Title of Invention

PROCESS FOR PRODUCTION OF OPTICALLY ACTIVE AMINE DERIVATIVES

Abstract A process for producing (S)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b] furan-8-yl) ethylamine or a salt thereof , which comprises step (i) : a step for asymmetrically reducing (E)-2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-ylidene) ethylamine or a salt thereof with a catalyst, and step (ii) : a step for catalytically reducing the reaction product obtained in step (i) at a reaction temperature of 40°C to 100°C and pH 3 to 9 with a catalyst.
Full Text DESCRIPTION
PROCESS FOR PRODUCTION OF OPTICALLY ACTIVE AMINE
DERIVATIVES
Technical Field
The present invention relates to a process for
production of an optically active amine derivative having
high purity, wherein the formation of side products is
suppressed.
Background Art
Although JP-A 11-140073 and JP-A 2002-212063 disclose
a method for producing (S)-2-(1,6,7,8-tetrahydro-2H-
indeno[5,4-b]furan-8-yl)ethylamine hydrochloride by means
of asymmetric reduction from (E)-2-(1,6,7,8-tetrahydro-2H-
indeno[5,4-b]furan-8-ylidene)ethylamine hydrochloride as
starting material, both methods are not enough as an
industrial production method in which the formation of side
products is suppressed and high-purity crystals of (S)-2-
(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine
hydrochloride are produced with high yield. In particular,
problems are to control the side products represented by
the following formulae (III') and (IV').


On the other hand, dimerization of benzofuran compound
under the presence of Pd-catalyst is described in Liebigs.
Ann. Chem., 10,945 (1989) and J. Chem. Soc. (A), 1324
(1968). However, these cases are the dimerization by
binding of two aromatic rings, and the structures of their
dimers are different from those of dimers formed by the
reaction between aromatic ring and benzyl position, like
compound represented by the above formula (IV). In
addition, J. Chem. Soc. D, 736 (1970) discloses that
oxidation of benzyl position of benzofuran compound takes
place under the presence of Pd-catalyst, but formation of
dimer is not described therein.
Disclosure of Invention
The object of the present invention is to provide an
industrial process for production of an optically active
amine derivative with high yield and high purity, wherein
the formation of side products is controlled.

As a result of intensive studies to solve the above
problem, the present inventors found that in the steps of
production of the optically active amine derivative, the
formation of side products represented by the above
formulae (III') and (IV) can be controlled by controlling
pH and temperature of the reaction solution at the time of
catalytic reduction with Pd-C and the solution at the time
of post-treatment thereof, and completed the present
invention.
That is, the present invention provides:
(1) A process for producing (S)-2-(1,6,7,8-tetrahydro-
2H-indeno[5,4-b]furan-8-yl)ethylamine or a salt thereof,
which comprises step (i) : a step for asymmetrically
reducing (E)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-
ylidene)ethylamine or a salt thereof with a catalyst, and
step (ii) : a step for catalytically reducing the reaction
product obtained in step (i) at a reaction temperature of
40°C to 100°C and pH 3 to 9 with a catalyst,
(2) The process according to the above-mentioned (1),
wherein the reaction temperature in step (ii) is 50°C to
70°C,
(3) The process according to the above-mentioned (1),
wherein the pH in step (ii) is 5 to 7,
(4) The process according to the above-mentioned (1),
wherein the catalyst in step (i) is Ru-BINAP catalyst,

(5) The process according to the above-mentioned (1) ,
wherein the catalyst in step (ii) is Pd-C catalyst,
(6) A process for producing crystals of (S)-N-[2-
(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-
yl)ethyl]propionamide, comprising step (a): a step for
propionylating the amino group of (S)-2-(1,6,7,8-
tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine or a salt
thereof obtained in the process according to the above-
mentioned (1) , and step (b) : a step for crystallizing by
adding aqueous solvent to the reaction solution obtained in
step (a),
(7) Crystals of (S)-N-[2-(1,6,7, 8-tetrahydro-2H-
indeno[5,4-b]furan-8-yl)ethyl]propionamide, wherein each
content of the compounds represented by the following
formulae (I), (II), (III) and (IV) is 0.15% by weight or
less, and the total content of the compounds represented by
the following formulae (I) to (IV) is 0.2% by weight or
less,


(8) Crystals of (S)-N-[2-(1,6,7,8-tetrahydro-2H-
indeno[5,4-b]furan-8-yl)ethyl]propionamide, wherein each
content of the compounds represented by the following
formulae (I), (III) and (IV) is 0.15% by weight or less,
and the content of the compound represented by the
following formula (II) is 0.02 to 0.15% by weight, and
further the total content of the compounds represented by
the following formulae (I) to (IV) is 0.2% by weight or
less,


(9) The crystals according to the above-mentioned (7)
or (8), wherein the content of the compound represented by
formula (I) is 0.10% by weight or less,
(10) A composition comprising (S)-N-[2-(1,6,7,8-
tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide
and the compounds represented by the following formulae (I),
(II), (III) and (IV), wherein relative to 100 parts by
weight of (S) -N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-
b]furan-8-yl)ethyl]propionamide, each content of the
compounds represented by the following formulae (I), (II),
(III) and (IV) is 0 to 0.15 part by weight and the total
content of the compounds represented by the following
formulae (I) to (IV) is 0 to 0.2 part by weight,


(11) A composition comprising (S)-N-[2-(1,6,7,8-
tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide
and the compounds represented by the following formulae (I),
(II) , (III) and (IV), wherein relative to 100 parts by
weight of (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-
b] furan-8-yl)ethyl]propionamide, each content of the
compounds represented by the following formulae (I), (III)
and (IV) is 0 to 0.15 part by weight, and the content of
the compound represented by the following formula (II) is
0.02 to 0.15 part by weight, and further the total content
of the compounds represented by the following formulae (I)
to (IV) is 0 to 0.2 part by weight,


(12) The composition according to the above-mentioned
(10) or (11), wherein the content of the compound
represented by formula (I) is 0 to 0.10 part by weight
relative to 100 parts by weight of (S)-N-[2-(1,6,7,8-
tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide,

(13) The crystals according to the above-mentioned (7)
or the composition according to the above-mentioned (10),
which is prepared on a commercial scale,
(14) A process for producing 1,2,6,7-tetrahydro-8H-
indeno[5,4-b]furan-8-one, comprising a step for reducing
4,5-dibromo-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one

with Pd-C catalyst under the condition:
hydrogen pressure (MPa) > -0.02 x gas-liquid overall mass
transfer volume coefficient (1/hr) + 0.43,
(15) Use of the crystals according to the above-
mentioned (7) for the manufacture of a preventive or
therapeutic agent for sleep disorder,
(16) The composition according to the above-mentioned
(10) which is a preventive or therapeutic agent for sleep
disorder, and
(17) A method for the prevention or treatment of sleep
disorder, comprising administering the crystals according
to the above-mentioned (8) or the composition according to
the above-mentioned (10).
Brief Description of Accompanying Drawings
Figure 1 is a HPLC chart which shows result of
analysis of compound (I) to (IV) in the crystals of (S)-N-
[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-
yl)ethyl]propionamide.
Best Mode for Carrying Out the Invention
Examples of the salt of (S)-2-(1,6,7,8-tetrahydro-2H-
indeno[5,4-b]furan-8-yl)ethylamine in the present invention
include salts with an inorganic acid such as hydrochloric
acid, sulfuric acid, and nitric acid, salts with an organic

acid such as formic acid, acetic acid, and trifluoroacetic
acid, and the like.
In addition, (E)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-
b]furan-8-ylidene)ethylamine which is a raw compound to be
used for the production of (S)-2-(1,6,7,8-tetrahydro-2H-
indeno[5,4-b]furan-8-yl)ethylamine or a salt thereof of the
present invention can be produced by a method described in
JP-A 2002-212063, that is, method of catalytically reducing
4,5-dibromo-l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one
with catalytic reduction catalyst such as Pd-C, then
reacting the obtained 1,2,6,7-tetrahydro-8H-indeno[5,4-
b]furan-8-one with diethyl cyanomethylphosphonate, followed
by hydrogenating with cobalt catalyst, or analogous methods
thereto.
In the catalytic reduction step, catalytic reduction
of 4,5-dibromo-l,2,6,7-tetrahydro-8H-indeno[5, 4-b]furan-8-
one can be carried out by mixing 4,5-dibromo-l,2,6,7-
tetrahydro-8H-indeno[5,4-b]furan-8-one, organic solvent,
and if desired, a base, then preferably after displacing
the system with nitrogen, adding catalytic reduction
catalyst thereto, followed by pressurizing with hydrogen
and stirring.
Here, from the viewpoint of formation control of side
product (specifically, dimer), it is preferred that the
reaction should be carried out under the condition of

hydrogen pressure and gas-liquid overall mass transfer
volume coefficient, which meets the inequality:
hydrogen pressure (MPa) > -0.02 x gas-liquid overall mass
transfer volume coefficient (1/hr) + 0.43.
Herein, the gas-liquid overall mass transfer volume
coefficient can be determined with Na2SO3 method as
described in detail in the after-mentioned Example 1.
Further, the hydrogen pressure in the present reaction
is usually 0.1 to 1 MPa, preferably 0.3 to 0.5 MPa.
In gas-liquid system, rate NA in which gas dissolves
in solution per unit contact area can be expressed like in
the case of dissolution rate in solid-liquid system,
extraction rate in liquid-liquid system and transfer
phenomenon in heat transfer by convection, and given in the
form of (mass transfer coefficient) x (concentration
difference).
NA = KL(C1-C) (1)
Here, KL is a mass transfer coefficient for liquid, C1 is a
concentration which is in equilibrium with gas partial
pressure in gas bubble and C is a saturated concentration
at a given time, and (C1-C) is a driving force for gas
absorption.
In addition, given that A is a gas-liquid contact area
and VL is a volume of liquid, since increasing rate VLdC/dt
of gas concentration in solution is equal to dissolution

rate of gas, the following equation can be given.
NAA = VLdC/dt (2)
Thus, equation:
dC/dt = KLA(C1-C)/VL (3)
is derived from formulae (1) and (2).
Furthermore, given that A/VL is represented by a: gas-
liquid interface area per unit area, equation:
dC/dt = KLa(C1-C) (4)
is given.
Since it is difficult to obtain the gas-liquid
interface area: a independently in gas-liquid stirring
operation, mass transfer volume coefficient for liquid KLa
which is a product of a and mass transfer coefficient for
liquid KL is used as an index to express gas absorbability.
In addition, from the fact that when stirring rate is
increased, gas-liquid interface area: a becomes larger, it
can generally be said that KLa becomes larger with stirring
rate.
Examples of the organic solvent used in the present
reaction include formic acid, acetic acid, methanol,
ethanol, N-methylpyrrolidone and the like, and particularly
preferred is methanol. These solvents may be used alone, or
with a mixture of 2 or more of them. The amount of solvent
to be used is 5 to 100 mL, preferably 15 to 25 mL, per 1 g
of raw compound.

Examples of the base used in the present reaction
include anhydrous sodium acetate, Et3N, pyridine, NaHCO3,
Na2CO3, and the like. In particular, anhydrous sodium
acetate and Et3N are preferred. The amount of base to be
used is usually 2 to 3 equivalent moles.
Examples of the catalytic reduction catalyst used in
the present reaction include Pd-C, PtO2, Rh-Al2O3,
(RhCl [P (C6H5) 3] 3) and the like. The amount of catalytic
reduction catalyst to be used is 1/10 equivalent mole to
5/1000 equivalent mole, preferably 1/100 equivalent mole to
3/100 equivalent mole relative to 1 mole of raw compound to
be used in step (i).
The reaction temperature of the present reaction is
usually 10°C to 100°C, preferably 30°C to 50°C, and the
reaction time is usually 1 to 50 hrs, preferably 2 to 10
hrs.
(E)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-
ylidene)ethylamine used in the present invention can be
used in a form of free compound or a salt thereof. Examples
of such salt include a salt with an inorganic acid such as
hydrochloric acid, sulfuric acid, and nitric acid, a salt
with an organic acid such as formic acid, acetic acid, and
trifluoroacetic acid, and the like.
The process for producing (S)-2-(1,6,7,8-tetrahydro-
2H-indeno[5,4-b]furan-8-yl)ethylamine or a salt thereof of

the present invention is comprised of step (i) for
asymmetrically reducing the raw compound: (E)-2-(1,6,7,8-
tetrahydro-2H-indeno[5,4-b]furan-8-ylidene)ethylamine or a
salt thereof, and step (ii) for converting the side product
in the reaction products obtained in step (i) to target
compound by catalytic reduction.
The asymmetric reduction in step (i) is carried out by
using catalyst, and examples of such catalyst for
asymmetric reduction include Ruthenium-optically active
phosphine complex (Ru-BINAP), Rhodium-optically active
phosphine complex (Rh-BINAP), Iridium-optically active
phosphine complex (Ir-BINAP), and the like.
As a Ru-BINAP catalyst, specifically, Ru2Cl4[(R)-
BINAP]2N(C2H5)3, {RuCl (Benzene) [ (R)-BINAP] }C1, {RuCKp-
Cymene)[(R)-BINAP]}C1, {RuBr(p-Cymene)[(R)-BINAP]}Br,
{Rul(p-Cymene)[(R)-BINAP]}I3, {Rul(p-Cymene)[(R)-BINAP]}I
and the like are exemplified. These catalysts can be
prepared according to a known method, for example, methods
described in JP-B 07-57758, JP-A 11-140073, etc.
As an asymmetric reduction catalyst,
{RuCl(Benzene)[(R)-BINAP]}C1 is preferably used.
When a salt of (E)-2-(1,6,7,8-tetrahydro-2H-
indeno[5,4-b]furan-8-ylidene)ethylamine is used as raw
compound in the asymmetric reduction reaction of step (i) ,
it is converted to a free compound by alkali treatment,

dissolved in organic solvent, and asymmetric reduction
catalyst is added to the solution, and then the asymmetric
reduction reaction is carried out under pressure and
hydrogen atmosphere.
Examples of the organic solvent include aromatic
hydrocarbons (e.g., toluene, benzene, etc.), alcohols (e.g.,
methanol, ethanol, etc.), aliphatic esters (ethyl acetate,
n-propyl acetate, n-butyl acetate, etc.), ethers (e.g.,
isopropyl ether, diethyl ether, tetrahydrofuran (THF),
etc.), halogenated hydrocarbons (e.g., dichloromethane,
dichloroethane, etc.), amides (e.g., N,N-dimethylformamide,
etc.), and the like. These solvents may be used alone, or
with a mixture of 2 or more of them, and among them, a
mixed solvent of toluene and methanol, a mixed solvent of
tetrahydrofuran and methanol, and the like are preferred.
The amount of solvent to be used is 1 to 1000 mL,
preferably 2 to 20 mL, per 1 g of raw compound.
The amount to be added of the asymmetric reduction
catalyst used in the present reaction is 1/2 equivalent
mole to 1/2000 equivalent mole, preferably 1/10 equivalent
mole to 1/1000 equivalent mole relative to 1 mole of raw
compound, and the hydrogen pressure is 0.5 to 15 MPa,
preferably 3 to 11 MPa.
In addition, the reaction temperature is 0 to 150°C,
preferably 10 to 80°C, and the reaction time is 0.5 to 200

hrs, preferably 5 to 50 hrs.
The catalytic reduction reaction of the above-
mentioned step (ii) is carried out using the reaction
solution obtained in step (i) . In the reaction solution
obtained in step (i) , the compound represented by the
following formula (III') is included as side product, and
in the step (ii) , this side product is converted by the
catalytic reduction to the target compound, that is, (S)-2-
(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine.

The reaction of the above-mentioned step (ii) is
carried out as follows. That is, to the reaction solution
obtained in step (i) is added enough amount of dilute
hydrochloric acid to dissolve the reaction product at a
temperature below 10CC, and the reaction product is
transferred to aqueous layer by stirring or shaking, then
the aqueous layer is separated. The obtained aqueous layer
is adjusted to pH 3 to 9, preferably 5 to 7, with aklali
such as dilute aqueous sodium hydroxide solution, and
catalytic reduction catalyst is added thereto to reduce
under pressure and hydrogen atmosphere.
Examples of the catalytic reduction catalyst used in

the present reaction include Pd-C, PtO2, Rh-Al2O3,
(RhCl[P(C6H5)3]3) , and the like. The amount of catalytic
reduction catalyst to be used is 1/2 equivalent mole to
1/2000 equivalent mole, preferably 1/10 equivalent mole to
1/500 equivalent mole relative to 1 mole of raw compound to
be used in step (i), and the hydrogen pressure is 0.5 to 15
MPa, preferably 3 to 11 MPa.
In addition, the reaction temperature is 40°C to 100°C,
preferably 50°C to 70°C, and the reaction time is 0.5 to
200 hrs, preferably 3 to 20 hrs.
The reaction solution obtained in the catalytic
reduction reaction is filtered to remove the catalyst, and
treated using a method known per se (e.g., concentration,
crystallization, recrystallization, chromatography, etc.)
to give (S)-2-(1, 6, 7, 8-tetrahydro-2H-indeno[5,4-b]furan-8-
yl)ethylamine.
Furthermore, the resulting (S)-2-(1,6,7,8-tetrahydro-
2H-indeno[5,4-b]furan-8-yl)ethylamine can be converted to a
desired salt according to a conventional method.
When the reaction and the post-treatment of the above-
mentioned step (ii) are carried out without pH control,
that is, under a strongly acidic condition below about pH 1,
the above-mentioned benzofuran derivative (III1) is formed
with about 5 to 10% and dihydrobenzofuran dimer (IV) is
formed with about 0.2%, which are side products. In

contrast, the production amount of these side products can
be suppressed to below 0.07%, and to below 0.02%,
respectively, by carrying out under the condition of pH 3
to 9, preferably pH 5 to 7 of the present invention.
The process for producing a crystal of (S)-N-[2-
(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-
yl)ethyl]propionamide of the present invention will be
described below. The process is comprised of step (a) for
propionylating the amino group of (S)-2-(1,6,7,8-
tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine, and step
(b) for crystallizing out of the reaction solution obtained
in step (a). Namely, in step (a), the amino group of (S)-2-
(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine
obtained in the above-mentioned process is reacted with a
propionylating agent to propionylate. When the raw material,
(S)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-
yl)ethylamine is used in the form of salt, it is converted
to free compound by a conventional method, followed by
subjecting to propionylation reaction. Examples of the
propionylating agent include propionyl halides such as
propionyl chloride and propionyl bromide. The amount of
propionylating agent to be used is a ratio of 1 - 2 mol to
1 mol of (S)-2-(l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-
yl)ethylamine.
The reaction is carried out in a solvent, and examples

of the solvent include ethers such as tetrahydrofuran,
diethyl ether, dioxane and 1,2-dimethoxyethane, alcohols
such as methanol, ethanol and propanol, hydrocarbons such
as benzene, toluene, cyclohexane and hexane, amides such as
N,N-dimethylformamide and N,N-dimethylacetamide,
halogenated hydrocarbons such as dichloromethane,
chloroform, carbon tetrachloride and 1,2-dichloroethane,
nitriles such as acetonitrile and propionitrile, sulfoxides
such as dimethylsulfoxide, and the like and a mixed solvent
thereof, inter alia, tetrahydrofuran is preferred. The
reaction time is usually 5 minutes to 48 hrs, preferably 30
minutes to 6 hrs. The reaction temperature is usually -20
to 200°C, preferably -10 to 50°C.
In step (b), crystals of (S)-N- [2-(1,6,7,8-tetrahydro-
2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide is
crystallized by adding aqueous solvent to the reaction
solution obtained in step (a) . Examples of the aqueous
solvent include city water, pure water, purified water, etc.
The amount of aqueous solvent to be added is a ratio by
volume of 0.5 - 5 to the reaction solution obtained in step
(a). The crystallization temperature is usually -20 to 60°C,
preferably -10 to 40°C.
The crystals of (S)-N-[2-(1,6,7,8-tetrahydro-2H-
indeno[5,4-b]furan-8-yl)ethyl]propionamide is obtained with
high yield of 97% by collecting the precipitated crystals

by filtration. Highly pure crystals of (S)-N-[2-(1,6,7,8-
tetrahydro-2H-indeno[5, 4-b]furan-8-yl)ethyl]propionamide
can be obtained by further recrystallizing the obtained
crystals from ethanol-water (1:2).
Although the crystals of (S)-N-[2-(1,6,7,8-tetrahydro-
2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide obtained in
the process of the present invention may have a possibility
of containing the compounds represented by the following
formulae (I) to (IV) as impurities (in the present
specification, hereinafter, sometimes referred to as
compound (I) to (IV), respectively), each content of the
compounds (I) to (IV) is 0.15% by weight or less and
further total content of the compounds (I) to (IV) is about
0.20% by weight or less.

For example, in the crystals of (S)-N-[2-(1,6,7,8-

tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide obtained in the process
of the present invention, the contents of compound (III) and (IV) are each below the
detection limit of less than 0,02% by weight (HPLC), the content of compound (I) is
about 0.1% by weight or less (preferably, 0.3% by weight or less), and the content of
compound (II) is about 0.02 to about 0.15% by weight, and further total content of
the compounds (I) to (IV) is about 0.20% by weight or less.
As described above, higher-quality crystals of (S) -N-[2-(l,6,7,8-tetrahydro-2H-
indeno[5,4-b]furan-8-yl)ethyl]propionamide can be produced by controlling the
content of impurities, and as a result, improvement of crystallinity accompanied with
improvement of purity, improvement of stability and the like are expected.
Furthermore, when (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-
yl)ethyl]propionamide is used as medicine, reduction of impurities has extremely
significant meaning from the viewpoint of quality assurance to patients. According
to the present invention, such crystals can be produced on a commercial scale. In
addition, by using such crystals, the composition of the present invention can be

manufactured according to a known method.
(S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-
yl)ethyl]propionamide of the present invention has a
physiological activity such as affinity for melatonin
receptor, in addition, has low toxicity and fewer side
effects. Therefore, it can be used for preventing and
treating sleep-wakefulness dysrhythmia, jet lag, biorhythm
upset due to work in three shifts etc., seasonal
melancholia, disease of reproduction and neuroendocrine,
senile dementia, Alzheimer's disease, various diseases
accompanied with aging (e.g., prevention of aging etc.),
cerebral circulation disorder (cerebral apoplexy etc.),
head injury, bone marrow injury, stress, epilepsy,
convulsion, anxiety, depression, Parkinson's disease,
hypertension, glaucoma, cancer, insomnia, diabetes, cluster
headache, and the like, and furthermore, it is also
effective for immunomodulation, nootropism, mental
stabilization and ovulation adjustment (e.g.,
contracepyion).
The compounds of the present invention can be used in
combination with antidepressant (e.g., imipramine,
clomipramine, noxiptiline, phenelzine, amitriptyline
hydrochloride, nortriptyline hydrochloride, amoxapine,
mianserin hydrochloride, maprotiline hydrochloride,
sulpiride, fluvoxamine maleate, trazodone hydrochloride,

paroxetine hydrochloride, milnacipran hydrochloride,
fluoxetine, venlafaxine, Mitrazapine, Sertraline,
citalopram, duloxetine, reboxetine, Moclobemide),
antianxiety drug (e.g., diazepam, oxazolam, bromazepam,
alprazolam, clonazepam, buspirone, tandospirone citrate),
mood stabilizer (e.g., lithium, valproic acid,
carbamazepine), antidementia drug (e.g., tacrine, donepezil,
rivastigmine, galantamine, memantine), antipsychotic drug
(e.g., haloperidol, olanzapine, risperidone, quetiapine,
ziprasidone, chlorpromazine, sulpiride, Aripiprazole),
antiepileptic drug (e.g., phenobarbital, gabapentin,
tiagabin, pregabalin) , cerebral circulation improving drug,
brain metabolic stimulant, and the like.
Examples of administration form include (1)
administration of a single preparation obtained by
formulating the compound of the present invention and the
joint use drug simultaneously, (2) simultaneous
administration of two kinds of preparations obtained by
formulating the compound of the present invention and the
joint use drug separately, via an identical administration
route, (3) sequential and intermittent administration of
two kinds of preparations obtained by formulating the
compound of the present invention and the joint use drug
separately, via an identical administration route, (4)
simultaneous administration of two kinds of preparations

obtained by formulating the compound of the present
invention and the joint use drug separately, via different
administration routes and (5) sequential and intermittent
administration of two kinds of preparations obtained by
formulating the compound of the present invention and the
joint use drug separately, via different administration
routes (e.g. administration in an order of the compound of
the present invention — the joint use drug, or
administration in a reverse order). A dose of the joint use
drug can be selected appropriately based on the clinically
used dosage. In addition, a ratio of blending the compound
of the present invention and the joint use drug can be
appropriately selected depending on an administration
subject, an administration route, subject disease, symptom,
a combination, and the like. For example, when the
administration subject is human, 0.01 to 100 parts by
weight of the joint use drug can be used relative to 1 part
by weight of the compound of the present invention.
(S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno[5, 4-b]furan-8-
yl)ethyl]propionamide of the present invention can be used
as a pharmaceutical raw material with grinding by Jet mil
etc., and a content uniformity in preparation and the like
can be assured by adjusting the particle size (median size)
to about 1 to 10 urn.
The particle size can be measured as follows by using

commercially available measuring apparatus.
A 100 mL Erlenmeyer flask equipped with stopper is
charged with 0.05 g of sample, and 50 mL of dispersion
medium is added thereto. The mixture is irradiated with
ultrasonic wave for about 5 minutes with shaking and mixing
to give a suspension. To 40 mL of dispersion medium is
added about 100 uL of this suspension, and a test is
carried out under the following condition.
[Dispersion medium]
0.1% sodium lauryl sulfate solution saturated with (S)-N-
[2- (1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-
yl)ethyl]propionamide
[Apparatus]
HELOS system KF (Sympatec GmbH)
HELOS sensor
CUVETTE dispersion unit (wet disperser)
HELOS standard software: WINDOX 3.2 (for Windows) or
equivalent
[Condition for measurement]
Focal length: 100 mm
Stirring speed: 50%
Sampling time: 1 second
Measurement time: 10 seconds
The compound of the present invention can be safely
administered orally or parenterally (e.g. local, rectal,

intravenous administration etc.) as it is or by formulating
into pharmaceutical preparations such as tables (including
sugar-coated tablets, film coating tablets), powders,
granules, capsules, solutions, emulsions, suspensions,
injectables, suppositories, sustained-release agents and
adhesive preparations by mixing with a pharmacologically
acceptable carrier according to a conventional method (e.g.,
method described in Japanese Pharmacopoeia, etc.). A
content of the compound in the pharmaceutical composition
is usually about 0.01 to 100% by weight based on the whole
composition.
The present invention will be further explained in
detail by way of the following Reference Examples and
Examples, but the present invention is not limited to these
Examples. In addition, each abbreviation in the Reference
Examples and Examples has the following meanings.
DBF: 2,3-dihydrobenzofuran
FBA: 2,3-dihydrobenzofuran-5-carbaldehyde
PPN: ethyl (E)-3-(2,3-dihydrobenzofuran-5-yl)propenoate
PPE: ethyl 3-(2,3-dihydrobenzofuran-5-yl)propionate
DBA: 3-(6,7-dibromo-2,3-dihydrobenzofuran-5-yl)propi onic
acid
BIF: 4,5-dibromo-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-
8-one
THI: 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one

ICN: (E)-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-
ylidene)acetonitrile
EAI-HC1: (E)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-
ylidene)ethylamine hydrochloride
(S)-AMI-HC1: (S)-2-(1,6,7,8-tetrahydro-2H-indeno [5,4-
b]furan-8-yl)ethylamine hydrochloride
Reference Example 1
2,3-Dihydrobenzofuran-5-carbaldehyde

2,3-Dihydrobenzofuran (100 g, 832 mmol) and N,N-
dimethylformamide (134 g, 1830 mmol) were mixed and heated,
and phosphorus oxychloride (255 g, 1643 mmol) were added
thereto at an inner temperature of 70 to 80°C over 2 hrs.
The reaction mixture was heated at an inner temperature of
80 to 90°C and stirred for 7.5 hrs. Then, the resulting
mixture was added dropwise to water (1000 g) under cooling,
and stirred at room temperature for 5 hrs. The resulting
mixture was extracted with toluene, and the extract was
washed sequentially with water, saturated sodium
bicarbonate aqueous solution and water, and the organic
layer was concentrated under vacuum to give a toluene
solution of the title compound (amount 340 g, apparent

yield 100%).
Reference Example 2
Ethyl (E)-3-(2,3-dihydrobenzofuran-5-yl)propenoate

To the solution (340 g) of 2,3-Dihydrobenzofuran-5-
carbaldehyde (832 mmol) in toluene obtained in the above
step was added dropwise triethyl phosphonoacetate (205 g,
916 mmol) under cooling. Then, a suspension of sodium t-
butylate (88.0 g, 1187 mmol) in toluene (530 g) was added
dropwise, and stirred for 1 hr, and further acetic acid (20
g) and water (500 g) were added dropwise thereto. The
reaction mixture was warmed to room temperature, and
separated the layers. The organic layer was washed
sequentially with saturated sodium bicarbonate aqueous
solution and water, and the organic layer was concentrated
to below 300 mL under vacuum. Then to the residue was added
methanol (396 g) to heat and dissolve. To the solution was
added dropwise water (500 g) at room temperature, and
stirred to deposit crystals, which was collected by
filtration and dried under reduced pressure to give title
compound (amount 161 g, yield 88.1%).

Reference Example 3
Ethyl 3-(2,3-dihydrobenzofuran-5-yl)propionate

Ethyl (E)-3-(2,3-dihydrobenzofuran-5-yl)propenoate
(50.0 g, 227 mmol) was dissolved in acetic acid (312 g) ,
and the reaction system was replaced with nitrogen. Then,
5% Pd/C (4.96 g, as dry weight) was added to the solution
and pressurized with hydrogen to 196 to 294 kPa. The
mixture was reacted at 50°C for 1 hr under a pressure of
196 to 294 kPa. The catalyst was filtered, and washed with
acetic acid (208 g) to give a solution of the title
compound in acetic acid (amount 569 g, apparent yield 100%) .
Reference Example 4
3-(6,7-Dibromo-2,3-dihydrobenzofuran-5-yl)propionic acid

To the solution of PPE in acetic acid (569 g, 227
mmol) obtained in the above step was added anhydrous sodium
acetate (18.6 g) , and bromine (222 g) was added dropwise
thereto under stirring and cooling over 2 hrs. After

reacting for 4 hrs at room temperature, the reaction
mixture was added dropwise to a cooled 15% aqueous solution
of sodium sulfite (670 niL) , and stirred for 30 minutes. To
the reaction solution was added acetonitrile (118 g) , and
reacted for 2 hrs with heating under reflux, then cooled
gradually and stirred for 1 hr to crystallize. The crystals
were collected by filtration, washed with water, and dried
under vacuum to give title compound (amount 63.3 g, yield
73.2%).
Reference Example 5
4,5-Dibromo-l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one

3-(6,7-Dibromo-2,3-dihydrobenzofuran-5-yl)propionic
acid (40.0 g, 114 mmol), o-dichlorobenzene (182 g) and N,N-
dimethylformamide (0.1 g) were mixed, and thionyl chloride
(17.7 g, 149 mmol) was added dropwise thereto at inner
temperature of 42°C, followed by stirring for 30 to 40
minutes to give a solution of acid chloride. Then, to the
solution was added anhydrous aluminium chloride (17.5 g,
132 mmol) in several portions under ice-cooling, and
stirred for 30 minutes. Methanol (475 g) was prepared

separately, and the reaction solution was added dropwise to
the methanol to crystallize. To the crystallization
solution was added dropwise water (76 g) under cooling, and
stirred for 30 minutes. The crystals were collected by
filtration, and the wet crystals were washed sequentially
with methanol, water, saturated aqueous solution of sodium
bicarbonate, water, and methanol, followed by drying under
vacuum to give 31.6 g of title compound (yield 92.2%).
Example 1
1,2,6,7-Tetrahydro-8H-indeno[5,4-b]furan-8-one

(1) 4,5-Dibromo-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-
one (280 kg, 843mol), anhydrous sodium acetate (173 kg,
2109 mol), methanol (6384 L) were mixed, and the reaction
system was replaced with nitrogen. Then, to the reaction
mixture was added 10% Pd/C (30.8 kg, as dry weight), and
pressurized with hydrogen to 0.29 to 0.49 MPa, and
catalytically reduced at about 40°C for 8 hrs with stirring
at such a stirring rate that the gas-liquid overall mass
transfer coefficient KLa(l/hr) is about 15. The catalyst
was filtered, and the filtrate was concentrated under
reduced pressure, and further water was added to the

residue, followed by concentrating under reduced pressure
to substitute the solvent, cooling and stirring for 1 hr to
mature. The crystallization solution was filtered to give
wet crystals of title compound (amount 127 kg as dry weight,
yield 86.6%). The content of dimer in the wet crystals was
less than 0.1% by weight.
(2) Purification step
Wet crystals (127 kg as dry weight) , activated
charcoal (6 kg, Shirasagi A: trade name) and methanol (1723
L) were mixed, and stirred for 1 hr under reflux, and
filtered. The filtrate and washings were concentrated under
reduced pressure, then, the residue was refluxed for 1 hr
and cooled. Water (306 L) was added thereto under cooling,
matured for 1 hr, and the precipitate was collected by
filtration, followed by drying under reduced pressure to
give title compound (amount 117 kg, yield 92.1%).
(3) Gas-liquid overall mass transfer coefficient
Here, the gas-liquid overall mass transfer coefficient
was determined by Na2SO3 method.
1) Na2SO3 method (sodium sulfite method)
(a) Principle
Sodium sulfite (Na2SO3) , in an aqueous solution
thereof, converts to sodium sulfate (Na2SO4) by reacting
with oxygen which was incorporated from air. The reaction
rate is sufficiently fast compared to absorption rate of

oxygen (oxygen absorption is rate-determining step).
Therefore, oxygen absorption rate (NA) can be obtained by
measuring the concentration change of sodium sulfite.
Now, the gas-liquid overall mass transfer volume
coefficient KLa is defined by the following equation.
NA = KLa(C*-C)
Since actually in this measurement system,
concentration of dissolved oxygen in the aqueous solution
of sodium sulfite can be deemed as 0, the following
equation is given.
KLa = NA/C*
On the other hand, solubility of oxygen in aqueous solution
can be expressed by the following, using Henry's law.
C* = p/H
From these, KLa can be calculated.
In addition, symbols in the above equation have the
following meanings.
KLa: gas-liquid overall mass transfer volume coefficient
[1/Hr]
NA: oxygen absorption rate [mol/L-Hr]
C: oxygen concentration in liquid [mol/L]
C*: solubility of oxygen in saturation [mol/L]
p: partial pressure of oxygen in gas phase [Pa]
H: Henry constant [Pa-L/Hr]
(b) Measurement method

(i) Pure water (475 ml, same liquid volume as feed scale of
BIF 23.34 g) is charged into 1 L autoclave (Glass Reactor,
TEM-V-1000 type).
(ii) Na2SO3 (9.5 g) is added thereto, and mixed for about 2
minutes to dissolve.
(iii) A prepared 0.1 mol/L CuSO4 solution (4.75 ml) is
added to the aqueous solution of Na2SO3 (CuSO4 concentration
after the addition = 1x10-3 M) , and the reaction solution is
stirred slowly for 1 minute (reaction initiation).
(iv) Immediately, 10 ml of the dissolution solution is
precisely sampled, and titrated according to the procedure
of the following (c) . (titration volume = T1 [ml] )
(v) The reaction solution is stirred with a given rotation
rate for a given time ∆θ (= 1.0 [Hr] ) . At this time, a
certain amount of air is streamed into the upper of the
vessel to prevent decrease in partial pressure of oxygen in
gas phase in autoclave (about 200 ml/L).
(vi) 10 ml is precisely sampled from the solution of (v) ,
and titrated according to the procedure of the following
(c) . (titration volume = T2 [ml] )
(vii) From the result of titration, oxygen absorption rate
NA is calculated according to the following equation. Here,
F represents a factor of N/10 iodine solution reagent.


(c) Titration method (method for titration of sodium
sulfite)*1
(i) A 200 ml Erlenmeyer flask containing pure water (100 m),
acetic acid-sodium acetate buffer*2 (10 ml) , and N/10
iodine solution reagent (40 ml) is prepared beforehand,
(ii) Sample solution (10 ml) is added thereto gently,
(iii) After about 5 minutes, the sample solution is
titrated with N/10 sodium thiosulfate solution using a
starch solution*3 (0.5 - 1 ml) as an indicator.
*1: Titration principle is based on that after
oxidizing sulfite radical existing in the sample solution
with iodine, the remaining iodine is titrated with sodium
thiosulfate, and each step can be represented by the
following reaction formula.
oxidation of sulfite radical: Na2SO3 + I2 + H2O - 2NaI +
H2SO4
titration of iodine: I2 + 2Na2S2O3 - 2NaI + Na2S4O6
*2: 75 g of sodium acetate (CH3COONa-3H2O) is dissolved
in 500 ml of aqueous acetic acid (CH3COOH : H2O = 1 : 2) .
*3: 1.0 g of starch is scrubbed and mixed with 10 ml
of water, and the resulting mixture is fed into 200 ml of
hot water. After boiling until this turns into semi-
transparent, it is left to cool.
Reference Example 6

(E)-(1,6,7,8-Tetrahydro-2H-indeno[5,4-b]furan-8-
ylidene)acetonitrile

To a solution of toluene (184 g) , 1,2,6,7-tetrahydro-
8H-indeno[5,4-b]furan-8-one (8.5 g, 48.9 mmol) and diethyl
cyanomethylphosphonate (10.4 g, 58.7 mmol) was added
dropwise 28% sodium methoxide solution in methanol (11.3 g)
over 1 hr under ice-cooling, and reacted for 4 hrs. To the
reaction solution was added dropwise water (85 g), and
warmed, then the layers were separated. The organic layer
was washed with water, and filtered to remove dusts under
pressurization. The organic layer was concentrated under
reduced pressure, and to the residue was added methanol and
concentrated under reduced pressure to substitute the
solvent. After stirring for 1 hr under heating with reflux,
the solution was cooled and matured for lhr. The
crystallization solution was filtered, and the crystals
were dried under reduced pressure to give title compound
(amount 8.1 g, yield 84.4%).
Reference Example 7
(E)-2-(1,6,7,8-Tetrahydro-2H-indeno[5,4-b]furan-8-

ylidene)ethylamine hydrochloride

To a mixed suspension of (E)-(1,6,7,8-tetrahydro-2H-
indeno[5,4-b]furan-8-ylidene)acetonitrile (10.0 g, 50.7
mmol) in toluene (37.5 mL) and methanol (12.5 mL) were
added activated cobalt (7.22 g) and 14.4% aqueous solution
of potassium hydroxide (1.4 g), and stirred for 6.5 hrs at
34 to 50°C under hydrogen atmosphere (0.2 MPa). The
reaction solution was filtered, and to the filtrate were
added toluene (170 mL) and methanol (35 mL) to separate the
layers. 0. 5N Hydrochloric acid (101 mL) was added to the
organic layer, and stirred for 30 minutes at 25 to 30°C.
Then, the layers were separated, and active charcoal (1 g)
was added to the aqueous layer, followed by stirring. The
active charcoal was removed by filtration to give an
aqueous solution of title compound (246 g, Net 12.0 g,
yield 99.6%).
Example 2
(S)-2- (1,6,7,8-Tetrahydro-2H-indeno[5,4-b]furan-8-
yl)ethylamine hydrochloride


To an aqueous solution of (E)-2-(1,6,7,8-tetrahydro-
2H-indeno[5,4-b]furan-8-ylidene)ethylamine hydrochloride
(1979 kg, Net 122kg, 513 mol) were added toluene (532 L)
and 5% aqueous solution of sodium hydroxide (456 L) , and
stirred. The layers were separated, and to the organic
layer were added methanol (155 kg) and [RuCl (bebzene) (R)-
BINAP]C1 (894 g) under nitrogen atmosphere, followed by
stirring at 80°C for 15 hrs under hydrogen atmosphere (4.9
MPa) . The reaction solution was cooled, and water (330 L)
and concentrated hydrochloric acid (52.3 kg) were added at
below 30°C, followed by stirring for 30 minutes, then the
layers were separated. The aqueous layer was washed with
toluene (195 L), and pH was adjusted to about 6.0 by adding
5% aqueous solution of NaOH to the aqueous layer
(containing 5.0% of compound III'). 5% Pd-C (50% wet, 9.7
kg) was added thereto, and stirred at 60 °C for 6 hrs under
hydrogen atmosphere (4.9 MPa). The reaction mixture was
filtered, and the filtrate was adjusted to around pH 6.0
with 5% aqueous solution of NaOH or dilute hydrochloric
acid, followed by concentration under reduced pressure. The
residue was recrystallized from mixed solution of n-butanol

and water to give title compound (88.6 kg, yield 73.0%,
compound (III') is not detected, compound (IV) is not
detected).
In addition, the content of compound (III') and
compound (IV) (dimer) in the obtained crystals of the
title compound was determined by HPLC under the following
condition.
detector: ultraviolet absorptiometer (wavelength for
measurement: 220 nm)
column: Develosil UG-3, 4.6 mmi.d.x75 mm
column temperature: given temperature around 25°C
mobile phase: mixed solution of 0.1 mol/L potassium
dihydrogenphosphate (pH 3.0)/methanol (75 : 25)
Example 3
(i) (S)-N-[2-(1,6,7,8-Tetrahydro-2H-indeno[5,4-b]furan-8-
yl)ethyl]propionamide

To a mixed solution of (S)-2-(1,6,7,8-tetrahydro-2H-
indeno[5,4-b]furan-8-yl)ethylamine hydrochloride (74 kg,
309 mol) in tetrahydrofuran (185 L) and city water (259 L)
were added 30% aqueous solution of sodium hydroxide (70 L)

and propionyl chloride (32.8 kg), and stirred at room
temperature for 1 hr. To the reaction solution was added
city water (592 L) , and cooled. The precipitated crystals
were collected by filtration, and dried under reduced
pressure to give title compound (78.0 kg, yield 97.4%).
(ii) Purification step
The crystals (77.3 kg, 298 mol) obtained in (i) were
dissolved in mixed solution (178 kg) of ethanol and
purified water (10 : 1), and active charcoal (0.78 kg) was
added thereto, then stirred for 10 minutes, followed by
filtration (washed with mixed solution (74 kg) of ethanol
and purified water (10 : 1) ) . To the filtrate was added
water (588 L) under warming, cooled, and the precipitated
crystals were collected by filtration, which were dried
under reduced pressure. The resulting crystals were
pulverized with jet mil to give title compound (74.0 kg,
yield 95.7%, compound (I) 0.02%, compound (II) 0.06%,
compound (III) and (IV) less than 0.02%, total analogous
material 0.08%) .
(iii) Analysis condition
The content of compound (I) to (IV) in the crystals of
the title compound obtained in (ii) was determined by HPLC
under the following condition.
detector: ultraviolet absorptiometer (wavelength for
measurement: 288 nm)

column: YMC-Pack ODS-AM AM-302.5pm, 4.6 mm i.d.xl50 mm
(manufactured by YMC)
column temperature: given temperature around 25°C
mobile phase: A; mixed solution of 0.01 mol/L phosphate
buffer (pH 7.0)/acetonitrile (4 : 1)
B; mixed solution of 0.01 mol/L phosphate

Resulting HPLC chart was shown in Figure 1. As obvious
from Figure 1, compound (I) and (II) were detected at each
side of main peak of (S)-N-[2-(1,6,7,8-tetrahydro-2H-
indeno[5,4-b]furan-8-yl)ethyl]propionamide, however,
compound (III) and (IV) were each below the detection limit
of less than 0.02%.
Industrial Applicability
According to the process of the present invention, by
controlling the pH of reaction solution in catalytic
reduction step and post-treatment solution thereof, highly
pure optically active amine derivatives which are useful as
medicine can be produced with high yield, and high-quality

pharmaceutical raw materials can be provided industrially.

We Claim;
1. A process for producing (S)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b] furan-8-yl)
ethylamine or a salt thereof, which comprises step (i) : a step for asymmetrically
reducing (E)-2-(1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-ylidene) ethylamine
or a salt thereof with a catalyst, and step (ii) : a step for catalytically reducing the
reaction product obtained in step (i) at a reaction temperature of 40°C to 100°C and
pH 3 to 9 with a catalyst.
2. The process as claimed in claim 1, wherein the reaction temperature in step (ii) is
50°C to 70°C.
3. The process as claimed in claim 1, wherein the pH in step (ii) is 5 to 7.
4. The process as claimed in claim 1, wherein the catalyst in step (i) is Ru-BINAP
catalyst.
5. The process as claimed in claim 1, wherein the catalyst in step (ii) is Pd-C catalyst.
6. A process for producing crystals of (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]
furan-8-yl) ethyl] propionamide, comprising step (a) : a step for propionylating the
amino group of (S)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b] furan-8-yl) ethylamine
or a salt thereof obtained in the process as claimed in claim 1, and step (b) : a step
for crystallizing by adding aqueous solvent to the reaction solution obtained in
step(a).


A process for producing (S)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b] furan-8-yl) ethylamine
or a salt thereof , which comprises step (i) : a step for asymmetrically reducing (E)-2-
(1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-ylidene) ethylamine or a salt thereof with a
catalyst, and step (ii) : a step for catalytically reducing the reaction product obtained in step
(i) at a reaction temperature of 40°C to 100°C and pH 3 to 9 with a catalyst.

Documents:

00831-kolnp-2007-correspondence-1.1.pdf

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00831-kolnp-2007-international search authority report-1.1.pdf

00831-kolnp-2007-priority document-1.1.pdf

0831-kolnp-2007 abstract.pdf

0831-kolnp-2007 assignment.pdf

0831-kolnp-2007 claims.pdf

0831-kolnp-2007 correspondence others.pdf

0831-kolnp-2007 description(complete).pdf

0831-kolnp-2007 drawings.pdf

0831-kolnp-2007 form-1.pdf

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0831-kolnp-2007 international publication.pdf

0831-kolnp-2007 international search authority report.pdf

0831-kolnp-2007 pct form.pdf

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0831-kolnp-2007 priority document.pdf

831-KOLNP-2007-ABSTRACT 1.1.pdf

831-KOLNP-2007-AMANDED CLAIMS.pdf

831-KOLNP-2007-CORRESPONDENCE 1.1.pdf

831-KOLNP-2007-CORRESPONDENCE-1.2.pdf

831-KOLNP-2007-CORRESPONDENCE.pdf

831-KOLNP-2007-DESCRIPTION (COMPLETE) 1.1.pdf

831-KOLNP-2007-DRAWINGS 1.1.pdf

831-KOLNP-2007-EXAMINATION REPORT.pdf

831-KOLNP-2007-FORM 1-1.1.pdf

831-KOLNP-2007-FORM 13.1.pdf

831-KOLNP-2007-FORM 13.pdf

831-KOLNP-2007-FORM 18.1.pdf

831-kolnp-2007-form 18.pdf

831-KOLNP-2007-FORM 2-1.1.pdf

831-KOLNP-2007-FORM 3-1.1.pdf

831-KOLNP-2007-FORM 3.pdf

831-KOLNP-2007-FORM 5-1.1.pdf

831-KOLNP-2007-FORM 5.pdf

831-KOLNP-2007-FORM-27.pdf

831-KOLNP-2007-GPA.pdf

831-KOLNP-2007-GRANTED-ABSTRACT.pdf

831-KOLNP-2007-GRANTED-CLAIMS.pdf

831-KOLNP-2007-GRANTED-DESCRIPTION (COMPLETE).pdf

831-KOLNP-2007-GRANTED-DRAWINGS.pdf

831-KOLNP-2007-GRANTED-FORM 1.pdf

831-KOLNP-2007-GRANTED-FORM 2.pdf

831-KOLNP-2007-GRANTED-SPECIFICATION.pdf

831-KOLNP-2007-OTHERS 1.1.pdf

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831-KOLNP-2007-PETITION UNDER RULE 137-1.1.pdf

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831-KOLNP-2007-REPLY TO EXAMINATION REPORT-1.1.pdf

831-KOLNP-2007-REPLY TO EXAMINATION REPORT.pdf

831-KOLNP-2007-TRANSLATED COPY OF PRIORITY DOCUMENT.pdf


Patent Number 249941
Indian Patent Application Number 831/KOLNP/2007
PG Journal Number 47/2011
Publication Date 25-Nov-2011
Grant Date 23-Nov-2011
Date of Filing 08-Mar-2007
Name of Patentee TAKEDA PHARMACEUTICAL COMPANY LIMITED
Applicant Address 1-1, DOSHOMACHI 4-CHOME, CHUO-KU OSAKA-SHI, OSAKA
Inventors:
# Inventor's Name Inventor's Address
1 SHIGEHARU SUGISAKI 96, HOLYWELL, KILMACUD ROAD, DUBLIN 14, IRELAND
2 SHINICHI URAYAMA C/O TAKEDA PHARMACEUTICAL COMPANY LIMITED 17-85, JUSOHONMACHI 2-CHOME, YODOGAWA-KU, OSAKA-SHI, OSAKA
3 ATSUSHI INAGAKI C/O TAKEDA PHARMACEUTICAL COMPANY LIMITED 17-85, JUSOHONMACHI 2-CHOME, YODOGAWA-KU, OSAKA-SHI, OSAKA
4 TAKASHI OKADA C/O TAKEDA PHARMACEUTICAL COMPANY LIMITED 4720, AZA-TAKEDA, OAZA-MITSUI, HIKARI-SHI, YAMAGUCHI
5 EIGO MUTOU C/O TAKEDA PHARMACEUTICAL COMPANY LIMITED 17-85, JUSOHONMACHI 2-CHOME, YODOGAWA-KU, OSAKA-SHI, OSAKA
PCT International Classification Number C07D 307/77,A61K 31/343,A61P 25/20
PCT International Application Number PCT/JP2005/016761
PCT International Filing date 2005-09-12
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 2004-265307 2004-09-13 Japan