C,H,CH3) Example 9゜Into a reactor, 5 ml of methylene chloride and 240 mg of pyridine (
3,Q mmol) and 130 mg (0.95 mmol) of 2-(2-aminophenyl)ethanol were added and stirred to form a homogeneous solution. 405 mg p-toluenesulfonyl chloride (2,12 mm
1) gradually.

After holding for 1 hour, the reaction temperature was slowly returned to room temperature. After stirring at room temperature for 10 hours, post-treatment and column purification were carried out in the same manner as in Example 1.
(90%) obtained.

Physical properties of 1-(p-toluenesulfonyl)indoline Melting point: 97-99°C IR (CHCI3) 2950.1630.1595.1490.1360°1160.975,760 cm'' H-NMR (CI) CI, ) δ 2 .4 (s, 3H, CH3) δ 3.05
(t, J=3.3N(z, 2H.

Ar　CH2) δ 4.10 (t, J=8.3Hz, 2H.

N-CH2) δ 6.9-7.6 (m, 8H, Ar -H) Example 10゜Reactor pressure Benzene 6ml, triethylamine 320mg
(3.2 mmol) and 130 mg (0.95 mmol) of 2-(2-aminophenyl)ethanol are added to make a homogeneous solution. 420 mg (2.4 mmo) of benzenesulfonyl chloride
l) gradually.

After maintaining the temperature for 1 hour, the reaction temperature was slowly returned to room temperature. After further stirring at room temperature for 1 hour, post-treatment and column nM were performed in the same manner as in Example 1, yielding 215 mg (87%) of 1-benzenesulfonylindoline as white crystals.
) obtained.

Product i raw melting point of 1-benzenesulfonylindoline; 13
0-132°C lICHCl3) 3030.2920.2860.1607.1495.
1470.1360.1175.960.755cm'
IH-NMR, (CDCl5) δ 2.95 (t, 8.2Hz, 2H, Ar
-CH2) δ 4.05 (t, 8.2Hz,
2H,N-Cll2) δ 7.0-7.7 (m, 9H, Ar-H) Example 1 165 mg (1.1 mmol) of 2-(2-aminophenyl)-2-methylethanol was placed in a 11° reactor. Add 6 ml of methylene chloride and stir to make a homogeneous solution. −
After cooling to 10°C, 170 mg (9 mmol) of methane/L/honyl chloride and 220 mg (2.2 mmol) of triethylamine were added. After stirring for 30 minutes, add more triethyl/l/7
After adding 2220 mg (2.2 mmol) of Mi7, the reaction temperature was gradually returned to room temperature and stirred for 7 hours.

After cooling the mixture to -10° C. again, 115 mg (1.1 mmol) of methanesulfonyl chloride was added dropwise over 1 hour. After stirring at the same temperature for 30 minutes, the mixture was slowly returned to room temperature. After further stirring at room temperature for 1 hour, post-treatment and column purification were performed in the same manner as in Example 1 to obtain 195 mg (84%) of 1-methanesulfonyl-4-methylindoline as a yellow oil.

Physical properties of 1-methanesulfonyl-4-methylindoline IR (Neat) 2950.1600, ]480.1340.1155.
980 cm-'' H-NMR (CDCl5) δ 2.22 (s, 3H, CH3) δ 2.79
(s, 3H, CH, 5O2) δ 2.98 (t,
J = 8.4Hz, 2H.

Ar-CH2) δ 3.92 (t, J = 8.4Hz, 2H,
N-CH2) δ 6.7-7.2 (m, 3H, Ar
-H) Example 12 2 (2-amino-6
-methylphenyl)ethanol, 2-(2-
When the reaction was carried out from 1 using aminophenyl)-2-methylethanol, 204 mg (88%) of 1-methanesulfonyl-3-methylindoline was obtained as a yellow oil.

Physical properties of 1-methanesulfonyl-3-methylindoline IR (Neat) 2945.1598.11175.1455.1345
．． 1] 55.980cm7' IH-NMR (CDCl5) δ 1.36 (d, J = 6.0
Hz, 3H, CH3) δ 2.82 (s,
3H, CH35O2) δ 3.2-4.3 (m, 3
H, CHCI (2N) δ 7.0 ~ 7.4
(m, 4H, Ar -H) Examples 13 to 56 Table 2 shows the results obtained by performing almost the same operation as in Example 1, but using different raw materials, sulfonyl chloride, base, and solvent. Table 2A "Indolines" refers to the following reaction formula: 02-Z Formula obtained when using the raw material compounds shown in Table 2 (
2) means an indoline compound corresponding to 2).

Effects of the Invention Industrially useful indolines can be efficiently obtained from readily available 2 (2-aminophenyl)ethanols by simple operations.

Claims (1)

[Claims] Formula (1) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (1) [In formula (1), R_1 is hydrogen, C_1_-_4 alkyl group, hydroxymethyl group, chlorine atom, bromine atom, cyano group or group COOR (R represents an alkyl group of C_1_-_4), R_2 represents hydrogen, an alkyl group of C_1_-_7 or a cycloalkyl group, and X and Y are hydrogen, a halogen atom, a substituted or unsubstituted Represents the same or different groups selected from the group consisting of C_1_-_4 alkyl groups, C_1_-_4 alkoxy groups, amino groups, and hydroxyl groups)
2-(2-aminophenyl)ethanol and Z-SO_2Cl(2) [In formula (2), Z is a methyl group, a phenyl group, or a P-
Formula (3), which is characterized by reacting a sulfonyl chloride (representing a toluyl group) in an organic solvent in the presence of a base ▲There are mathematical formulas, chemical formulas, tables, etc.▼(3) [Formula (3) R_1, R_2, X, Y and Z have the same meanings as above.] A method for producing indolines.