JPS5959676A - Novel morpholine derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I (A is group shown by the formula II or formula III; R<1> is H, lower alkyl, or aralkyl) and its acid addition salt. EXAMPLE:2-(1-Hydroxy-4-indanyloxymethyl)morpholine. USE:An intermediate for preparing an indanyloxymethylmorpholine, an antidepressant. PROCESS:A 2,3-epoxypropane derivative shown by the formula IV is reacted with a compound shown by the formula V[B is halogen, or -OSO3R<2>(R<2> is H, aryl, or lower alkyl)] in the presence of a base (e.g., NaOH, KOH, barium hydroxide, etc.) to give a compound shown by the formula I . The reaction is carried out in a solvent such as water, methanol, etc. under heating.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention refers to a group having the general formula (I) A-OCR2CCH2. The same applies hereinafter] In the presence of a base, a 2,3-epoxypropane derivative represented by the general formula (■) HNCH2CH2B (II) 1 [In the formula, R1 is a hydrogen atom, a lower alkyl group, or the same] The present invention relates to a novel morpholine derivative or its acid addition salt represented by the general formula (III) (wherein A and R' are the same as above), which is characterized by reacting with an acid addition salt, and a method for producing the same.

Compound (111) of the present invention is a new compound.

Indenyloxymethylmorpholine derivatives useful as antidepressants (Japanese Patent Publication No. 56-161.55, No. 21037)
No. 51-35450).

That is, the compound of the present invention represented by the general formula (IV) can be obtained by using a reducing agent such as lithium aluminum hydride or sulfur borohydride. The compound represented by Formula 9 (V) which can be converted into a compound is then converted into p-1-luenesulfonic acid,
The corresponding indenyloxymethylmorpholine derivative can be obtained by heating in the presence or absence of a catalyst such as a mineral acid.

Examples of the lower alkyl group for R+ in the above formula include a methyl group, ethyl group, innorovyl group, and t-butyl group, and examples of the aralkyl group include a benzyl group. Examples of the halogen atom of B include a chloro atom, a prohiro atom, etc. R2
Examples of the lower alkyl group include a methyl group and an ethyl group, and examples of the aryl group include a phenyl group and a p-)lyl group. Acid addition salts of compound (II) include salts with mineral acids such as hydrochloric acid, sulfuric acid, and phosphoric acid. Examples of the base that can be used include alkali metal hydroxides or alkaline earth metal hydroxides such as IJ hydroxide, potassium hydroxide, barium hydroxide, and the like.

To carry out the process of the present invention, compound fI) and an equimolar to molar excess of compound (II) are mixed in the presence of a molar excess of a base;
Water or methanol, ethanol, impropatul, n
- The target compound (110 is obtained by heating in an alcohol such as butanol, t-butanol, ethylene glycol, an organic solvent such as tetrahydrofuran, dioxane, or a mixed solvent thereof. In the production method of the present invention, the reaction intermediate Formula (VI) [wherein A and R
1 has the same meaning as above. The hydroxyethylamino-2-nolopanol derivative represented by the following formula can be isolated. Therefore, in the production method of the present invention, this intermediate is reacted with a small excess amount of crosssulfonic acid in an organic solvent such as pyridine, chloroform, or methylene chloride in the presence of a base such as pyridine or triethylamine, and then The target compound (III) can also be obtained by heating in the presence of a base such as a metal hydroxide and an alkaline earth metal hydroxide.

The acid addition salt of the compound (III) of the present invention is as follows.

hydrochloride, hydrobromide, phosphate, sulfate, oxalate,
Lactate, tartrate, acetate, gluconate, salicylate, citrate, ascorbate, benzoate or 1
, 1-methylene-bis(2-hydroxy-3-naphtonite), and the like.

After the reaction is completed, isolation and purification are carried out by conventional processing means such as filtration, concentration, extraction, distillation, caranometry, chromatography, and recrystallization.

Example 1 1-(1-hydroxy-4-indanyloxy) dissolved in 10 ml of ethanol in a mixed solution of 6 g of 20% aqueous sodium hydroxide solution and 38 g of 2-aminoethyl sulfuric acid.
Add 2.0g of 2,3-epoxypropane and heat at 60°C.
Stir the time. 2.0 g of 20% aqueous sodium hydroxide solution was added to this, and the mixture was further stirred at 60'C for 16 hours.

From now on, add 50 mt of water and extract 3 times with 20 mZ of toluene. After washing the extract with water and drying with anhydrous sodium sulfate,
The solvent is removed under reduced pressure. The residue was subjected to silica gel column chromatography, and chloroporm-methanol (9:1
) from the fraction eluting with 2-(1-hydroxy-
4-indanyloxymethyl)morpholine, (melting point 1.
15-117°C) was obtained.

Elemental analysis value (as Cl4H+oNOs) C (capital)
H% N(% Calculated value 67.45 7,68 5.62 Experimental value
67.01 7.66 5.43 Nuclear magnetic resonance spectrum (CDCIJ3.ppm) 3.4-4.0 (5H
,m, -0-cH,! ! (O< ) Example 2 1-(1-oxo-4-indanyloxy)-2, dissolved in 10 m4 of ethanol in a mixed solution of 6 g of 20% aqueous sodium hydroxide solution and 3.8 g of 2-aminoethyl sulfuric acid,
Add 2.0g of 3-epoxypronogun and heat at 60"C.
Stir the time. Add to this 20% sodium hydroxide solution
Add 2.0 g and stir at 60°C for another 6 hours. From now on, add 50mZ of water and extract with 20ml of toluene.

After washing the extract with water.

Dry over anhydrous sodium sulfate, and remove the solvent under reduced pressure. The residue was subjected to phosphoric gel column chromatography, and 11 g of 2-(1-oxo-4-indanyloxymethyl)morpholine was obtained as an oily product from the fraction eluted with chloroform-methanol (98:2).

Elemental analysis value (as Cl4H17NO3) C (%)
H(%i N(%) Calculated value 67.99 6,93 5.66 Experimental value 67.83 6,92 5.60 Nuclear magnetic resonance spectrum (CDCl3; ppm) 2.1 (L H
,,"N2H Example 3 4-innorobyl-2-(1-oxo-4-indanyloxymethyl)morpholine nuclear magnetic resonance spectrum (CDCl5'; ppm)
CH3 δ: 1.05 (d, 6H, >N-CH<.H3) - Example 4 4-innorobyl-2-(3-oxo-7-indanyloxymethyl)morpholine nuclear magnetic resonance spectrum (CDCl3; ppm ), CH
3 δ:1. os (a, 6H, > N-CH < cH,) Continued from page 1 0 Inventor Junhisa Nozaki 4-17-5 Minamitanaka, Nerima-ku, Tokyo 0 Inventor Shinji Usuda 1068 Hegasaki, Matsudo City [ Inventor Masatomi Harada 1-72-6 Nisshincho, Omiya City

Claims (1)

[Claims] means a group that is Also, R1 is a hydrogen atom. do. ] means a morpholine derivative or a group represented by the following. The same applies below] in the presence of a base, where R1 is a hydrogen atom, a lower alkyl group, or an aralkyl group, and B is a hydrogen atom or -08O8R2 (in the formula R
2 means a hydrogen atom, an aryl group or a lower alkyl group. ) means. The same applies hereinafter] A method for producing a morpholine derivative or an acid addition salt thereof, characterized in that it is reacted with a compound represented by the following or an acid addition salt thereof: [In the formula, A and R' are the same as above].