U.S. patent application number 14/079607 was filed with the patent office on 2014-03-06 for process for production of optically active amine derivatives.
This patent application is currently assigned to Takeda Pharmaceutical Company Limited. The applicant listed for this patent is Takeda Pharmaceutical Company Limited. Invention is credited to Atsushi Inagaki, Eigo Mutou, Takashi Okada, Shigeharu Sugisaki, Shinichi Urayama.
Application Number | 20140066499 14/079607 |
Document ID | / |
Family ID | 36059992 |
Filed Date | 2014-03-06 |
United States Patent
Application |
20140066499 |
Kind Code |
A1 |
Urayama; Shinichi ; et
al. |
March 6, 2014 |
PROCESS FOR PRODUCTION OF OPTICALLY ACTIVE AMINE DERIVATIVES
Abstract
An industrial process for production of high-purity optically
active amine derivatives in high yield while inhibiting the
formation of by-products, which comprises subjecting
(E)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylidene)ethylamine
to asymmetric reduction, catalytically reducing the obtained
product at a reaction temperature of 40 to 100.degree. C. and a pH
of 3 to 9, subjecting the obtained
(S)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine to
propionylation, and then crystallizing the reaction mixture.
Inventors: |
Urayama; Shinichi;
(Yamaguchi, JP) ; Mutou; Eigo; (Osaka, JP)
; Inagaki; Atsushi; (Yamaguchi, JP) ; Okada;
Takashi; (Yamaguchi, JP) ; Sugisaki; Shigeharu;
(Osaka, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Takeda Pharmaceutical Company Limited |
Osaka-Shi |
|
JP |
|
|
Assignee: |
Takeda Pharmaceutical Company
Limited
Osaka-Shi
JP
|
Family ID: |
36059992 |
Appl. No.: |
14/079607 |
Filed: |
November 13, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13597361 |
Aug 29, 2012 |
8609871 |
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14079607 |
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13325946 |
Dec 14, 2011 |
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13597361 |
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11662684 |
Sep 12, 2008 |
8097737 |
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PCT/JP05/16761 |
Sep 12, 2005 |
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13325946 |
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Current U.S.
Class: |
514/468 ;
549/458 |
Current CPC
Class: |
A61P 25/06 20180101;
A61P 25/24 20180101; C07D 307/77 20130101; A61P 5/00 20180101; A61P
25/08 20180101; A61P 25/22 20180101; A61P 27/06 20180101; A61P 3/10
20180101; A61P 9/12 20180101; C07D 307/80 20130101; A61P 25/20
20180101; A61P 25/16 20180101; A61P 21/02 20180101; C07D 307/81
20130101; A61P 37/02 20180101; A61P 5/24 20180101; A61P 35/00
20180101; A61P 9/00 20180101; A61P 25/18 20180101; A61P 25/28
20180101; A61P 15/18 20180101; A61K 31/343 20130101; A61P 25/00
20180101 |
Class at
Publication: |
514/468 ;
549/458 |
International
Class: |
C07D 307/77 20060101
C07D307/77 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 13, 2004 |
JP |
2004-265307 |
Claims
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.degree. C. to 100.degree. C. and pH 3
to 9 with a catalyst.
2. The process according to claim 1, wherein the reaction
temperature in step (ii) is 50.degree. C. to 70.degree. C.
3. The process according to claim 1, wherein the pH in step (ii) is
5 to 7.
4. The process according to claim 1, wherein the catalyst in step
(i) is Ru-BINAP catalyst.
5. The process according to 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]propionami-
de, 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 claim 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]propionami-
de, 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.
##STR00019##
8. Crystals of
(S)--N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionami-
de, 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. ##STR00020##
9. The crystals according to claim 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]propionami-
de 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]propionami-
de, 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. ##STR00021##
11. A composition comprising
(S)--N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionami-
de 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]propionami-
de, 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. ##STR00022##
12. The composition according to claim 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]propionami-
de. ##STR00023##
13. The crystals according to claim 7 or the composition according
to claim 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.times.gas-liquid overall mass transfer
volume coefficient(1/hr)+0.43.
15. Use of the crystals according to claim 7 for the manufacture of
a preventive or therapeutic agent for sleep disorder.
16. The composition according to claim 10 which is a preventive or
therapeutic agent for sleep disorder.
17. A method for the prevention or treatment of sleep disorder,
comprising administering the crystals according to claim 8 or the
composition according to claim 10.
Description
TECHNICAL FIELD
[0001] 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
[0002] 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').
##STR00001##
[0003] 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
[0004] 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.
[0005] 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.
[0006] That is the present invention provides:
[0007] (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.degree. C. to 100.degree. C. and pH 3
to 9 with a catalyst,
[0008] (2) The process according to the above-mentioned (1),
wherein the reaction temperature in step (ii) is 50.degree. C. to
70.degree. C.,
[0009] (3) The process according to the above-mentioned (1),
wherein the pH in step (ii) is 5 to 7,
[0010] (4) The process according to the above-mentioned (1),
wherein the catalyst in step (i) is Ru-BINAP catalyst,
[0011] (5) The process according to the above-mentioned (1),
wherein the catalyst in step (ii) is Pd--C catalyst,
[0012] (6) A process for producing crystals of
(S)--N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionami-
de, 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),
[0013] (7) Crystals of
(S)--N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionami-
de, 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,
##STR00002##
[0014] (8) Crystals of
(S)--N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionami-
de, 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,
##STR00003##
[0015] (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,
[0016] (10) A composition comprising
(S)--N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionami-
de 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]propionami-
de, 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,
##STR00004##
[0017] (11) A composition comprising
(S)--N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionami-
de 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]propionami-
de, 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,
##STR00005##
[0018] (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]propionami-
de,
##STR00006##
[0019] (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,
[0020] (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.times.gas-liquid overall mass
transfer volume coefficient(1/hr)+0.43,
[0021] (15) Use of the crystals according to the above-mentioned
(7) for the manufacture of a preventive or therapeutic agent for
sleep disorder,
[0022] (16) The composition according to the above-mentioned (10)
which is a preventive or therapeutic agent for sleep disorder,
and
[0023] (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 DRAWINGS
[0024] FIG. 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]propionami-
de.
BEST MODE FOR CARRYING OUT THE INVENTION
[0025] 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.
[0026] 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[5,4b]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-1,2,6,7-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.
[0027] In the catalytic reduction step, catalytic reduction of
4,5-dibromo-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one can be
carried out by mixing
4,5-dibromo-1,2,6,7-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.
[0028] 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.times.gas-liquid overall mass
transfer volume coefficient(1/hr)+0.43.
Herein, the gas-liquid overall mass transfer volume coefficient can
be determined with Na.sub.2SO.sub.3 method as described in detail
in the after-mentioned Example 1.
[0029] Further, the hydrogen pressure in the present reaction is
usually 0.1 to 1 MPa, preferably 0.3 to 0.5 MPa.
[0030] In gas-liquid system, rate N.sub.A 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).times.(concentration difference).
N.sub.A=K.sub.L(C.sub.l-C) (1)
Here, K.sub.L is a mass transfer coefficient for liquid, C.sub.l 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 (C.sub.l-C) is a driving force for gas absorption.
[0031] In addition, given that A is a gas-liquid contact area and
V.sub.L is a volume of liquid, since increasing rate V.sub.LdC/dt
of gas concentration in solution is equal to dissolution rate of
gas, the following_equation can be given.
N.sub.AA=V.sub.LdC/dt (2)
[0032] Thus, equation:
dC/dt=K.sub.LA(C.sub.l-C) (3)
is derived from formulae (1) and (2).
[0033] Furthermore, given that A/V.sub.L is represented by a:
gas-liquid interface area per unit area, equation:
dC/dt=K.sub.La(C.sub.l-C) (4)
is given.
[0034] Since it is difficult to obtain the gas-liquid interface
area: a independently in gas-liquid stirring operation, mass
transfer volume coefficient for liquid K.sub.La which is a product
of a and mass transfer coefficient for liquid K.sub.L is used as an
index to express gas absorbability.
[0035] In addition, from the fact that when stirring rate is
increased, gas-liquid interface area: a becomes larger, it can
generally be said that K.sub.La becomes larger with stirring
rate.
[0036] 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.
[0037] Examples of the base used in the present reaction include
anhydrous sodium acetate, Et.sub.3N, pyridine, NaHCO.sub.3,
Na.sub.2CO.sub.3, and the like. In particular, anhydrous sodium
acetate and Et.sub.3N are preferred. The amount of base to be used
is usually 2 to 3 equivalent moles.
[0038] Examples of the catalytic reduction catalyst used in the
present reaction include Pd--C, PtO.sub.2, Rh--Al.sub.2O.sub.3,
(RhCl[P(C.sub.6H.sub.5).sub.3].sub.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).
[0039] The reaction temperature of the present reaction is usually
10.degree. C. to 100.degree. C., preferably 30.degree. C. to
50.degree. C., and the reaction time is usually 1 to 50 hrs,
preferably 2 to 10 hrs.
[0040]
(E)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylidene)ethylamin-
e 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.
[0041] 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.
[0042] 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.
[0043] As a Ru-BINAP catalyst, specifically,
Ru.sub.2Cl.sub.4-[(R)-BINAP].sub.2N(C.sub.2H.sub.5).sub.3,
{RuCl(Benzene)[(R)-BINAP]}cl, {RuCl(p-Cymene)[(R)-BINAP]}Cl,
{RuBr(p-Cymene)[(R)-BINAP]}Br, {RuI(p-Cymene)[(R)-BINAP]}I.sub.3,
{RuI(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.
[0044] As an asymmetric reduction catalyst,
{RuCl(Benzene)[(R)-BINAP]}Cl is preferably used.
[0045] 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.
[0046] 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.
[0047] 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.
[0048] In addition, the reaction temperature is 0 to 150.degree.
C., 0.25 preferably 10 to 80.degree. C., and the reaction time is
0.5 to 200 hrs, preferably 5 to 50 hrs.
[0049] 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.
##STR00007##
[0050] 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 10.degree. C., 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.
[0051] Examples of the catalytic reduction catalyst used in the
present reaction include Pd--C, PtO.sub.2, Rh--Al.sub.2O.sub.3,
(RhCl[P(C.sub.6H.sub.5).sub.3].sub.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.
[0052] In addition, the reaction temperature is 40.degree. C. to
100.degree. C., preferably 50.degree. C. to 70.degree. C., and the
reaction time is 0.5 to 200 hrs, preferably 3 to 20 hrs.
[0053] 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.
[0054] 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.
[0055] 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 (III') 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.
[0056] The process for producing a crystal of
(S)--N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionami-
de 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-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine.
[0057] 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.degree. C., preferably -10 to 50.degree. C.
[0058] In step (b), crystals of
(S)--N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionami-
de 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.degree. C., preferably -10 to
40.degree. C.
[0059] The crystals of
(S)--N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionami-
de 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]propionami-
de can be obtained by further recrystallizing the obtained crystals
from ethanol-water (1:2).
[0060] Although the crystals of
(S)--N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionami-
de 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.
##STR00008##
[0061] For example, in the crystals of
(S)--N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionami-
de 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, 0.03% by weight o 0.03%
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.
r 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.
[0062] As described above, higher-quality crystals of
(S)--N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionami-
de 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]propi-
onamide 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.
[0063]
(S)--N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]prop-
ionamide 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).
[0064] 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.
[0065] 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.fwdarw.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.
[0066]
(S)--N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]prop-
ionamide 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 .mu.m.
[0067] The particle size can be measured as follows by using
commercially available measuring apparatus.
[0068] 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 .mu.L of this suspension, and
a test is carried out under the following condition.
[Dispersion Medium]
[0069] 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]propionami-
de
[Apparatus]
[0070] 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]
[0071] Focal length: 100 mm Stirring speed: 50% Sampling time: 1
second Measurement time: 10 seconds
[0072] 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.
[0073] 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)propionic 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.HCl:
(E)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylidene)ethyla-
mine hydrochloride (S)-AMI.HCl:
(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
##STR00009##
[0075] 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.degree. C. over 2 hrs. The reaction
mixture was heated at an inner temperature of 80 to 90.degree. 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
##STR00010##
[0077] 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
##STR00011##
[0079] 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.degree. 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
##STR00012##
[0081] 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 ml), 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-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one
##STR00013##
[0083] 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.degree. 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
##STR00014##
[0085] (1)
4,5-Dibromo-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one (280 kg,
843 mol), 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.degree. C. for 8 hrs
with stirring at such a stirring rate that the gas-liquid overall
mass transfer coefficient K.sub.La(1/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
[0086] 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
[0087] Here, the gas-liquid overall mass transfer coefficient was
determined by Na.sub.2SO.sub.3 method.
1) Na.sub.2SO.sub.3 Method (Sodium Sulfite Method)
(a) Principle
[0088] Sodium sulfite (Na.sub.2SO.sub.3), in an aqueous solution
thereof, converts to sodium sulfate (Na.sub.2SO.sub.4) 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 (N.sub.A) can be obtained by measuring the concentration
change of sodium sulfite.
[0089] Now, the gas-liquid overall mass transfer volume coefficient
K.sub.La is defined by the following equation.
N.sub.A=K.sub.La(C*-C)
[0090] 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.
K.sub.La=N.sub.A/C*
[0091] 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, K.sub.La can be calculated.
[0092] In addition, symbols in the above equation have the
following meanings.
K.sub.La: gas-liquid overall mass transfer volume coefficient
[1/Hr] N.sub.A: oxygen absorption rate [mol/LHr] 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 [PaL/Hr]
(b) Measurement Method
[0093] (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) Na.sub.2SO.sub.3 (9.5 g) is added thereto,
and mixed for about 2 minutes to dissolve. (iii) A prepared 0.1
mol/L CuSO.sub.4 solution (4.75 ml) is added to the aqueous
solution of Na.sub.2SO.sub.3 (CuSO.sub.4 concentration after the
addition=1.times.10.sup.-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=T.sub.1 [ml]) (v) The reaction solution is stirred with a
given rotation rate for a given time .DELTA..theta. (=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=T.sub.2 [ml])
(vii) From the result of titration, oxygen absorption rate N.sub.A
is calculated according to the following equation. Here, F
represents a factor of N/10 iodine solution reagent.
N A = 0.1 .times. F 4 .times. 10 .times. .DELTA. .theta. ( T 1 - T
2 ) ##EQU00001##
(c) Titration method (method for titration of sodium
sulfite)*.sup.1 (i) A 200 ml Erlenmeyer flask containing pure water
(100 m), acetic acid-sodium acetate buffer*.sup.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*.sup.3 (0.5-1 ml) as
an indicator.
[0094] *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:
Na.sub.2SO.sub.3+I.sub.2+H.sub.2O.fwdarw.2NaI+H.sub.2SO.sub.4
titration of iodine:
I.sub.2+2Na.sub.2S.sub.2O.sub.3.fwdarw.2NaI+Na.sub.2S.sub.4O.sub.6
[0095] *2: 75 g of sodium acetate (CH.sub.3COONa.3H.sub.2O) is
dissolved in 500 ml of aqueous acetic acid
(CH.sub.3COOH:H.sub.2O=1:2).
[0096] *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
##STR00015##
[0098] 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 1 hr. 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
##STR00016##
[0100] 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 to
50.degree. 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.degree. 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
##STR00017##
[0102] 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 122 kg, 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]Cl (894 g)
under nitrogen atmosphere, followed by stirring at 80.degree. 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.degree. 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.degree. 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).
[0103] 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 mm i.d..times.75 mm column
temperature: given temperature around 25.degree. 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]propion-
amide
##STR00018##
[0105] 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
[0106] 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
[0107] 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-302.5 .mu.m, 4.6 mm
i.d..times.150 mm (manufactured by YMC) column temperature: given
temperature around 25.degree. C. mobile phase: A; mixed solution of
0.01 mol/L phosphate buffer (pH 7.0)/acetonitrile (4:1) [0108] B;
mixed solution of 0.01 mol/L phosphate buffer (pH 7.0)/acetonitrile
(3:7) [0109] gradient condition
TABLE-US-00001 [0109] time (min.) mobile phase A mobile phase B 0
90% 10% 60 40% 60% 70 40% 60% 70.1 90% 10% 85 90% 10%
[0110] Resulting HPLC chart was shown in FIG. 1. As obvious from
FIG. 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]propionami-
de, however, compound (III) and (IV) were each below the detection
limit of less than 0.02%.
INDUSTRIAL APPLICABILITY
[0111] 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.
* * * * *