U.S. patent application number 16/791169 was filed with the patent office on 2020-08-20 for process for preparation of molindone.
This patent application is currently assigned to LUPIN LIMITED. The applicant listed for this patent is LUPIN LIMITED. Invention is credited to Amit Madanrao AGARKAR, Rajesh Bharat GAPAT, Tejas Vilas PURANIK, Umesh Babanrao RANANAWARE, Radhakrishna Bhikaji SHIVDAVKAR, Girij Pal SINGH.
Application Number | 20200262788 16/791169 |
Document ID | 20200262788 / US20200262788 |
Family ID | 1000004673247 |
Filed Date | 2020-08-20 |
Patent Application | download [pdf] |
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United States Patent
Application |
20200262788 |
Kind Code |
A1 |
AGARKAR; Amit Madanrao ; et
al. |
August 20, 2020 |
PROCESS FOR PREPARATION OF MOLINDONE
Abstract
The present invention provides process for preparation of
molindone (I) comprising: a) reacting compound with
cyclohexane-1,3-dione to form
2-(2-oxopentan-3-yl)cyclohexane-1,3-dione wherein X is Cl, Br or I,
b) cyclizing 2-(2-oxopentan-3-yl)cyclohexane-1,3-dione to
2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole, c) reacting
2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole with morpholine and
formaldehyde to give molindone (I), and d) optionally converting
molindone (I) to its salt. The present invention further provides
process for preparation of compound comprising: a) reacting
compound with ethyl halide and another halide source to form
compound wherein R is alkyl and X is Cl, Br or I; b)converting
compound to compound.
Inventors: |
AGARKAR; Amit Madanrao;
(Pune, IN) ; PURANIK; Tejas Vilas; (Pune, IN)
; GAPAT; Rajesh Bharat; (Pune, IN) ; RANANAWARE;
Umesh Babanrao; (Pune, IN) ; SHIVDAVKAR; Radhakrishna
Bhikaji; (Pune, IN) ; SINGH; Girij Pal; (Pune,
IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
LUPIN LIMITED |
Mumbai |
|
IN |
|
|
Assignee: |
LUPIN LIMITED
Mumbai
IN
|
Family ID: |
1000004673247 |
Appl. No.: |
16/791169 |
Filed: |
February 14, 2020 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 209/08 20130101;
C07C 49/403 20130101 |
International
Class: |
C07D 209/08 20060101
C07D209/08; C07C 49/403 20060101 C07C049/403 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 16, 2019 |
IN |
201921006197 |
Nov 11, 2019 |
IN |
201921045841 |
Claims
1. A process for the preparation of molindone (I) comprising:
##STR00006## a) reacting compound (2) with cyclohexane-1,3-dione
(3) to form 2-(2-oxopentan-3-yl)cyclohexane-1,3-dione (4)
##STR00007## wherein X is Cl, Br or I, b) cyclizing
2-(2-oxopentan-3-yl)cyclohexane-1,3-dione (4) to
2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (5), ##STR00008##
c) reacting 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (5)
with morpholine and formaldehyde to give molindone (I), and d)
optionally converting molindone (I) to its salt.
2. The process for preparation of compound (2) as described in
claim 1, comprising: a) reacting compound (1') with ethyl halide
and another halide source to form compound (2') wherein R is alkyl
and X is Cl, Br or I, ##STR00009## b) converting compound (2') to
compound (2).
3. A compound, 2-(2-oxopentan-3-yl)cyclohexane-1,3-dione (4),
##STR00010##
4. The process according to claim 1, wherein the cyclization
process of step (b) is carried out in presence of reagent selected
from ammonium acetate, aqueous ammonia, methanolic ammonia,
ammonium chloride or urea and choline chloride.
5. The process according to claim 2, wherein ethyl halide is
selected from ethyl iodide, ethyl bromide or ethyl chloride.
6. The process according to claim 2, wherein halide source is
selected from N-chlorosuccimide, N-bromosuccinimde,
N-Iodosuccinimide orsulfuryl chloride.
7. The process according to claim 2, wherein compound (2') is
converted to compound (2) by treating with acid selected from
hydrochloric acid, sulfuric acid, acetic acid or para toluene
sulfonic acid.
8. The process according to claim 1, wherein molindone salt is
hydrochloride salt.
9. The process according to claim 1, wherein the reaction of
compound (2) and cyclohexane-1,3-dione is carried out in presence
of solvent and base.
10. The process according to claim 9, wherein the solvent is
selected fromacetonitrile, propionitrile, butyronitrile, ethyl
acetate, ethyl acetoacetate, butyl acetate, propyl acetate,
tetrahydrofuran, dioxane, dimethoxyethane, dimethyl ether,
diisopropyl ether, diethyl ether, methyl tert-butyl ether,
1,2-dimethbxy ethane, dimethylformamide, toluene, dichloro methane
or ethylene dichloride.
11. The process according to claim 9, wherein the base is selected
from ethylamine, dimethylamine, diethylamine, diisopropyl amine,
diisopropylethylamine, diisobutylamine, triethylamine,
tributylamine, tert.butyl amine, pyridine or
4-dimethylaminopyridine.
Description
FIELD OF INVENTION
[0001] The present invention provides novel process for preparation
of Molindone and its salts. The present invention also provides
novel intermediate for preparation of Molindone.
BACKGROUND OF THE INVENTION
[0002] Molindone is chemically known as4H-Indol-4-one,
3-ethyl-1,5,6,7- tetrahydro- 2-methyl-5-(4-morpholinylmethyl) and
represented by formula I. Molindone is indicated for management of
schizophrenia and is under clinical trial for alternate
therapies.
##STR00001##
[0003] The compound molindone, process for its preparation and its
pharmaceutically acceptable salts are disclosed in U.S. Pat. No.
3,491,09. Another application WO 2014042688 discloses methods of
producing molindone. Since there are very limited methods for
preparation of molindone reported in literature there exist a need
for alternate process for preparation of molindone. The present
invention provides novel process for preparation of Molindone (I)
and its salts.
SUMMARY OF THE INVENTION
[0004] The present invention provides process for preparation of
molindone (I) comprising:
##STR00002## [0005] a) reacting compound (2) with
cyclohexane-1,3-dione (3) to form
2-(2-oxopentan-3-yl)cyclohexane-1,3-dione (4)
[0005] ##STR00003## [0006] wherein X is Cl, Br or I, [0007] b)
cyclizing 2-(2-oxopentan-3-yl)cyclohexane-1,3-dione (4) to
2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (5),
[0007] ##STR00004## [0008] c) reacting
2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (5) with morpholine
and formaldehyde to give molindone (I), and [0009] d) optionally
converting molindone (I) to its salt.
[0010] The present invention further provides process for
preparation of compound (2) comprising: [0011] a) reacting compound
(1') with ethyl halide and another halide source to form compound
(2') wherein R is alkyl and X is Cl, Br or I
[0011] ##STR00005## [0012] b) converting compound (2') to compound
(2).
DETAILED DESCRIPTION OF THE INVENTION
[0013] In the first embodiment, the present invention provides
process for preparation of molindone (I) or its pharmaceutically
salts thereof, comprising [0014] a) reacting pentan-2-one (1) with
a halide source to form compound (2), wherein X is Cl, Br or I
[0015] b) reacting compound (2) with cyclohexane-1,3-dione (3) to
form 2-(2-oxopentan-3-yl)cyclohexane-1,3-dione (4), [0016] c)
cyclizing 2-(2-oxopentan-3-yl)cyclohexane-1,3-dione (4) to
2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (5), [0017] d)
reacting 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (5) with
morpholine and formaldehyde to give molindone, and [0018] e)
optionally converting molindone to its salt.
[0019] In the second embodiment, the present invention provides
process for preparation of molindone (I) or its pharmaceutically
salts thereof, comprising [0020] a) reacting compound (2) with
cyclohexane-1,3-dione (3) to form
2-(2-oxopentan-3-yl)cyclohexane-1,3-dione (4), wherein X is Cl, Br
or I, [0021] b) cyclizing 2-(2-oxopentan-3-yl)cyclohexane-1,3-dione
(4) to 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (5), [0022]
c) reacting 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (5)
with morpholine and formaldehyde to give molindone, and [0023] d)
optionally converting molindone to its salt.
[0024] In the third embodiment, the present invention provides
novel compound 2-(2-oxopentan-3-yl)cyclohexane-1,3-dione (4). The
compound (4) is useful as an intermediate for preparation of
molindone. The compound (4) was isolated in a purity of above 95%.
2-(2-oxopentan-3-yl)cyclohexane-1,3-dione (4) is characterized by
.sup.1H NMR (500 MHz, CDCl.sub.3), .delta. 5.14; (S 1H), .delta.
4.37; (d 1H), .delta. 2.50-2.55; (m 2H) .delta. 2.35-2.38; (m 2H),
.delta. 2.16; (s 3H), .delta. 2.00-2.05; (m 2H) .delta. 1.88-1.90;
(m 2H), .delta. 1.00-1.02; (m 3H); .sup.13C NMR (500 MHz,
CDCl.sub.3),206.04,199.34,176.63,103.70,77.12,36.62,28.88,25.44,21.00,16.-
55,9.41 ppm; Dept135 NMR(500 MHz, CDCl.sub.3):
103.70,83.78,36.62,28.87,28.65,25.45,24.69,21.00,9.41ppm; Mass:
[M+1]=197.
[0025] In the fourth embodiment, the present invention provides
process for preparation of
2-(2-oxopentan-3-yl)cyclohexane-1,3-dione (4), comprising [0026] a)
reacting pentan-2-one (1) with a halide source to form compound
(2), and wherein X is Cl Br or I [0027] b) reacting compound (2)
with cyclohexane-1,3-dione (3) to form
2-(2-oxopentan-3-yl)cyclohexane-1,3-dione (4)
[0028] In the fifth embodiment, the present invention provides
process for preparation of molindone (I) or its pharmaceutically
salts thereof, comprising [0029] a) converting
2-(2-oxopentan-3-yl)cyclohexane-1,3-dione (4) to
2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (5), [0030] b)
reacting 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (5) with
morpholine and formaldehyde to give molindone (I), and [0031] c)
optionally converting molindone (I) to its salt.
[0032] In the sixth embodiment, the present invention provides
process for preparation of
2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (5) comprising
reacting compound (2) with cyclohexane-1,3-dione (3) in presence of
R-NH.sub.2, base, solvent and catalyst, wherein R is H, alkyl or
aryl.
[0033] In the seventh embodiment, the present invention provides
process for preparation of molindone (I) or its pharmaceutically
salts thereof, comprising [0034] a) reacting compound (2) with
cyclohexane-1,3-dione (3) in presence of R-NH.sub.2, base, solvent
and catalyst, wherein R is H, alkyl or aryl to give
2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (5) and [0035] b)
reacting 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (5) with
morpholine and formaldehyde to give molindone (I), and [0036] c)
optionally converting molindone (I) to its salt.
[0037] In aneight embodiment, the present invention provides
process for preparation of compound (2) comprising: [0038] a)
reacting compound (1') with ethyl halide and another halide source
to form compound (2') wherein R is alkyl and X is Cl, Br or I
[0039] b) converting compound (2') to compound (2)
[0040] In the present invention, the reaction of compound (1') with
ethyl halide can be carried out in presence of base and a solvent .
In the compound (1'), R is alkyl selected from straight chain or
branched like methyl, ethyl, propyl, butyl and the like. In the
reaction ethyl halide can be selected from ethyl iodide, ethyl
bromide , ethyl chloride. The reaction can be carried out at a
temperature of about 40 to 100.degree. C. for 12 to 16 hours.
[0041] In the present invention, further reaction with another
halide source can be carried out in presence of a solvent at a
temperature of about 0 to 100.degree. C. for 30 minutes to 6 hours.
Another halide source can be selected from N-chlorosuccimide,
N-bromosuccinimde, N-Iodosuccinimide, sulfuryl chloride and the
like.
[0042] In the present invention, compound (2') is converted to
compound (2) by treating compound (2') with acid in presence of
water or aqueous solvent or a solvent. The acid can be selected
from inorganic acid or organic acid. Inorganic acid may be selected
from hydrochloric acid, sulfuric acid, and the like. Organic acid
may be selected from acetic acid, para toluene sulfonic acid and
the like. The reaction can be carried out at a temperature of about
20 to 100.degree. C. for about 24 hours.
[0043] In the above reactions the solvent can be selected from
organic polar or non-polar solvent. Polar solvent can be selected
from alcohols like methanol, ethanol, butanol, propanol; nitriles
like acetonitrile, propionitrile, butyronitrile; esters like ethyl
acetate, ethyl acetoacetate, butyl acetate, propyl acetate; ketones
like acetone, methyl ethyl ketone, methyl isobutyl ketone; ethers
like tetrahydrofuran, dioxane, dimethoxyethane; dimethyl ether,
diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1
,2-dimethbxy ethane, tetrahydrofuran, 1,4-dioxane; acids like
acetic acid; other polar solvents like dimethylacetamide,
dimethylformamide, dimethyl sulfoxide, water and mixtures thereof.
Non-polar solvent can be selected from hydrocarbon solvent such as
hexane, heptane, cyclohexane, petroleum ether, benzene, toluene,
xylene and the like; chlorinated hydrocarbons like chloroform,
dichloro methane, ethylene dichloride; or mixtures thereof.
[0044] The base can be selected from inorganic bases or organic
base, the inorganic base can be selected from alkali metal
carbonates such as sodium carbonate, potassium carbonate, lithium
carbonate, cesium carbonate and the like; alkali metal bicarbonates
such as sodium bicarbonate, potassium bicarbonate lithium
bicarbonate, cesium bicarbonate and the like; alkali metal
hydroxides such as sodium hydroxide, potassium hydroxide, lithium
hydroxide and the like; alkali metal alkoxides such as sodium
methoxide, sodium ethoxide, potassium methoxide, potassium
ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium
tert.butoxide and the like; alkali metal hydrides such as sodium
hydride, potassium hydride, lithium hydride and the like; alkali
metal amides such as sodium amide, potassium amide, lithium amide
and the like; ammonia; and the organic base can be selected
fromalkyl and aryl amines such as methylamine, ethylamine,
dimethylamine, diethylamine, diisopropyl amine,
diisopropylethylamine, diisobutylamine, triethylamine,
tributylamine, tert.butyl amine, pyridine, 4-dimethylaminopyridine
or mixtures thereof.
[0045] In the present invention, preparation of compound (2) can be
carried out in stepwise manner, by isolation of the intermediates
or can be carried out in-situ.
[0046] In the present invention, the reaction of pentan-2-one (1)
with a halide source can be carried out in presence of a solvent.
The solvent can be selected from organic polar or non-polar
solvent. Polar solvent can be selected from alcohols like methanol,
ethanol, butanol, propanol; nitriles like acetonitrile,
propionitrile, butyronitrile; esters like ethyl acetate, ethyl
acetoacetate, butyl acetate, propyl acetate; ketones like acetone,
methyl ethyl ketone, methyl isobutyl ketone; ethers like
tetrahydrofuran, dioxane, dimethoxyethane; dimethyl ether,
diisopropyl ether, diethyl ether, methyl tert-butyl ether,
1,2-dimethbxy ethane, tetrahydrofuran, 1,4-dioxane; acids like
acetic acid; other polar solvents like dimethylacetamide,
dimethylformamide, dimethyl sulfoxide, water and mixtures thereof.
Non-polar solvent can be selected from hydrocarbon solvent such as
hexane, heptane, cyclohexane, petroleum ether, benzene, toluene,
xylene and the like; chlorinated hydrocarbons like chloroform,
dichloro methane, ethylene dichloride; or mixtures thereof. The
halide source can be selected from N-chlorosuccimide,
N-bromosuccinimde, N-Iodosuccinimide, sulfuryl chloride and the
like. The reaction can be optionally carried out in presence of
catalyst selected from sodium iodide, sodium bromide and the like.
The compound (2) may be isolated by techniques known in art or may
be used in-situ for further reactions. The reaction can be carried
out at a temperature of 0-5.degree. C. to reflux temperature of the
solvent over a period 30 minutes to 24 hours.
[0047] The reaction of compound (2) with cyclohexane-1,3-dione (3)
can be carried out in presence of a solvent and a base and
optionally in presence of catalyst. The solvent can be selected
from organic polar or non-polar solvent. Polar solvent can be
selected from nitriles like acetonitrile, propionitrile,
butyronitrile; esters like ethyl acetate, ethyl acetoacetate, butyl
acetate, propyl acetate; ketones like acetone, methyl ethyl ketone,
methyl isobutyl ketone; ethers like tetrahydrofuran, dioxane,
dimethoxyethane, dimethyl ether, diisopropyl ether, diethyl ether,
methyl tert-butyl ether, 1,2-dimethbxy ethane, tetrahydrofuran,
1,4-dioxane and the like; other polar solvents like
dimethylacetamide, dimethylformamide, dimethyl sulfoxide, water and
mixtures thereof. Non-polar solvent can be selected from
hydrocarbon solvent such as hexane, heptane, cyclohexane, petroleum
ether, benzene, toluene, xylene and the like; chlorinated
hydrocarbons like chloroform, dichloro methane, ethylene
dichloride; or mixtures thereof.
[0048] The base can be selected from inorganic bases or organic
base, the inorganic base can be selected from alkali metal
carbonates such as sodium carbonate, potassium carbonate, lithium
carbonate, cesium carbonate and the like; alkali metal bicarbonates
such as sodium bicarbonate, potassium bicarbonate lithium
bicarbonate, cesium bicarbonate and the like; alkali metal
hydroxides such as sodium hydroxide, potassium hydroxide, lithium
hydroxide and the like; alkali metal alkoxides such as sodium
methoxide, sodium ethoxide, potassium methoxide, potassium
ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium
tert.butoxide and the like; alkali metal hydrides such as sodium
hydride, potassium hydride, lithium hydride and the like; alkali
metal amides such as sodium amide, potassium amide, lithium amide
and the like; ammonia; and the organic base can be selected
fromalkyl and aryl amines such as methylamine, ethylamine,
dimethylamine, diethylamine, diisopropyl amine,
diisopropylethylamine, diisobutylamine, triethylamine,
tributylamine, tert.butyl amine, pyridine, 4-dimethylaminopyridine
or mixtures thereof.
[0049] The catalyst can be selected from quaternary ammonium salts,
like tetra-n-butylammonium bromide, benzyltriethylammonium
chloride, methyltricaprylammonium chloride, methyltributylammonium
chloride and the like. The reaction can be carried out at a
temperature of 25-30.degree. C. to reflux temperature of the
solvent over a period 30 minutes to 24 hours. The product
2-(2-oxopentan-3-yl)cyclohexane-1,3-dione (4) can be isolated by
techniques known in art or may be used in-situ for further
reactions.
[0050] The cyclization of 2-(2-oxopentan-3-yl)cyclohexane-1,3-dione
(4) to 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (5) can be
carried out in presence of suitable reagent selected from
urea/choline chloride, ammonium acetate, aqueous ammonia,
methanolic ammonia, ammonium chloride or the like in presence of
solvent. The solvent can be selected from organic polar or
non-polar solvent, water or mixtures thereof. Polar solvent can be
selected from alcohols like methanol, ethanol, butanol, propanol;
esters like ethyl acetate, ethyl acetoacetate, butyl acetate,
propyl acetate; ketones like acetone, methyl ethyl ketone, methyl
isobutyl ketone; ether solvents such as ethers like
tetrahydrofuran, dioxane, dimethoxyethane, dimethyl ether,
diisopropyl ether, diethyl ether, methyl tert-butyl ether,
1,2-dimethbxy ethane, tetrahydrofuran, 1,4-dioxane and the like;
nitrile solvents such as acetonitrile, propionitrile,
isobutyronitrile and the like; acids like acetic acid and the like;
other polar solvents like dimethylacetamide, dimethylformamide,
dimethyl sulfoxide, water and mixtures thereof. Non-polar solvent
can be selected from hydrocarbon solvent such as hexane, heptane,
cyclohexane, petroleum ether, benzene, toluene, xylene and the
like; chlorinated hydrocarbons like chloroform, dichloro methane,
ethylene dichloride; or mixtures thereof. The product
2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (5) can be isolated
by techniques known in art.
[0051] The reaction of compound (2) with cyclohexane-1,3-dione (3)
to give 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (5) can be
carried out in presence of R-NH.sub.2, base, solvent and catalyst,
wherein R is H, alkyl or aryl.
[0052] The base is organic base selected from alkyl and aryl amines
such as methylamine, ethylamine, dimethylamine, diethylamine,
diisopropyl amine, diisopropylethylamine, diisobutylamine,
triethylamine, tributylamine, tert.butyl amine, pyridine,
4-dimethylaminopyridine or mixtures thereof. The catalyst is
preferably sulphonic acids on Wang resins, like Wang sulfonic acid
and the like.
[0053] The solvent can be selected from organic polar, organic
non-polar or water. Polar solvent can be selected from alcohols
like methanol, ethanol, butanol, propanol; nitriles like
acetonitrile, propionitrile, butyronitrile; esters like ethyl
acetate, ethyl acetoacetate, butyl acetate, propyl acetate; ketones
like acetone, methyl ethyl ketone, methyl isobutyl ketone; ethers
like tetrahydrofuran, dioxane, dimethoxyethane; dimethyl ether,
diisopropyl ether, diethyl ether, methyl tert-butyl ether,
1,2-dimethbxy ethane, tetrahydrofuran, 1,4-dioxane; acids like
acetic acid; other polar solvents like dimethylacetamide,
dimethylformamide, dimethyl sulfoxide, water and mixtures thereof.
Non-polar solvent can be selected from hydrocarbon solvent such as
hexane, heptane, cyclohexane, petroleum ether, benzene, toluene,
xylene and the like; chlorinated hydrocarbons like chloroform,
dichloro methane, ethylene dichloride; or mixtures thereof.
[0054] The reaction of
2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (5) with morpholine
and formaldehyde can be carried out in presence of solvent selected
fromalcohols like methanol, ethanol, butanol, propanol. The
reaction can be carried out at a temperature of 25-30.degree. C. to
reflux temperature of the solvent over a period 30 minutes to 24
hours. The product molindone can be isolated by techniques known in
art.
[0055] The compound molindone can be optionally converted into
pharmaceutically acceptable salt. The salt can be selected from
hydrochloride, hydro bromide, sulfuric, nitric, phosphoric, oxalic,
tartaric, citric, acetic, succinic, maleic and the like. The salt
formation can be carried out by techniques known in the art.
[0056] In the present invention, the compounds and intermediates
can be isolated by techniques known in the art like filtration,
concentration, crystallization, removal of solvent by evaporation,
distillation, centrifugation, cooling etc.
[0057] The present invention is further illustrated by the
following representative examples and does not limit the scope of
the invention.
EXAMPLES
Example 1: Preparation of methyl
2-chloro-2-ethyl-3-oxobutanoate
[0058] A mixture of methyl acetoacetate (100 g), potassium tertiary
butoxide (101.5 g) and tetrahydrofuran (400 ml) was stirred and a
solution of ethyliodide (141 g) in tetrahydrofuran (200 ml) was
added to it. The reaction mixture was stirred at 60.degree. C. for
about 15 hours. Water (250 ml) was added to the reaction mixture at
25.degree. C. followed by addition of dichloromethane (500 ml). The
organic layer was separated and concentrated. To the concentrate
was added dichloromethane (1000 ml) and sulfuryl chloride (93.7 g)
and the solution was stirred for about 18 hours at 25-30.degree. C.
Water (500 ml) was added to the reaction mixture. The organic layer
was separated and concentrated to give the title compound.
Example 2: Preparation of 3-chloropentan-2-one.
[0059] A mixture of methyl 2-chloro-2-ethyl-3-oxobutanoate (98.8 g)
and water (240 ml) was treated with sulfuric acid (260 g) and
stirred for 90 minutes at 75-80.degree. C. The reaction mixture was
poured into water (500 ml) and dichloromethane (500 ml). The
organic layer was separated and concentrated. The concentrate was
subjected to fractional distillation and pure compound was
collected.
Example 3: Preparation of 3-chloropentan-2-one.
[0060] A mixture of petane-2-one (15 g), acetic acid (60 ml) and
N-chlorosuccinimide (24.4 g) was stirred for about 18 hours at
80-85.degree. C. The reaction mixture was cooled and
dichloromethane (100 ml) was added to it. The mixture was treated
with sodium bicarbonate solution. The organic layer was separated
and concentrated to give the title compound (2).
Example 4: Preparation of 2-(2-oxopentan-3-yl)cyclohexane-1,
3-dione (4).
[0061] A mixture of3-bromopentan-2-one (17 g),
cyclohexane-1,3-dione (11.5 g), triethyl amine (15.6 g) and
acetonitrile (100 ml)) was stirred for about 2 hours at
55-60.degree. C. The reaction mixture was concentrated and ethyl
acetate (170 ml) and water (85 ml) was added. The organic layer
separated and concentrated. The residue was subjected to column
chromatography (ethylacetate: cyclohexane). The title compound was
obtained. .sup.1H NMR (500 MHz, CDCl.sub.3), .delta. 5.14; (S 1H),
.delta. 4.37; (d 1H), .delta. 2.50-2.55; (m 2H) .delta. 2.35-2.38;
(m 2H), .delta. 2.16; (s 3H), .delta. 2.00-2.05; (m 2H) .delta.
1.88-1.90; (m 2H), .delta. 1.00-1.02; (m 3H); .sup.13C NMR (500
MHz,
CDCl.sub.3),206.04,199.34,176.63,103.70,77.12,36.62,28.88,25.44,21.00,16.-
55,9.41 ppm; Dept135 NMR(500 MHz, CDCl.sub.3):
103.70,83.78,36.62,28.87,28.65,25.45,24.69,21.00,9.41ppm; Mass:
[M+1]=197.
Example 5:Preparation of
2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (5)
[0062] A mixture of 2-(2-oxopentan-3-yl)cyclohexane-1, 3-dione
(10g), acetic acid (40 ml) and ammonium acetate (19.6 g) was
stirred for about 3 hours at 95-100.degree. C. The reaction mixture
was cooled and concentrated. To the residue a mixture of ethyl
acetate (60 ml) and water (50 ml) was added. The organic layer
separated and concentrated to give the title compound.
[0063] Example 6: preparation of
2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (5)
[0064] A mixture of cyclohexane-1,3-dione (3 g), dimethyl sulfoxide
(15 ml), triethyl amine (2.7 g) and 3-chloropentan-2-one (3.2 g)
was stirred for about 24 hours at 40-45.degree. C. Aqueous ammonia
(15 ml) was added to the mixture and stirred for about 10 hours at
25-30.degree. C. A mixture of water (60 ml) and ethyl acetate (30
ml) was added to it. The organic layer separated and concentrated.
The residue was subjected to column chromatography (ethyl
acetate/n-hexane). The title compound was obtained.
[0065] Example 7: preparation of molindone hydrochloride.
[0066] A mixture of 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole
(5 g), morpholine (4.42 g), paraformaldehyde (1.52 g) and ethanol
(70 ml) was stirred for about 24 hours at 75-80.degree. C. The
reaction mixture was concentrated and water (50 ml) was added to
the residue. The mixture was treated with concentrated hydrochloric
acid followed by aqueous ammonia in presence of ethyl acetate. The
organic layer was separated and concentrated to obtain molindone as
a residue. Isopropanol hydrochloride was added to the residue and
stirred for 30 minutes at 25-30.degree. C. The solution was
concentrated and ethyl acetate (15 ml) was added. The solid was
filtered, washed with ethyl acetate and dried to obtain molindone
hydrochloride.
* * * * *