Note: Descriptions are shown in the official language in which they were submitted.
3,~4~
This invelltion relates to a process for -the preparation of
acid addition salt o~ 2-(7-indenyloxymethyl)morpholine compound
represen-ted by the general formula ~ a
O-CH2
~ \~ON~ a
wherein R represents a hydrogen atom, a lower alkyl group, a
cycloalkyl group, a phenyl group, o:r a benzyl group.
The process comprises subjecting an acid addition salt of
a mixture of the 4-isomer of the formula:
O-CH2
~ ~ ~ S III-b
R
and the 7-isomer of the formula III-a, as represented above, to
fractional crystallization from an oryanic solvent to recover the
7-isomer.
Antidepressing agents having morpholine ring are already
20 known as disclosed in, for example, U.S. patent no. 3,714,167
(British patent no. 1,138,405; Belgian patent no. 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 no. 7557; etc.) and U.S. patent
25 no. 3,712,890 (Br:itish patent no. 1,260,866; Canadian patent no.
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-
30 azine (see, "Nature"; 238. ~57-158 (1972)). A series of studies
made by K.B. Mallion, ~.~l. Todd, R.W. Turner, et al., who are
the inventors oE Viloxazine sugyest the relationship between the
chemical structures and the pharmocological activi-ties oE these
compounds. That is, it is preEerred that the compound has one
substituent a-t the 2-position of a phenoxy group bonded to morpho-
line. Fur-thermore, when the phenoxy group forms a fused ring,
it is preferred that, for example, a tetralin-type ring is formed
by the condensation of a tetramethylene group. But, when the con-
densed ring forms an indane-type ring by the condensation of a tri-
methylene group, the pharmacological effect becomes less.
Previously, -the inventors have prepared compounds represented
by the general formula (A)
O-CH
R ~ ~ ~ (A)
R2
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 meaning as above and have found these compounds have excellent
antidepressing activity.
As the result of further investigations, the inventors have
discovered an industrially useful process for the preparation of a
mixture of 2-(7-indenyloxymethyl)morpholine compound (hereinaf-ter
referred to as 7-isomer) represented by the general formula III-a, -
O-CH2
III-a
12
~- ' '
and 2-(4-indenyloxymethyl)morpholine compound (hereinafter, re-
referred to as ~}~isomer) represented by the general formula III-b
O-CH2 LII-b
and have further discovered useful isomerization process 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-
indenyloxymethyl)morpholine compound has more excellent pharmaco-
logical effect as compared with the 4-isomer and hence can be more
favorably used as medicaments.
The process of preparing the 7-isomer is as follows:
That is, 1,2-epoxy-3-(7-indenyloxy)propane represented by
the formula I-a
~ o I-a
and/or 1,2-epoxy-3-(4-indenyloxy)propane represented by the
formula I-b
L \ /
~ O I-b
is caused to react with the amine compound represented by the
general formula II
HN-CH2CH2-Z
R2 II
wherein Z represents a halogen atom or -OSO3R (wherein R repre-
sents a hydrogen atom, an aryl group, or a lower alkyl group) and
R has the same significance as defined above, in the pres.ence of
a base to produce a mixture of 2-(7-indenyloxymethyl)morpholine
compound III-a and 2-(4-indenyloxymethyl)morpholine compound III-b
and to the mix-ture obtained is added an acid in an amount slightly
less than the stoichiometric amoun-t to isomerize the 2-(4-indenyl-
oxymethyl)morpholine compounds, whereby the acid addition salt ofthe 2-(7-indenyloxymethyl)morpholine compound III-a is obtained.
Now, the lower alkyl group shown by R and R in the compounds
represented by general formulae II, III-a and III-b means a
straight chain or branched chain alkyl group having up to 6 carbon
-.--- . _ _ _ ___. ~ .
3a
atoms and practical examples of the alkyl group are methyl group,
ethyl group, propyl group, isopropyl group, butyl 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 ~ 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
the mixture prepared above has an unexpected property that the 4-
isomer can be isomerized into the 7-isomer by the addition of a
small amount of a base and hence only the 7-isomer can be obtained
as the acid addition salt thereof by isomerizing the mixture of the
both isomers (free hases) obtained by the reaction as it is or
after purification by adding thereto in organic solvent an acid in
an amount of slight].y less than the stoichiometric amount to par-
ticipate the remaini.ng 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
'
material to the salts in an organic solvent. The purification of
the mixture of the isomers can be perEormed 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
acia, 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 by
adding to the isomer mixture, as it is or after purification, a
stoichiometric amount or a slightly 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
organic 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 antir~eserpine 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
administration is about 1/2 of known compounds and the compounds
Oi this invention show excellent safety coefficient in medical
treatment on considering the potential activi-ties of the compounds.
The compounds of this invention Eurther show higher activities
in the potentiation of the effect of 5-hydroxytryptophan, which is
one of the desirable effects as antidepression agent, than those
of 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-
isomeL acid addition salt.
Moreover, in the isomerization reaction, it is unnecessary
to dissolve the tautomeric mixture (free bases, acid addition
salts) in solvent, namely the tautomeric mixture may remain as it
is in the reaction system and no complete dissolution is required.
The following examples will illustrate the present invention.
Example 1
a) In a mixed solution of 29 ml. of 70/O sodium hydroxide solu-
tion and 35 g. of 2-aminoethyl hydrogen sulfate (H2~-CH2CH2OS~3H)
was added 9.4 g. of 1-(7-indenyloxy)-2,3-epoxypropane (containing
20 about 35% 1-(4-indenyloxy)-~,3-epoxypropane)dissolved in 50 ml. of
methanol and the mixture was stirred for one hour at 55C. To the
mixture was added 50 ml. of 70 % sodium hydroxide and stirred for
further 16 hours at 55C. 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 extracts were combined,
washed with water, dried, and then the residue was distilled. By
collecting the fractions having boiling points of 146-156C./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
~ . '
.. ~
chromatography a~ter trifluoroacetylation the lsomer mixture with
trifluoroacetic anhydride.
Elemental analysis for C14H17N02:
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
overnlght in an ice chamber at -10C. to precipitate crystals,
which ~ere recovered by filtration to provide 2.8 g (yield 80.4%)
of 2-(7-indenyloxymethyl)morpholine hydrochloride ~containing 40%
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 C14H18N02Cl:
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-
tated were recovered by filtration 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 melting point of 159-163C. Then, by
3;~
repeating the recrystalliz3tion ~rom methanol, pure 2-(4-indenyl-
oxymethyl)morpholine hydrochloride showing melting point of 175-
176C. was obtained.
Elemental analysis for C14H18NO2Cl:
N(%)
Calculated: 5.23
Found: 5.31
~uclear magnetic resonance spectra: (CDC13 + D6-DMSO; ppm)
3 0-3.4 ( 4H, m, H ~ N ~ EI
4. 0-4.1 (4H, m -0-OEI2-, ~H
4.3 ( lH, m, ~
3 . 4 (2H, ~ ~ H
6.5 (lH, doublet, ~ , J = 6HZ)
7 o 0 ( lH, doublet~ - ~H ~ J = 6HZ )
6.8 (lH, q, ~
O- :
7 .1 ( 2H, d,
H--
9.5 (2H, +
~ N ~
H 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 Eormed were recovered by filtration and washed with
acetone to provide I.7 g. of 2-(7-indenyloxymethyl)morpholine
hydrochloride (containlng 10% 4-indenyloxy isomer) showing a
melting point of 138-153C. The proportiOns of the both isomers
was measured by gas chromatography after -trifluoroacetylating the
~ " .
.
product with trifluoroacetic anhydride. Then, by repainting the
recrystallization from methanol, 1.7 g. of pure 2-(7-indenyloxy-
methyl)morpholine hydrochloride having the following properties
was obtained.
Elemental analysis for Cl4Hl8N02Cl.
N(%)
Calculated: 5.23
Found: 5.29
Nuclear magnetic resonance spectra:
(CDC13 ~ D6-DMS0: ppm): H
3.0-3.4 (4H, m, H ~ N ~ H H
4.0-4.2 (4H, m -0-CH2-, ~ ~ H)
H~0~
4.3 (lH, m, ~ J
3.34 (2H, ~ H
6. 58 (lH, doublet, ~ , J = 6 Hz)
6.84 (lH, doublet,0_ 1 1 , J = 6 Hz)
6.7 8 ( lH, d, ~ ~
7 04 (lH, d, ~ 0_
7.20 (lH, t,
lO.0 (2H, -N'
H Cl-
Example 2
To a mixture of 6 g. of 20~/o sodium hydroxide solution and
38 g. of 2-aminoethyl hydrogen sulfate was added 2.0 g. of l-(l-
25 hydroxy-4-indanyloxy) -2~ 3-epoxypropane dissolved in lO ml. of
ethanol and the mixture was stirred for one hour at 60C. To the
solution was added 2,0 g. of 20~/o sodium hydroxide solution and the
mixture was further stirred for 16 hours at 60C. After cooling,
50 ml. of water was added to the mixture and the reaction was
extracted thrice each with 20 ml. of toluene. The extracts were
com~ined~ washed with water, dried anhydrous sodium sulEate, 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-methanol (9 : 1 by volume ratjo) to
5 provide 900 my. of 2-(1-hydroxy-4-indanyoxymethyl)morpholine
having a melting point of 115-117C.
Elemental analysis for C14HlgN03:
C(%) H(%) N(%)
Calculated: 67.45 7.68 5.62
10 Found: 67.01 7.66 5.43
Nuclear magnetic resonance spectra: (CDCl3, ppm):
1.9-3.0 (8H, m, ~ H , H ~ ~ H
3.4-4.G (5H, m, -0-CH2 ~ ~ H
15 5.1 (lH, t, ~
O-- .
6.64 ~lH, d, 0 ~ )
7.0 (lH, d, ~
H 0-
20 7.1 (lH, t,
Example 3
To a mixed solution of 6 g. of 20% sodium hydroxide solution
and 3.8 g. of 2-aminoethylhydrogen sulfate was added 2.0 g. of
25 1-(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 20% 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
1 0
..... ~
was washed with water, dried over anhydrous sodium sul~ate, 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 110 mg. of oi:Ly 2-~1-oxo-4-indanyloxy-
methyl)morpholine ~rom the eluate.
Elemental analysis for C14H17N03: r
C(%) H(%) N(%)
Calculated: 67.99 6.93 5.66
Found: 67.83 6.92 5.60
~uclear magnetic resonance spectra (CDC13; ppm):
2.1 (lH, \~ )
H H H
2.6-3.2 (8H, m~ I ~ H
~ H H H
3.6-4.2 (5H, m, -0-CH2 H ~ ~ H )
H
7.0 (lH, m,
O_
7.3 (2H, d, ~ )
H
Example ~
A mixture of 4.7 g. of a mixture of 1-(4-indenyloxy-2,3-
epoxypropane and 1-(7-indenyloxy)-2,3-epoxypropane, 11~5 g. of
2-chloroethylamine hydrochloride, 10 g. o~ sodium hydroxide, 100
ml. of ethanol, and 50 ml. of water was stirred for 24 hours at
60-65C. A~ter coo:Ling, 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
., .
extracted thrice each with 50 ml. of 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. of 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).
Example 5
Into 10.6 ml. of pyridine was added 2.5 g. of chlorosulfonic
acid with stirring at 0-5C. 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 25C. and then the solvent was distilled
away under reduced pressure. The oily material obtained was added
to a solution consisting of 2.4 g. of 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
formed 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)-
morpholine and 2-(7-indenyloxymethyl)morpholine (the proportions
30 of the 7-indenyl compound and the 4-indenyl compound was 17 : 8)
~ 12
~ i_
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:
O - CH2 - 1
N
~J R
Each of the products prepared was a mixture of 4-indenyloxy-
methyl morpholine derivative and 7-indenyloxymethylmorpholine
derivative.
Example 6
R2 -CH3
Property:
Elemental analysis for C18H19O2N :
C(%) H(%) N(%)
Calculated: 73.44 7.81 5.71
Found: 73.59 7.93 5.69
Example 7
R2 2 5
Property:
Elemental analysis for C16H21O2~:
C(%) H(%) N(%)
Calculatecl: 74.10 8.16 5.40
Found: 73.83 7.99 5.41 ,
Example 8 / CH3
R : -CH\
CH3
Property:
.
.
Elemental analysis for C17H23O2N :
C(%) H(%) N(%)
Calculated: 74.69 8.48 5.12
Found: 74.41 8.23 4.98
5 Example 9 3
R2 \ CH3
Property: CH3
Elemental analysis for C18H,25O2N :
C(%) H(%) N(%)
Calculated: 75.23 8.77 4.87
Found: 75.39 8.78 4.90
Example 10
R : -CH
Property:
Elemental analysis for C21H23O2N:
C(%) H(%) N(%)
Calculated: 78.47 7.21 4.36
Found: 78.11 7.32 4.59
Example 11
R :
Property:
Elemental analysis for C20H27O2N:
C(%) H(%) N(%)
. Calculated: 76.64 8.68 4.47
Found: 76.73 8.67 4.53
Example 12
,
R :
Property:
Elemental analysis for C20H21O2N:
C(%) H(%) N(%)
14
~ . .
Calculated: 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 hydrocnloride and after adding to the 5US-
pension 3 g. of a mixture (3 : 7) of 2-(4-indenyloxyme-thyl)-
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 HH ~ H 0 H
4.0-4.2 (m, 4H, -OCH2 - ~ ~ H
H~'o~ ~N~
4 3 (m, lH~ ~NJ H
3.34 ( 2H, ~ ~ = H )
6.58 (doublet, lH, ~ H J = 6 Hz)
6.84 (doublet, lH, 0 ~ J = 6 Hz)
6.78 (d, lH, 0 ~ )H
7.04 (d, lH, ~ 0
7.20 (t, lH, H
10.0 (lH, -N~
30 Example 14 15
~3~'~7
In 20 ml. of isopropyl alcohol was dissolved a mixture of
10 g (0.043 mol) t3 : 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 r,ecovered by filtration,
thoroughly washed with acetone, and then recrystallized from 40 ml.
of methanol to provide 7.7 g. of 2-(7-indenyloxymethyl)morpholine
hydrochloride.
Elemental analysis for C14H18O2NCl
C(%) H(%) N(%) 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
recovered by filtration, thoroughly washed with acetone, and re-
crystallized from 40 ml. of methanol to provide 6.3 g. of 2-(7-
indenyloxymethyl)morpholine hydrochloride.
Elemental analysis for C14H18O2~Cl:
C(%) H(%) ~(%) C1(%)
Calculated: 62.80 6.78 5.23 13.24
Found: 62.77 6.83 5.40 13.29
~ 16
