JPH0145462B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the formula 4-(3-isopropylamino-2
-Relating to a new method for producing (hydroxypropoxy) indole. This compound exhibits β-adrenergic neuroleptic action and is therefore useful as a medicine.

Conventionally, as a method for producing a compound represented by the above formula (), A method is known in which 4-hydroxy-indole of the formula is condensed with epichlorohydrin in the presence of a base and then further condensed with isopropylamine. However, this method not only risks the use of epichlorohydrin, which has mutagenic properties, but also the raw material 4-
The disadvantage of producing hydroxyindole from 2-hydroxy-6-nitrotoluene is that it requires five reaction steps. Further, the condensation yield of 4-hydroxyindole and epichlorohydrin is itself low, and furthermore, there are disadvantages such as large losses in the production process after condensation.

The present inventors have conducted various studies to solve the drawbacks of the conventional methods, and as a result, as shown in the following formula, 4-(3-isopropylamino -2-Hydroxypropoxy)indole has been completed. The method of the present invention is shown in the following chemical formula.

Next, to explain the present invention in detail, first, the formula 3-(Benzylisopropylamino)-2-benzyloxypropanol-1 represented by the formula Dicyclohexylcarbodiimide represented by
React at 100-120℃ for 1-2 hours to form the formula N,N′-dicyclohexyl-o-
[3-(Benzylisopropylamino)-2-benzyloxypropyl]isourea is obtained. In this case, the amount of dicyclohexylcarbodiimide added is 0.8 to 1.0 with respect to the compound represented by the above formula ().
It is preferable to use twice the molar amount. A solvent may be used without a solvent, or a solvent such as toluene or xylene may be used. Completion of the reaction can be confirmed by infrared spectroscopy.

Then the expression By adding 2-hydroxy-6-nitrotoluene represented by the formula and heating at 100℃ to 120℃ for 2 to 10 hours, A novel 2-[3-(benzylisopropylamino)-2-benzyloxypropoxy]-6-nitrotoluene is obtained. In this case, the compound represented by the formula () to be added is preferably used in an amount of 0.7 to 0.9 times the molar amount of dicyclohexylcarbodiimide.

The resulting formula () compound is given by the general formula (In the formula, R represents a lower alkyl group) is reacted with bis-(dialkylamino)-tertiary butoxymethane at 100 to 130°C for 1 to 2 hours to form A novel 2-[3-(benzylisopropylamino)-
2-benzyloxypropoxy]-6-nitro-
β-dialkylaminostyrene is produced. In this case, bis-(dialkylamino)-tertiary-butoxymethane is preferably used in an amount of 1.0 to 10.0 times the molar amount of the compound represented by the above formula (). The solvent is preferably dimethylformamide,
It may be solvent-free.

Next, the compound represented by the general formula () is subjected to catalytic reduction ring closure with hydrogen using, for example, platinum oxide or 10% palladium-carbon in ethyl acetate to obtain the formula 4-[3-(Benzylisopropylamino)-2-benzyloxypropoxy]indole represented by is produced.

Next, the compound represented by the above formula () is hydrolyzed, for example, in ethanol using 10% palladium on carbon to remove the benzyl group. After completion of the reaction, the desired product is recrystallized from methanol to obtain 4-(3-isopropylamino-2-hydroxypropoxy)indole represented by the above formula () in a high yield.

Starting material 3-(benzylisopropylamino)-2- of the method of the present invention, represented by the above formula ()
Benzyloxypropanol-1 has the formula 2,3-epoxypropanol-1 represented by
For example, by reacting with an excess amount of 2,3-dihydropyran in the presence of the pyridine salt of para-toluenesulfonic acid, the formula Novel 2,3-epoxypropyl represented by
Tetrahydropyranyl ether is produced, and the resulting compound of formula (XI) and the formula benzylisopropylamine in an equimolar ratio in a stainless steel sealed tube at 120 to 130°C to form the formula Novel 3-(benzylisopropylamino)-
2-Hydroxypropyl-tetrahydropyranyl ether is obtained which is then benzylated with a benzylating agent such as benzyl halide in a solvent in the presence of a base to give the formula Novel 3-(benzylisopropylamino)-
2-benzyloxypropyltetrahydropyranyl ether, which is then hydrolyzed under acidic conditions to give the formula Novel 3-(benzylisopropylamino)-2-benzyloxypropanol-1 represented by
It is manufactured by producing.

Next, Examples will be given to further specifically explain the present invention.

Example 1 2-[3-(Benzylisopropylamino)-
2-benzyloxypropoxy]-6-nitrotoluene 3-(benzylisopropylamino)-2-benzyloxypropanol-18.90g (0.028mol), dicyclohexylcarbodiimide 5.53g
After reacting 0.25 g (2.04 mmol) of cuprous chloride (0.027 mol) and cuprous chloride at 100-120° C. for 2 hours under an argon stream, complete reaction of dicyclohexylcarbodiimide is confirmed by infrared spectroscopy. Next, 2-hydroxy-6-nitrotoluene
Add 4.0 g (0.026 mol). After 2.5 hours, after confirming the completion of the reaction by thin layer chromatography, the reaction system was cooled, diluted by adding benzene, and after filtering out insoluble materials, it was concentrated under reduced pressure.
15.2 g of crude product was obtained. This was purified using silica gel column chromatography [developing solvent: benzene/ethyl acetate (10:1)] to obtain 10.7 g (0.024 mol) of the target compound.

NMR δ ^CDCl _3TMC : 1.0 (dd, 6H), 2.8 (s, 3H), 2.5~3.4 (m, 3H), 3.6 (s, 2H) 3.6~4.2 (m, 3H), 4.7 (s, 2H) 6.8 ~7.6 (m, 13H) IR ν _nax (cm ^-1 ): 2950, 1605, 1530, 1350,
1265, 1060, Mass: m ⁺ 448 Example 2 4-[3-(Benzylisopropylamino)-
2-benzyloxypropoxy]-indole 2-[3-(benzylisopropylamino)-
0.59 g (1.35 mmol) of 2-benzyloxypropoxy]-6-nitrotoluene was dissolved in 7 ml of dimethylformamide, and then 2.0 g (11.5 mmol) of bis-(dimethylamino-tert-butoxymethane) was added and the mixture was heated at 130°C. After reacting for 4 hours, the completion of the reaction was confirmed by thin layer chromatography. The reaction solution was cooled, washed with water, dried with sodium sulfate, and concentrated under reduced pressure to obtain 0.70 g of a crude product. The crude product obtained was dissolved in 20 ml of ethyl acetate,
3 at room temperature and pressure using 0.01g of platinum oxide.
Perform time contact reduction. The obtained crude product was purified by silica gel column chromatography (developing solvent: benzene) to give 0.39 g.
(0.92 mmol) of the target compound was obtained.

NMR δ ^CDCl _3TMC : 1.0 (dd, 6H), 2.5~3.0 (m,
3H), 3.5 (s, 2H), 3.4-4.3 (m, 3H), 4.6 (s, 2H), 6.3 (dd, 1H), 6.5 (m, 1H), 6.8-7.4 (m, 12H), 7.9 (m, 1H) IR ν _nax (cm ^-1 ): 3400, 2950, 1500, 1360,
1240, 1085 Mass: m ⁺ 428 Example 3 4-(3-isopropylamino-2-hydroxypropoxy)indole 4-[3-(benzylisopropylamino)-
2-benzyloxypropoxy]indole 0.48
g (1.12 mmol) 10% in 30 ml ethanol
The benzyl group is hydrolyzed using 0.69 g of palladium on carbon. After the reaction is completed, filter the reaction solution,
Concentrate the liquid. Recrystallize from methanol
0.22 g (0.89 mmol) of the target compound was obtained.

NMR δ ^DMSOd _6TMS : 1.0 (d, 6H), 2.3~2.7 (m,
2H), 3.0 to 3.3 (m, 3H), 3.8 (s, 3H), 6.3 (m, 2H), 6.8 to 7.2 (m, 3H) IR ν _nax (cm ^-1 ): 3220, 1580, 1360, 1240 ，
1090 mp: 168.4-169.0℃ Example 4 2,3-epoxypropyl-tetrahydropyranyl ether 30.0g (0.41 mol) of 2,3-epoxypropanol-1 was dissolved in 60ml of anhydrous methylene chloride, and 2, 3-dihydropyran 145g
(1.73 mol) and 8.5 g (0.03 mol) of para-toluenesulfonic acid pyridine salt. This mixture is stirred at room temperature for 2 hours. The reaction solution is then washed with dilute aqueous alkaline solution, the residue is dried and concentrated under reduced pressure to the calculated amount. The crude product thus obtained was purified by silica gel column chromatography using a solvent system of benzene/ethyl acetate (9:2) to obtain 2,3-epoxypropyl-tetrahydropyrani as a colorless transparent liquid. leether
32.0g (0.20mol) was obtained. The physical properties of this product are as follows.

NMR δ ^CDCl _3TMS : 1.3-1.8 (m, 6H), 2.4-2.7 (m
，
2H) 2.8~3.1 (m, 1H), 3.2~3.9 (m, 4H) 4.5 (s, 1H) IR ν _nax (cm ^-1 ): 2940, 1440, 1260, 1200,
1120, 1030 Example 5 3-(Benzylisopropylamino)-2-hydroxypropyl-tetrahydropyranyl ether 14.0 g (0.09 mol) of benzylisopropylamino and 15.0 g (0.09 mol) of 2,3-epoxypropyltetrahydropyranyl ether made of stainless steel. into a sealed tube and react overnight at 120-130°C. Thereafter, the contents are diluted with benzene, washed with dilute alkaline water and saturated saline, dried, and concentrated under reduced pressure. The crude product thus obtained was purified by silica gel chromatography using a solvent system of benzene/ethyl acetate (3:1) to yield 23.0 g (0.07 g) of the liquid target compound.
mole) was obtained. The physical properties of this product are as follows.

NMR δ ^CDCl _3TMS : 1.0 (dd, 6H), 1.3~1.8 (m,
6H), 2.4 (d, 2H), 2.7~3.1 (m, 2H), 3.2~4.0 (m, 7H), 4.5 (s, 1H), 7.2 (s, 5H) IR ν _nax (cm ^-1 ): 3450, 2950, 1460, 1365,
1130, 1040 Example 6 3-(Benzylisopropylamino)-2-benzyloxypropyl-tetrahydropyranyl ether After washing 1.14 g of 60% NaH with hexane, 30 ml of N,
Suspend in N-dimethylformamide. This was dissolved in 10 ml of N,N-dimethylformamide.
-Benzylisopropylamino-2-hydroxy-propyl-tetrahydropyranyl ether8.00
g (0.026 mol) was added dropwise over 20 minutes. Subsequently, 4.20 g (0.034 mol) of benzyl chloride was added, and the mixture was allowed to react overnight in a water bath. The reaction mixture was poured into ice water, extracted with benzene, washed with water, dried, and concentrated under reduced pressure. The crude product thus obtained is purified by silica gel column chromatography using a solvent system of hexane/ethyl acetate (20:1). 7.80 g of product (0.020 mol) was obtained as a viscous liquid. The physical properties of this product are as follows.

NMR δ ^CDCl _3TMS : 1.0 (d, 6H), 1,3~1.6 (m,
6H) 2.5 (d, 2H), 2.7~3.1 (t, 1H) 3.2~3.9 (m, 7H), 4.5 (s, 3H) 7.2 (s, 10H) IR ν _nax (cm ^-1 ): 2950, 1450 ,1360,1120,
1030 Mass: m ⁺ 397 Example 7 3-(Benzylisopropylamino)-2-benzyloxypropanol-1 6.40 g (0.016 mol) of 3-(benzylisopropylamino)-2-benzyloxypropyl-tetrahydropyranyl ether was stirred. While 3N
Drop 15 ml of HCl and then add 10 ml of methanol to it.
ml is added to homogenize the reaction system, and the system is stirred at room temperature for 1 hour. After the reaction is complete, the reaction mixture is concentrated under reduced pressure, neutralized with saturated aqueous sodium bicarbonate, and extracted with benzene. After washing with water and saturated saline, it is dried and concentrated under reduced pressure. The crude product thus obtained is purified by silica gel column chromatography using a solvent system of hexane/ethyl acetate (4:1). 4.80g of target compound as viscous liquid
(0.015 mol) was obtained. The physical properties of this product are as follows.

NMR δ ^CDCl _3TMS : 1.0 (dd, 6H), 2.4~2.6 (m, 2H
)
2.7~3.0 (t, 1H), 3.1~3.7 (m, 7H) 4.4 (s, 2H), 4.6 (s, 1H), 7.1 (s, 10H) 9.7 (s, 1H) IR ν _nax (cm ^-1 ): 3400, 2950, 1490, 1450,
1360, 1070 Elemental analysis (as C ₂₀ H ₂₇ O ₂ N) C H N calculated value: 76.64 8.68 4.47 Actual value: 76.40 8.75 4.42

Claims (1)

[Claims] 1 3-(Benzylisopropylamino)-2-
Benzyloxypropanol-1 is reacted with dicyclohexylcarbodiimide to produce N,N'-dicyclohexyl-0-[3-(benzylisopropylamino)-2-benzyloxypropyl]isourea, which is converted into 2-hydroxy-6-
Reaction with nitrotoluene yields 2-[3-(benzylisopropylamino)-2-benzyloxypropoxy]-6-nitrotoluene, which is reacted with bis-(dialkylamino)-tert-butoxymethane to produce 2-[ 3-(Benzylisopropylamino)-2-benzyloxypropoxy]
-6-nitro-β-dialkylaminostyrene is produced, which is ring-closed by reduction to form 4-[3-(benzylisopropylamino)-2-benzyloxypropoxy]indole, which is then hydrolyzed to produce 4- (3-isopropylamino-2-
A method for producing 4-(3-isopropylamino-2-hydroxypropoxy)indole, which comprises producing hydroxypropoxy)indole.