CA1086732A - Process for the preparation of acid addition salt of 2-(7-indenyloxymethyl) morpholine derivative - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

The specification describes a process of producing an acid addition salt of 2-(7-indenyloxymethyl)morpholine repre-sented by the general formula wherein R2 represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, a phenyl group, or a benzyl group. The process comprises adding to a mixture of the 2-(7-indenyloxymethyl)mor-pholine represented by the general formula wherein R2 has the same significance as defined above, and the 2-(4-indenyloxymethyl)morpholine represented by the general formula

Description

~ his invention relates to a process for the preparation o~
acid addition salt of 2-(7-indenyloxymethyl)morpholine compound represented by the general formula III-a ~ I? III-a R

wherein R represents a hydrogen atom, a lower alkyl group, a ~
cycloalkyl group, a phenyl group, or a benzyl group. ;
Antidepressing agents having morpholine ring are already - ~-~
known as disclosed in, for example, U.S.Patent ~o. 3,714,167 (British Patent ~o. 1,138,4051 Belglan Patent ~o. 708,557; Cana-dian Patent No. 860,341; Australian Patent No. 6,730,109, Swiss Patent Nos. 504,452 and 513,904; French Patent No. 1,571,341;
French Medical Specific Patent Mo. 7557; etc.,) and U.S. Patent ~o. 3,712,890 (British Patent ~o. 1,260,886; Canadian Patent ~o.
913,090; Swiss Patent No. 539,068; etc.,).
The compound which is believed to have the most excellent activity among the compounds disclosed in these patents is 2-(2-ethoxyphenoxymethyl)morpholine, which is generally known as Vilox-azine (see, "~ature"~ 238, 157-158 (1972)). A series of studies made by K. B. Mallion, A. H. Todd, R. W. Turner, et al., who are the ~nventors o Viloxazine suggest the relationship between the chemical structures and the pharmacological activities of these ~5 compounds. ~hat is, it is preferred that the compound has one substituent~at the~2-pos~ition of a phenoxy group bonded to morpho- -line. ~Furthermore, when the phenoxy group forms a fused ring, it is preferred tha;t, for example, a tetralin-type ring is formed by the condensation o~ a tetramethylene group. But, when the conden-:
30 sed ring forms an indane-type ring by the condensation of a tri- ~ -- .:
,~ : ::

~6;732 ~ thylene group, the pharmacolog:i.ccll eEEect becornes less.
Previously, the inventors have prepared compounds represented by the general formula (A) R ~ ~ OCH ~ o) (A) R

wherein R and R each represents a hydrogen atom, a lower alkyl .-group, or a phenyl group, one of the dotted lines represents a :-single bond and the other represents a double bond, and R has the same meanlng as above and have fpund these compounds have excelIent antidepressing actlvity.
As the result of further lnvestlgations, the inventors have discovered an industrially useful prOcess for the preparation of a -~
mixture of 2-(7-indenyloxymethyl)morpholine compound (hereinafter reerred to as 7-isomer) represe~nted~by~the general formula III-a, : ~ R2 . :

and 2-(4-i.ndenyloxymethyl)morpholine.compound ~hereinafterj re-ferred:to ;dS 4-1somer) repres~ented by the general formula III-b

2\y~
N ~ III-b ~5 : ~ 2 R . :.
and have~further:discovered useful isomerization pracess of pro~
ducing~only;~the 7~-isomer~from the mixture of the both isomers. ... ~
It:~has`~further been found that acid addition salt of 2-(7- .~ :
ndenyloxymethyl)morpholine:compound has more excellent pharmaco-30~ logiaal~effect as ompared wlth the 4-isomer and hence can be more.
~ 2 :: :

73~
: favorably used as medicaments.
The process of thia invention is as follows.
That is, 1,2-epoxy-3-(7-indenyloxy)propane represented by the formula I-a O-CH CH-CH ~ .
1 2 \ / 2 ~ O I-a and/or l,2-epoxy-3-(4-indenyloxy)propane represented by the formula I-b -.
O-CH CH-CH .. :
~ 2 \ / 2 I-b is caused to react with the amine compound represented by the general formula II. . -.
:

H~ H2 2 wherein Z represents a halogen atom or -OSO3R (wherein R repre-20 sents a hydrogen atom, an aryl group, or a lower alkyl group) and .. .
R has the same significance as defined above, in the presence of :.
a base to produce a mixture of a 2-(7-indenyloxymethyl)morpholine compound III-a and 2-(4-indenyloxymethyl)morpholine compound III-b .and to the mixture obtained is added an acid in an amount slightly .
~5 1Q9S than the stoichiometric amount to isomerize the 2-(4-indenyl- : .-: .
oxymethyl)morpholine compounds, whereby the acid addition salt of :
' - ' . . .
the 2-(7-indenyloxymethyl)morpholine compound III-a is obtained. .- :
~ow, the lower alkyl group shown by R and R in the compounds .
represented by general formulae II, III-a and III-b means a -. :
30 straight chain or branched chain alkyl group having up to 6 carbon .

3 .:

~IL08 Ei~
. " ~
atoms and practical examples ~f the alkyl group are methyl group, ethyl group, propyl group, isopropyl groupJ bu-tyl group, isobutyl group, pentyl group, neopentyl group, hexyl group, isohexyl group, etc.
Also, examples of the halogen shown by Z of the compound of general formula II are chlorine atom, bromine atom, and iodine atom. And, the aryl group shown by R in the compound includes a phenyl group and a p-tolyl group. The reaction is carried out in a solvent such as water, methanol, ethanol, isopropanol, n-butanol, tert-butanol, ethylene glycol, tetrahydrofuran, dioxane, and mix-ture of them in the presence of alkali metal hydroxide or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydrox-ide, barium hydroxide, and calcium hydroxide at room temperatures or temperatures higher than room temperatures. The product obtained is a mixture of the 7-isomer and 4-isomer as described above since the product obtained attains the equilibrium by tauto-merism under basic condition.
The mixture of the acid addition salt of the 7-isomer and the acid addition salt of the 4-isomer obtained by adding an acid to 20 the mixture prepared above has an unexpected property that the 4- ;
isomer can be isomerized into the 7-isomer by the addition of a sma~l amount of a base and hence only the 7-isomer can be obtained as the acid addi~ion salt thereof by isomerizing the mixture of the both isomers (free bases) obtained by the reaction as it is or after purification by adding thereto in organic solvent an acid in an amount of slightly less than the stoichiometric amount to par-ticipate the remaining free base itself as the base, or by adding to the mixture of the isomers an acid in a stoichiometric or slightly excessive amount to convert the whole isomer mixture into acid addition salts and then adding a small amount of a basic ' ' -1~ 73;~

material to the salts in an organlc solvent. rrhe purification of the mixture of the isomers can be perormed by an ordinary method such as, for example, filtration, concentration, extraction, dis-tillation, column chromatography, recrystallization, etc. AlSo, the examples of the acid used for forming the acid addition salts of the isomers are, for example, the organic acid such as citric acid, acetic acid, lactic acid, maleic acid, fumaric acid, benzoic acid, tartaric acid, ascorbic acid, succinic acid, malic acid, etc., and the inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, etc. Also, as the basic materials used for the isomerization, there are illustrated the free tauto-meric mixture and other organic and inorganic bases such as pyri-dine, triethylamine, sodium hydroxide, barium hydroxide, etc.
Furthermore, after converting the aforesaid mixture of isomers -into the mixture of the acid addition salts of the isomers byadding to the isomer mixture, as it is or after purification, a stoichiometric amount or a slight~y excessive amount of an acid, :
then the acid addition salt of the 7-isomer and the acid addition salt of the 4-isomer can be separated and recovered by fractional recrystallization. For the fractional recrystallization, an organ-ic solvent such as methanol or isopropanol is used.
The compounds of this invention show methamphetamine stereo-typed increasing activity which is one of the desired pharmacologi-cal properties as an antidepression agent and further the activity is stronger than that of the known antidepression agent, Amitripty-line.
The compounds of this invention also show antireserpine acti-vity, which is one of desired pharmacological properties as an ;-~
antidepression agent, stronger than those of known compounds.
The acute toxicity of the compounds of this invention on oral 3:;~
~, administration is about 1/2 of known compounds and the compounds of this invention show excellent safety coefficient in medical treatment on considering the potential activities of the compounds.
The compounds of this invention further show higher activities in the pokentiation of the effect of 5-hydroxytryptophan, which is one of the desirable effects as antidepression agent, than those o the known compounds, Amitriptyrine and Imipramine.
In addition, the isolated 7-isomer acid addition salts shows a more preferable pharmacological activity than that of the 4-isomex acid addition salt.
Moreover, in the isomerization reaction, it is unnecessary to dissolve the tautomeric mixture (free bases, acid addition salts) in solvent, nameIy the tautomeric mixture may remain as it is in the reaction system and no complete dissolution is required.
The foilowing examples will illustrate the present invention.
Example 1 a) In a mixed solution of 29 ml. of 7~/O sodium hydroxide solu-tion and 35 g of 2-aminoethyl hydrogen sulfate (H2~-C~2CH2OSO3H) was added 9.4 g. of 1-(7-indenyloxy)-2,3-epoxypropane (containing 20 about 35% 1-(4-indenyloxy)-2,3-epoxypropane)dissolved in 50 ml. of methanol and the mixture was stlrred for one hour at 55C. To the mixture was added 50 ml. of 70 % sodium hydroxide and stirred for ~urther 16 hours at 55 C. After cooling, 300 ml. of water was added to the reaction mixture and then the product was extracted - -thrice each with 100 ml. of toluene. The extr~cts were combined, washed with water,~dried, and then the residue was distilled. By collecting the fractions having boiling points of 146-156 C./0.5 .
mm Hg, 6.;7 g. (yield 58.0%) of oily 2-(7-indenyloxymethyl)morpho-line (containing 32% 2-(4-indenyloxymethyl)morpholine) was obtained.

The proportions of the both isomers was measured by gas . :

673X~
~ . .
chromatography after tri~luoroacetylation the isomer mixture with trifluoroacetic anhydride.
Elemental analysis for C14H17M02: -C(%) H(%) N(%) Calculated: 72.70 7.41 6.06 Found: 72.91 7.50 5.95 b) In 30 ml. of acetone was dissolved 3 g. of the oily base obtained in the procedure a), and after acidifying the solution thus obtained with isopropanol-hydrochloric acid, the solution was mixed with 50 ml. of ether. The mixture was allowed to stand overnight in an ice chamber at -10C. to precipitate crystals, which were recovered by filtration to provide 2.8 g (yield 80.4%) of 2-(7-indenyloxymethyl)morpholine hydrochloride (containing 4~/O
2-(4-indenyloxymethyl)morpholine hydrochloride)melting at 143-15 155C.
The proportions of the both isomers in the product was mea- ~:
sured by gas chromatography after trifluoroacetylating the product with trifluoroacetic anhydride.
Elemental analysis for C14H18~o2Cl:
C(%) H(%) N(%) C1(%) Calculated: 62.80 6.78 5.23 13.24 Found: 62.84 6.81 5.24 13.01 c). In 70 ml. of acetone was dissolved 3 g. of the oily base ;
obtained in the procedure a), the solution was weakly acidified by isopropanol-hydrochloric acid under ice-cooling and then allowed to stand overnight in a refrigerator. The crystals thus precipi-kated were recovered by iltration and washed with acetone and then ether to provide 1.1 g. of 2-(4-indenyloxymethyl)morpholine hydrochloride (containing 15% 2-(7-indenyloxymethyl)morpholine 30 hydrochloride) showing melking point of 159-163 C. Then, by ~ 7 -~;

repeating the recrystallization ~rom methanol, pure 2-(4-indenyl-oxymethyl)morpholine hydrochloride showing melting point of 175-176 C. was obtained.

Elemental analysis for C14H18~02Cl:

N(%) Calculated: 5~23 Found: 5.31 Nuclear magnetic resonance spectra: (CDC13 + D6-DMSO; ppm) 3.0-3.4 (4H, m,

4.0-4.1 (4H, m -0-CH2-, ~ ~ H

4.3 (lH, m, ~ ~

3.4 (2H, H H ,H
6.5 (lH, doublet, ~ ~ J = 6Hz) 7.0 (lH, doublet, ~ , J = 6Hz) H O- H
6.8 (lH, q, 7.1 (2H, d, ~
H ~I'`

9.5 (2H, +
\~ i , Hz Cl The mother liquor and washings were combined, dried up under reduced pressure, and after adding thereto 50 ml. of toluene fol-lowed by drying again under reduced pressure, the residue obtained was dissolved once in 30 ml. of acetone. The solution thus ob-tained was allowed to stand overnight at room temperature and thecrystals thus formed were recovered by filtration and washed with acetone t~o provide 1~7 g. of 2-(7-indenyloxymethyl)morpholine hydrochloride (containing 10~/o 4-indenyloxy isomer) showing a ~ -melting polnt of 138-153 C. The proportions of the both isomers was measured by gas chromatography after trifluoroacetylating the ,,.. ~, . .

~ 732 product with tri:Eluoroacetic anhydride. Then, by repainting the recrystallization ~rom methanol, 1.7 g. o~ pure 2-(7-indenyloxy-methyl)morpholine hydrochloride having the following properties was obtained.
Elemental analysis for cl4Hl8~2cl.
~1(%) "'' "' Calculated: 5.23 Found: 5.29 ~uclear magnetic resonance spectra:
1 0 ( CDC 13 + D6 -DMS O : ppm):
3~0~3~4 (4H~ m, H ~ N ~ H
4. o_4.2 (4H, m -~CH2 ~ ~ N ~ H
4.3 (lH, m, ~ ) . .
3 . 34 ( 2H~ ~;H

6. 58 (lHj doublet, ~ H~ J = 6 Hz) 6.84 (lH, doublet ~ , J = 6 Hz) -6 . 7 8 (lH, d, ~ ) :~
O--7 . 04 (lH, d, 7 . 2 0 (lH, t, H~
~ , '.
10.0 (2H, ~ ~
Cl-~xample 2 To a mixture of 6 g. of 20% sodium hydroxide solution and 38 g. of 2-aminoethyl hydrogen sulfate was added 2.0 g. of l-(l-hydroxy-4-indanyloxy)-2,3-epoxypropane dissolved in 10 ml. of ethanol and the mixture was stirred for one hour at 60 C~ To the solution was added 2,0 g. of 20% sodium hydroxide solution and the mixture was ~urther stirred for 16 hours at 60 C. After cooling, 50 ml. of water was added to the mixture and the reaction was extracted thrlce each with 20 ml. of toluene. The extracts were 9 ' '-' '. ' -;73Z
,.
combined, washed with water, dried anhydrous sodium sulfate, and then the solvent was distilled away from the under reduced pressure.
Then, the residue was subjected to silica gel column chromatography and eluted with chloroform-me-thanol (9 : 1 by volume ratio) to -provide 900 mg. of 2-(1-hydroxy-4-indanyoxymethyl)morpholine having a melting point of 115-117C.
Elemental analysis for C14HlgN03~:
C(%) H(%) ~(%) :.
Calculated: 67.45 7.68 5.62 ~--Found: 67.01 7.66 5.43 ~uclear magnetic resonance spectra: (CDC13, ppm): ~.
1.9-3.0 (8H, m, ~ H H ~ ~ H ) :
~><~
~ H H
3.4-4.0 ~5H, m, -0-CH2 ~ 0 ~ H

5.1 (lH, t, ~ ) . ~ .

H ~ ;

6.64 (lH, d, H .
H 0_

7.1 (lH, t, ~ ) ;
H

Example 3 To a mixed solution of 6 g. of 200/o sodium hydroxide solution :
and 3.~3 g. of 2-aminoethylhydrogen sulfate was added 2.0 g. of 1~ oxo-4-indanyloxy)-2,;3-epoxypropane dissolved in 10 ml. of ~ :
ethanol and the mixture was stirred for one hour at 60C. Then, .:-~ .
.
20 g. of 2O~D/O sodium hydroxide solution was added to the mixture and the resultant mixture was further stirred for 16 hours at 60C.
After~cooling, 50 ml. of water was added to the mixture and the ..
, reaction mixture was extracted with 20 ml. of toluene. The extract .. .
: : . , .:

" ~ .
was washed with water, dried over anhy~rous sodium sulfate, and then the solvent was distilled away under reduced pressure. The residue formed was subjected -to silica gel column chromatography and eluted by a solvent mixture of chloroform-methanol (98 : 2 by volume ratio) to obtain llO mg. of oily 2-(1-oxo-4-indanyloxy-methyl)morpholine from the eluate.
Elemental analysis for C14H17NO3:
C(%) H(%) N(%) Calculated: 67.99 6.93 5.66 Found: 67~83 6.92 5.60 Nuclear magnetic resonance spectra (CDCl3; ppm):
2.1 (lH, \ N/ ) ~:

2.6-3.2 (8H, m, ~ H ' H ~ I ~ H

3.6-4.2 (5H, m, -0-CH2 - ~ ~ H

H ~ , 7.0 (lH, m, 7.3 (2H, d, H ~ ~

~3~ '.
~ mixture of 4.7 g. of a mixture of 1-(4-indenyloxy-2,3-epoxypropane and l-(7-indenyloxy)-2,3-epoxypropane, 11.5 g. of 2-chloroethylamine hydrochloride, 10 g. of sodium hydroxide, 100 ml. of ethanol, and 50 ml. of water was stirred for 24 hours at 60-65 C. After cooling, the mixture was acidified by 5% hydro-chloric acid and ethanol was distilled away under reduced pressure.
The resulted aqueous solution was washed with ethyl acetate, alka-lified with an aqueous 5% sodium hydroxide solution, and then 11 ' : ' ' - ' i732 extracted thrice each with 50 ml. o~ ether. The extracts were combined and dried over anhydrous sodium sulfate and then ether was distilled away from the extract under reduced pressure. The oily material obtained was subjected to a silica gel chromatography and eluted by a solvent mixture of chloroform : methanol (9 : 1) and from the eluate 500 mg. o~ a mixture of 2-(4-indenyloxymethyl)-morpholine and 2-(7-indenyloxymethyl)morpholine (the proportions of 7-indenyl isomer : 4-indenyl isomer was 17 : 8) was obtained.
The product obtained coincided completely with the product obtained in Example l-a).
Æxample 5 Into 10.6 ml. of pyridine was added 2.5 g. of chlorosulfonic acid with stirring at 0-5 ~. and then 5.0 g. of a mixture of 1-(4-indenyloxy)-3-~-hydroxyethylamino-2-propanol and 1-(7-indenyloxy)- -3-~-hydroxyethylamino-2-propanol dissolved in 10 ml. of pyridine was added dropwise to the mixture. The reaction mixture was stirred for 3 hours at 25 C. and then the solvent was distilled -away under reduced pressure. The oily material obtained was added to a solution consisting of 2.4 g. o~ sodium hydroxide, 13 ml. of 20 water, and 26.4 ml. of ethanol and refluxed for 24 hours. After ~;~
cooling the reaction mixture, ethanol was distilled away under :
reduced pressure, 50 ml. of water was added to the residue, and the mixture was extracted thrice each with 50 ml. of ether. The extracts were combined, dried over anhydrous sodium sulfate, and then ether Was distilled away under reduced pressure. The residue ormed was subjected to silica gel column chromatography and eluted by a solution mixture of chloroform and methanol (9 : 1). ;
From the~eluate, 1.1 g. of a mixture of 2-(4-indenyloxymethyl)-morpho~line and 2-(7-indenyloxymethyl)morpholine (the proportions 30 of the 7-indenyl compound and the 4-indenyl compound was 17 : 8) , ~
was obtained. The product obtained coincided completely with that of obtained in Example 1 a).
Examples 6-12 ~ -According to the processes illustrated in Examples 1-5, the following compounds were prepared:

~ CH2 ~

Each of the products prepared was a mixture of 4-indenyloxy-methyl morpholine derivative and 7-indenyloxymethylmorpholine derivative.
Example 6 R2: 3 Property:
Elemental analysis for C18H1902N :
C(%) H(%) N(%) Calculated:73.44 7.81 5.71 Found: 73.59 7.93 5.69 ~ -Example 7 `

2H5 . .
Property:

Elemental analysis for C16H~102N:

C(%) H(%) ~(%) Calculated:74.10 8.16 5.40 Found: 73.83 7.99 5.41 xample 8 CH
R2 <C 3 Property~

Elemental analysis Eor C17H2302N :
C(%) H(%) ~(%) Calculated: 74.69 8.48 5.12 Found: 74.41 8.23 4.98 :
5 Example 9 R : -C \- C~3 Property:
Elemental analysis for C18H2502N:
C(%) H(%) ~(%) Calculated: 75.23 8.77 4.87 Found: 75.39 8.78 4.90 Example 10 R : -CH
Property:
Elemental analysis for C21H23O2~
C(%) H(%) ~¦%) Calculated: -78.47 ~.21 4.3~6 Found: 78.11 7,.32 4~59 Example 11 ~:~
R2 . ~ - :.
Property: ;
Elemental analysis for C20H2702N~
C(%) H(%) N(%) Calcuiated: 76.64 8.68 4.47 Found: 76.73 8.67 4.53 . -Example 12 -R
Property: .
Elemental analysis for C20H21O2~
C(%) H(%) N~%) ;

'.,' .-.:

~r.~8~;~3'~
,~ ~
Calcula-ted: 78.15 6.89 4.56 Found: 78.33 6.71 4.44 `
Example 13 In 20 ml. of acetone was suspended 10 g. of a mixture (3 : 7) of 2-(4-indenyloxymethyl)morpholine hydrochloride and 2-(7-indeny-loxymethyl)morpholine hydrochloride and after adding to the sus-pension 3 g. of a mixture (3 : 7) of 2-(4-indenyloxymethyl)-morpholine and 2-(7-indenyloxymethyl)morpholine, the resultant mixture was stirred for 24 hours at room temperature. The crystals thus precipitated were recovered by filtration, thoroughly washed with acetone, and 10 g. of the crude crystals recovered were recrystallized from 40 ml. of methanol to provide 7.0 g. of 2-(7-indenyloxymethyl)morpholine hydrochloride.
Elemental analysis for C14H1802NCl: - -~
C(%) H(%) N(%) Cl(%) Calculated: 62.80 6.78 5.23 13.24 Found: 63.01 6.75 5.11 12.98 Nuclear magnetic resonance spectra (CDC13 + D6-DMS0):
~(ppm) : 3.0-3.4 (m, 4H H ~ ~ H ) 4.0-4.2 (m, 4H, -OCH2 H

4.3 (m, IH, o ~ ~ ) 3.34 ( 2H, ~ H

6.58 (doublet, lH, ~ J = 6 Hz) 6.84 (doublet, lH, ~ ~ ~ J = 6 Hz) 6.78 (d, lH, o ~ )H
$
7.20 (t, lH, H

lO.0 (lH, ~N-.~
Example 14 - - '~

~ 73;~
In 20 ml. o~ isopropyl alcohol was ~issolved a mlxture of 10 g. (0.043 mol) (3 : 7) of 2-(4-indenyloxymethyl)morpholine and 2-(7-indenyloxymethyl)morpholine and after adding to the solution 5.9 ml. (0.032 mol) of 20% w/v hydrogen chloride in isopropyl alcohol, the mixture was stirred for 24 hours at room temperature.
The crystals thus precipitated were recovered by filtration, thoroughly washed with acetone, and then recrystallized from 40 ml.
of methanol to provide 7.7 g. of ?-(7-indenyloxymethyl)morpholine hydrochloride.
Elemental analysis for cl4H18o2~Cl:
C(%) H(%) ~(%) Cl(%) Calculated: 62.80 6.78 5.23 13.24 -Found: 62.54 6.63 5.08 13.00 Example 15 In 20 ml. of methanol was suspended 10 g. of a mixture (3 : 7) ;
of 2-(4-indenyloxymethyl)morpholine hydrochloride and 2-(7-indeny-loxymethyl)morpholine hydrochloride and after adding to the sus-pension 0.3 g. of triethylamine, the mixture was stirred for 24 hours at room temperature. The crystals thus precipitated were ~ ~
20 recovered by filtration, thoroughly washed with acetone, and re- ;
crystallized from ~0 ml. of methanol to provide 6.3 g. of 2-(7-indenylo~ymethyl)morpholine hydrochloride.
Elemental analysis for C14~1802~Cl:
C(%) ~I(%) ~(%) C1(%) Calculated: 62.80 6.78 5.23 13.24 Found: 62.77 6.83 5.40 13.29 :' ... ., ~ . ~ . , ., . .. . , , . - .. ..

Claims (12)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process of producing a pharmaceutically acceptable acid addition salt of a 2-(7-indenyloxymethyl)morpholine represented by the general formula:

wherein R2 represents a hydrogen atom, a lower alkyl group, a cycloalkyl group having 5 or 6 carbon atoms, a phenyl group or a benzyl group, which comprises either;
(a) reacting at least one of the 1,2-epoxy-3-(7-indenyloxy)propane represented by the formula:

and the 1,2-epoxy-3-(4-indenyloxy)propane represented by the formula:

with the amine represented by the general formula:

wherein R2 has the same significance as defined above and Z represents a halogen or -OSO3R4 (wherein R4 represents a hydrogen atom, a monocyclic aryl group or a lower alkyl group) in the presence of base to form a mixture of the following two compounds of the formulas (I) and (II); 2-(7-indenyloxymethyl)morpholine represented by the general formula:
(I) wherein R2 has the same significance as defined above and 2-(4-indenyloxymethyl)morpholine represented by the general formula (II) wherein R2 has the same significance as defined above and adding to the mixture of the above two compounds of the formulas (I) and (II) an acid in an amount of slightly less than the stoichiometric amount to isomerize the 2-(4-indenyloxymethyl)morpholine into the 2-(7-indenyloxymethyl)morpholine; or (b) adding to a mixture of the free bases of the following two compounds of the formulas (I) and (II) 2-(7-indenyloxymethyl)morpholine represented by the general formula (I) wherein R2 has the same significance as defined above, and 2-(4-indenyloxymethyl)morpholine represented by the general formula (II) wherein R2 has the same significance as defined above;
an acid in an amount of slightly less than the stoichio-metric amount to isomerize the 2-(4-indenyloxymethyl)-morpholine into the 2-(7-indenyloxymethyl)morpholine; or (c) adding to a mixture of the acid addition salts of the following two compounds of the formulas (I) and (II): 2-(7-indenyloxymethyl)morpholine represented by general formula (I) wherein R2 has the same significance as defined above, and 2-(4-indenyloxymethyl)morpholine represented by the general formula (II) wherein R2 has the same significance as above, a small amount of base to isomerize the 2-(4-indenyloxymethyl)-morpholine into the 2-(7-indenyloxymethyl)morpholine.

2. The process as claimed in claim 1, wherein R2 is hydrogen atom.

3. The process as claimed in claim 1, wherein R2 is isopropyl group.

4. A process of producing a pharmaceutically acceptable acid addition salt of a 2-(7-indenyloxymethyl)morpholine repre-sented by the general formula wherein R2 represents a hydrogen atom, a lower alkyl group, a cycloalkyl group having 5 or 6 carbon atoms, a phenyl group, or a benzyl group, which comprises reacting at least one of the 1,2-epoxy-3-(7-indenyloxy)propane represented by the formula:

and the 1,2-epoxy-3-(4-indenyloxy)propane represented by the formula:
with the amine represented by the general formula:

wherein R2 has the same significance as defined above and Z represents a halogen atom or -OSO3R4 (wherein R4 represents a hydrogen atom, a monocyclic aryl group or a lower alkyl group) in the presence of base to form a mixture of the following two compounds of the formulas (I) and (II):2-(7-indenyloxy-methyl)morpholine represented by the general formula (I) wherein R2 has the same significance as defined above and 2-(4-indenyloxymethyl)morpholine represented by the general formula:
(II) wherein R2 has the same significance as defined above, and adding to the mixture of the above two compounds of the formulas (I) and (II) an acid in an amount of slightly less than the stoichiometric amount to isomerize the 2-(4-indenyloxy-methyl)morpholine into the 2-(7-indenyloxymethyl)morpholine.

5. The process as claimed in claim 4, wherein R2 is hydrogen atom.

6. The process as claimed in claim 4, wherein R2 is isopropyl group.

7. A process of producing a pharmaceutically acceptable acid addition salt of 2-(7-indenyloxymethyl)morpholine represented by the general formula:

wherein R2 represents a hydrogen atom, a lower alkyl group, a cycloalkyl group having 5 or 6 carbon atoms, a phenyl group or a benzyl group, which comprises adding to a mixture of the free bases of the following two compounds of the formulas (I) and (II): 2-(7-indenyloxymethyl)morpholine represented by the general formula (I) wherein R2 has the same significance as defined above, and 2-(4-indenyloxymethyl)morpholine represented by the general formula (II) wherein R2 has the same significance as defined above; an acid in an amount of slightly less than the stoichiometric amount to isomerize the 2-(4-indenyloxymethyl)morpholine into the 2-(7-indenyloxymethyl)morpholine.

8. The process as claimed in claim 7, wherein R2 is hydrogen atom.

9. The process as claimed in claim 7, wherein R2 is isopropyl group.

10. A process of producing the pharmaceutically acceptable acid addition salt of a 2-(7-indenyloxymethyl)morpholine represented by the general formula:

wherein R2 represents a hydrogen atom, a lower alkyl group, a cycloalkyl group having 5 or 6 carbon atoms, a phenyl group, or a benzyl group which comprises adding to a mixture of the acid addition salts of the follwoing two compounds of the formulas (I) and (II): 2-(7-indenyloxymethyl)morpholine repre-sented by the general formula (I) wherein R2 has the same significance as defined above, and 2-(4-indenyloxymethyl)morpholine represented by the general formula (II) wherein R2 has the same significance as above, a small amount of base to isomerize the 2-(4-indenyloxymethyl)morpholine into the 2-(7-indenloxymethyl)morpholine.

11. The process as claimed in claim 10, wherein R2 is hydrogen atom.

12. The process as claimed in claim 10, wherein R2 is isopropyl group.