U.S. patent application number 10/212075 was filed with the patent office on 2003-04-03 for processes for producing 4-substituted benzopyran derivatives.
This patent application is currently assigned to CHUGAI SEIYAKU KABUSHIKI KAISHA. Invention is credited to Ishizawa, Takenori, Khlebnikov, Vladimir A., Suzuki, Yukio, Watanabe, Masashi.
Application Number | 20030065189 10/212075 |
Document ID | / |
Family ID | 27336467 |
Filed Date | 2003-04-03 |
United States Patent
Application |
20030065189 |
Kind Code |
A1 |
Suzuki, Yukio ; et
al. |
April 3, 2003 |
Processes for producing 4-substituted benzopyran derivatives
Abstract
Starting, for example, from 1-fluoro-2-fluoromethyl-3-butyn-2-yl
4-trifluoromethylphenyl ether,
N-(2-cyanoethyl)-5-fluoro-4-fluoromethyl-4-
-(4-trifluoromethylphenoxy)-2-pentynamide is produced and then
cyclized to synthesize
2,2-bis(fluoromethyl)-N-(2-cyanoethyl)-6-trifluoromethyl-2H-1--
benzopyran-4-carboxamide. The invention processes for producing
4-substituted benzopyran derivatives involve fewer steps, feature
greater safety and allow for easier purification than the prior art
processes.
Inventors: |
Suzuki, Yukio; (Shizuoka,
JP) ; Ishizawa, Takenori; (Shizuoka, JP) ;
Khlebnikov, Vladimir A.; (Shizuoka, JP) ; Watanabe,
Masashi; (Tokyo, JP) |
Correspondence
Address: |
BROWDY AND NEIMARK, P.L.L.C.
624 NINTH STREET, NW
SUITE 300
WASHINGTON
DC
20001-5303
US
|
Assignee: |
CHUGAI SEIYAKU KABUSHIKI
KAISHA
Tokyo
JP
|
Family ID: |
27336467 |
Appl. No.: |
10/212075 |
Filed: |
August 6, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10212075 |
Aug 6, 2002 |
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09787673 |
Mar 21, 2001 |
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6455708 |
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09787673 |
Mar 21, 2001 |
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PCT/JP99/05387 |
Sep 30, 1999 |
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Current U.S.
Class: |
548/126 ;
549/405 |
Current CPC
Class: |
C07D 311/58
20130101 |
Class at
Publication: |
548/126 ;
549/405 |
International
Class: |
C07D 285/14; C07D
311/74; C07D 311/76 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 30, 1998 |
JP |
277561/1998 |
Sep 30, 1998 |
JP |
277952/1998 |
Sep 30, 1998 |
JP |
278741/1998 |
Claims
What is claimed is
1. A process for producing 4-substituted benzopyran derivatives
represented by formula (G-VI) 18where R.sup.1 and R.sup.2, which
may be the same or different, represent a hydrogen atom, an
optionally substituted lower alkyl group, an optionally substituted
lower alkoxy group, an optionally substituted lower alkoxycarbonyl
group, an optionally substituted lower alkylsulfonyl group, an
optionally substituted arylsulfonyl group, a halogen atom, a nitro
group, a cyano group or NY.sub.aY.sub.b, where Y.sub.a and Y.sub.b,
which may be the same or different, each represents a hydrogen
atom, an optionally substituted lower alkyl group, an optionally
substituted lower alkoxycarbonyl group, an acyl group, an
optionally substituted lower alkylsulfonyl group or an optionally
substituted arylsulfonyl group or, when taken together with the
nitrogen atom to which they are bound, may form a 3- to 8-membered
ring or, when taken together, represent a substituent
.dbd.N.dbd.O--N.dbd.; R.sup.3 and R.sup.4, which may be the same or
different, represent a hydrogen atom or an optionally substituted
lower alkyl group or, when taken together with the carbon atom to
which they are bound, represent a polymethylene group or a
substituent forming a heterocycle, provided that R.sup.3 and
R.sup.4 are not both a hydrogen atom; R.sup.5 and R.sup.6, which
may be the same or different, represent a hydrogen atom or an
optionally substituted lower alkyl group; the process comprising
any one of the schemes (1), (2), (3), (4), and (5) containing a
plurality of steps as indicated below, namely, (1):
(1-1).fwdarw.(1-2).fwdarw.(1-3).fwdarw.(1-4).fwdarw.(1-5); (2):
(3-1).fwdarw.(3-2); (3): (4-1).fwdarw.(4-2); (4):
(a-1).fwdarw.(a-2).fwda- rw.(b-1).fwdarw.(b-2).fwdarw.(1-5); and
(5): (a-1).fwdarw.(a-2).fwdarw.(d-- 1).fwdarw.(d-2).fwdarw.(d-3);
(1-1) the step of reacting a compound of formula (II) 19where X and
Y, which may be the same or different, represent a leaving group
such as a halogen atom, an optionally substituted lower
alkylsulfonyloxy group or an arylsulfonyloxy group; R.sup.1and
R.sup.2 have the same meanings as defined above with an olefin of
formula (III) 20where R.sup.3 and R.sup.4 have the same meanings as
defined above to give a compound of formula (IV) 21where Y,
R.sup.1, R.sup.2, R.sup.3 and R.sup.4 have the same meanings as
defined above; (1-2) the step of reacting the resulting compound
formula (IV) with a halogenating agent to give a compound of
formula (V) 22where Y, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and Hal
have the same meanings as defined above; (1-3) the step of reacting
the resulting compound of formula (V) with a base to give a
compound of formula (VI) 23where Y, R.sup.1, R.sup.2, R.sup.3,
R.sup.4 and Hal have the same meanings as defined above; (1-4) the
step of reacting the resulting compound of formula (VI) with a base
to give a 4-halobenzopyran of formula (I) 24where Y, R.sup.1,
R.sup.2, R.sup.3, R.sup.4 and Hal have the same meanings as defined
above; (1-5) the step of reacting the compound of formula (I) with
carbon monoxide and a compound of formula (G-III) R.sup.5R.sup.6NH
(G-III) where R.sup.5 and R.sup.6, which may be the same or
different, represent a hydrogen atom or an optionally substituted
lower alkyl group in the presence of a metal to give a
4-substituted benzopyran derivative of formula (G-VI); (3-1) the
step of reacting a compound of formula (G-I) 25where R.sup.1,
R.sup.2, R.sup.3 and R.sup.4 have the same meanings as defined
above with carbon dioxide in the presence of a base to give a
compound of formula (G-II) 26where R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 have the same meanings as defined above or a salt thereof;
(3-2) the step of reacting the resulting compound of formula (G-II)
or salt thereof with a compound of formula (G-III) R.sup.5R.sup.6NH
(G-III) where R.sup.5 and R.sup.6, which may be the same or
different, represent a hydrogen atom or an optionally substituted
lower alkyl group to give a 4-substituted benzopyran derivative of
formula (G-VI); (4-1) the step of reacting a compound of formula
(G-I) 27where R.sup.1, R.sup.2, R.sup.3 and R.sup.4 have the same
meanings as defined above with a compound of formula (G-IVa)
28where R.sup.5 and R.sup.6, which may be the same or different,
represent a hydrogen atom or an optionally substituted lower alkyl
group or a compound of formula (G-IVb) R.sup.6aNCO (G-IVb) where
R.sup.6a represents an optionally substituted lower alkyl group in
the presence of a base to give a compound of formula (G-V) 29where
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 have the
same meanings as defined above; (4-2) the step of subjecting the
resulting compound of formula (G-V) to a thermal cyclization
reaction to give a 4-substituted benzopyran derivative of formula
(G-VI); (a-1) the step of reacting an alcohol of formula (C-I)
30where R.sup.3 and R.sup.4 have the same meanings as defined above
with a compound of formula (C-II) or (C-III) R.sup.7SO.sub.2Cl
(C-II) (R.sup.7SO.sub.2).sub.2O (C-III) where R.sup.7 represents an
optionally substituted alkyl group or an optionally substituted
aryl group in the presence of a base to give a compound of formula
(C-IV) 31where R.sup.7, R.sup.3 and R.sup.4 have the same meanings
as defined above; (a-2) the step of reacting the compound of
formula (C-IV) with a compound of formula (C-V) 32where R.sup.1 and
R.sup.2 have the same meanings as defined above, in the presence of
a base and a monovalent or divalent copper salt to give a compound
of formula (C-VI) 33where R.sup.1, R.sup.2, R.sup.3 and R.sup.4
have the same meanings as defined above; (b-1) the step of
subjecting the compound of formula (C-VI) which is the end product
of step (a-2) to a halogenation reaction to give a compound of
formula (D-II) 34where R.sup.1, R.sup.2, R.sup.3 and R.sup.4 have
the same meanings as defined above and Hal represents a halogen
atom; (b-2) the step of subjecting the compound of formula (D-II)
to a thermal cyclization reaction to give a 4-halobenzopyran
derivative of formula (I) 35where R.sup.1, R.sup.2, R.sup.3,
R.sup.4 and Hal have the same meanings as defined above; (d-1) the
step of reacting the compound of formula (C-VI), which is the end
product of step (a-2), with a compound of formula (H-II)
O.dbd.C(OR.sup.8).sub.2 (H-II) or a compound of formula (H-III)
ClC.dbd.O(OR.sup.8) (H-III) where R.sup.8 represents an optionally
substituted lower alkyl group to give a compound of formula (H-IV)
36where R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.8 have the
same meanings as defined above; (d-2) the step of subjecting the
compound of formula (H-IV) to a thermal cyclization reaction to
give a compound of formula (H-V) 37where R.sup.1, R.sup.2, R.sup.3,
R.sup.4 and R.sup.8 have the same meanings as defined above; (d-3)
the step of hydrolyzing the resulting compound of formula (H-V) and
then subjecting the hydrolyzate to dehydrative condensation with a
compound of formula (G-III) R.sup.5R.sup.6NH (G-III) where R.sup.5
and R.sup.6, which may be the same or different, represent a
hydrogen atom or an optionally substituted lower alkyl group, to
give a 4-substituted benzopyran derivative of formula (G-VI) set
forth above.
2. A process for producing 4-substituted benzopyran derivatives
represented by formula (G-VIa) 38where R.sup.1a represents a lower
perfluoroalkyl group, a nitro group or a cyano group; R.sup.3a and
R.sup.4a, which may be the same or different, represent a hydrogen
atom, an optionally substituted lower alkyl group or, when taken
together with the carbon atom to which they are bound, represent a
polymethylene group or a substituent forming a heterocycle,
provided that R.sup.3a and R.sup.4a are not both a hydrogen atom;
R.sup.5 and R.sup.6, which may be the same or different, represent
a hydrogen atom or an optionally substituted lower alkyl group; the
process comprising scheme (1a) containing a plurality of steps as
indicated below, namely, (1a)
(1a-1).fwdarw.(1a-2).fwdarw.(1a-3).fwdarw.(1a-4).fwdarw.(1a-5); and
(1a-1) the step of reacting a compound of formula (IIa) 39where X
and Y which may be the same or different represent a leaving group;
R.sup.1a has the same meaning as defined above with an olefin of
formula (IIIa) 40where R.sup.3a and R.sup.4a have the same meanings
as defined above to give a compound of formula (IVa) 41where Y,
R.sup.1a, R.sup.3a and R.sup.4a have the same meanings as defined
above; (1a-2) the step of reacting the resulting compound of
formula (IVa) with a halogenating agent to give a compound of
formula (Va) 42where Y, R.sup.1a, R.sup.3a and R.sup.4a have the
same meanings as defined above, and Hal represents a halogen atom;
(1a-3) the step of reacting the resulting compound of formula (Va)
with a base to give a compound of formula (VIa) 43where Y,
R.sup.1a, R.sup.3a, R.sup.4a and Hal have the same meanings as
defined above; (1a-4) the step of reacting the resulting compound
of formula (VIa) with a base to give a compound of formula (Ia)
44where R.sup.1a, R.sup.3a, R.sup.4a and Hal have the same meanings
as defined above; (Ia-5) the step of reacting the resulting
compound of formula (Ia) with carbon monoxide and a compound of
formula (G-III) R.sup.5R.sup.6NH (G-III) where R.sup.5 and R.sup.6,
which may be the same or different, represent a hydrogen atom or an
optionally substituted lower alkyl group, in the presence of a
metal to give a 4-substituted benzopyran derivative of formula
(G-VIa) set forth above 45where R.sup.1a, R.sup.3a, R.sup.4a,
R.sup.5 and R.sup.6 have the same meanings as defined above.
3. A process for producing 4-substituted benzopyran derivatives
represented by formula (G-VIb) 46where R.sup.1b represents a lower
perfluoroalkyl group; R.sup.3b and R.sup.4b, which may be the same
or different, represent a hydrogen atom, an optionally substituted
lower alkyl group or, when taken together with the carbon atom to
which they are bound, represent a polymethylene group, provided
that R.sup.3b and R.sup.4b are not both a hydrogen atom; R.sup.5
and R.sup.6, which may be the same or different, represent a
hydrogen atom or an optionally substituted lower alkyl group by
scheme (1b) containing a plurality of steps as indicated below,
namely, (1b) (1b-1).fwdarw.(1b-2).fwdarw.(1b-3)-
.fwdarw.(1b-4).fwdarw.(1b-5); and (1b-1) the step of reacting a
compound of formula (IIb) 47where X and Y, which may be the same or
different, represent a leaving group; R.sup.1b has the same meaning
as defined above, with an olefin of formula (IIIb) 48where R.sup.3b
and R.sup.4b have the same meanings as defined above, to give a
compound of formula (IVb) 49where Y, R.sup.1b, R.sup.3b and
R.sup.4b have the same meanings as defined above; (1b-2) the step
of reacting the resulting compound of formula (IVb) with a
halogenating agent to give a compound of formula (Vb) 50where Y,
R.sup.1b, R.sup.3b and R.sup.4b have the same meanings as defined
above, and Hal represents a halogen atom; (1b-3) the step of
reacting the resulting compound of formula (Vb) with a base to give
a compound of formula (VIb) 51where Y, R.sup.1b, R.sup.3b, R.sup.4b
and Hal have the same meanings as defined above; (1b-4) the step of
reacting the resulting compound of formula (VIb) with a base to
give a compound of formula (Ib) 52where R.sup.1b, R.sup.3b,
R.sup.4b and Hal have the same meanings as defined above; (Ib-5)
the step of reacting the resulting compound of formula (Ib) with
carbon monoxide and a compound of formula (G-III) R.sup.5R.sup.6NH
(G-III) where R.sup.5 and R.sup.6, which may be the same or
different, represent a hydrogen atom or an optionally substituted
lower alkyl group, in the presence of a metal to give a
4-substituted benzopyran derivative of formula (G-VIb) 53where
R.sup.1b, R.sup.3b, R.sup.4b, R.sup.5 and R.sup.6 have the same
meanings as defined above.
4. A process for producing 4-substituted benzopyran derivatives
represented by formula (G-VIc) 54where R.sup.1b represents a lower
perfluoroalkyl group; R.sup.3c and R.sup.4c, which are the same,
represent a lower alkyl group or a lower fluoroalkyl group;
R.sup.5c represents a hydrogen atom and R.sup.6 represents an
optionally substituted lower alkyl group; the process comprising
scheme 1c containing a plurality of steps as indicated below: (1c)
(1c-1).fwdarw.(1c-2).fwdarw.(1c-3).fwdarw.(1c-4).fwdarw.(1c-5);
(1c-1) the step of reacting a compound of formula (IIb) 55where X
and Y, which may be the same or different, represent a leaving
group; R.sup.1b has the same meaning as defined above, with an
olefin of formula (IIIc) 56where R.sup.3c and R.sup.4c have the
same meanings as defined above, to give a compound of formula (IVc)
57where Y, R.sup.1b, R.sup.3c and R.sup.4c have the same meanings
as defined above; (1c-2) the step of reacting the resulting
compound of formula (IVc) with a halogenating agent to give a
compound of formula (Vc) 58where Y, R.sup.1b, R.sup.3c and R.sup.4c
have the same meanings as defined above, and Hal represents a
halogen atom; (1c-3) the step of reacting the resulting compound of
formula (Vc) with a base to give a compound of formula (VIc)
59where Y, R.sup.1b, R.sup.3c and R.sup.4c have the same meanings
as defined above, and Hal represents a halogen atom; (1c-4) the
step of reacting the resulting compound of formula (VIc) with a
base to give a compound of formula (Ic) 60where R.sup.1b, R.sup.3c,
R.sup.4c and Hal have the same meanings as defined above; (Ic-5)
the step of reacting the resulting compound of formula (Ic) with
carbon monoxide and a compound of formula (G-IIIc)
R.sup.5cR.sup.6aNH (G-IIIc) where R.sup.5c represents a hydrogen
atom and R.sup.6a represents an optionally substituted lower alkyl
group, in the presence of a metal to give a 4-substituted
benzopyran derivative of formula (G-VIc).
5. A process for producing 4-substituted benzopyran derivatives
represented by formula (G-VId) 61where R.sup.1b represents a lower
perfluoroalkyl group; R.sup.5c represents a hydrogen atom; and
R.sup.6b represents a lower alkyl group which may optionally have a
cyano group, by scheme (id) containing a plurality of steps as
indicated below: (1d)
(1d-1).fwdarw.(1d-2).fwdarw.(1d-3).fwdarw.(1d-4).fwdarw.(1d-S); and
(1d-1) the step of reacting a compound of formula (IId) 62where X
and Y, which may be the same or different, represent a leaving
group; R.sup.1b has the same meaning as defined above, with an
olefin of formula (IIId) 63to give a compound of formula (IVd)
64where Y and R.sup.1b have the same meanings as defined above;
(1d-2) the step of reacting the resulting compound of formula (IVd)
with a halogenating agent to give a compound of formula (Vd)
65where Y and R.sup.1b have the same meanings as defined above, and
Hal represents a halogen atom; (1d-3) the step of reacting the
resulting compound of formula (Vd) with a base to give a compound
of formula (VId) 66where Y, R.sup.1b and Hal have the same meanings
as defined above; (1d-4) the step of reacting the resulting
compound of formula (VId) with a base to give a 4-halobenzopyran
derivative of formula (Id) 67where R.sup.1b and Hal have the same
meanings as defined above; (Id-5) the step of reacting the
resulting compound of formula (Id) with carbon monoxide and a
compound of formula (G-IIId) R.sup.5cR.sup.6bNH (G-IIId) where
R.sup.5c represents a hydrogen atom and R.sup.6b represents a lower
alkyl group which may optionally have a cyano group, in the
presence of a metal to give a 4-substituted benzopyran derivative
of formula (G-VId) set forth above.
6. A process for producing 4-substituted benzopyran derivatives
represented by formula (G-VIe) 68where R.sup.1e represents a
trifluoromethyl group or a pentafluoroethyl group; R.sup.5c
represents a hydrogen atom; R.sup.6d represents a cyanoethyl group;
by scheme (1e) containing a plurality of steps as indicated below:
(1e)
(1e-1).fwdarw.(1e-2).fwdarw.(1e-3).fwdarw.(1e-4).fwdarw.(1e-5); and
(1e-1) the step of reacting a compound of formula (IIe) 69where
R.sup.1e has the same meaning as defined above with an olefin of
formula (IIId) 70to give a compound of formula (IVe) 71where
R.sup.1e has the same meaning as defined above; (1e-2) the step of
reacting the resulting compound of formula (IVe) with a
halogenating agent to give a compound of formula (Ve) 72where
R.sup.1e has the same meaning as defined above; Hal represents a
halogen atom; (1e-3) the step of reacting the resulting compound of
formula (Ve) with a base to give a compound of formula (VIe)
73where R.sup.1e and Hal have the same meanings as defined above;
(1e-4) the step of reacting the resulting compound of formula (VIe)
with a base to give a 4-halobenzopyran derivative of formula (Ie)
74where R.sup.1e and Hal have the same meanings as defined above;
(1e-5) the step of reacting the resulting compound of formula (Ie)
with carbon monoxide and a compound of formula (G-IIIe)
R.sup.5cR.sup.6dNH (G-IIIe) where R.sup.5c represents a hydrogen
atom and R.sup.6d represents a cyanoethyl group, in the presence of
a metal to give a 4-substituted benzopyran derivative of formula
(G-VIe) set forth above.
7. A process according to scheme (3) or (4) recited in claim 1 for
producing 4-substituted benzopyran derivatives represented by
formula (G-VIg) 75where R.sup.1g and R.sup.2g, which may be the
same or different, represent a hydrogen atom, an optionally
substituted lower alkyl group, an optionally substituted lower
alkoxy group, an optionally substituted lower alkoxycarbonyl group,
an optionally substituted lower alkylsulfonyl group, an optionally
substituted arylsulfonyl group, a halogen atom, a nitro group, a
cyano group or NY.sub.aY.sub.b where Y.sub.a and Y.sub.b, which may
be the same or different, each represent a hydrogen atom, an
optionally substituted lower alkyl group, an optionally substituted
lower alkoxycarbonyl group, an acyl group, an optionally
substituted lower alkylsulfonyl group or an optionally substituted
arylsulfonyl group or, when taken together with the nitrogen atom
to which they are bound, may form a 3- to 8-membered ring; R.sup.3g
and R.sup.4g, which may be the same or different, represent a
hydrogen atom or an optionally substituted .alpha.-haloalkyl group,
provided that they are not both a hydrogen atom; R.sup.5 and
R.sup.6, which may be the same or different, represent a hydrogen
atom or an optionally substituted lower alkyl group; the process
comprising the steps of: reacting an alcohol of formula (C-Ig)
76where R.sup.3g and R.sup.4g have the same meanings as defined
above with a compound of formula (C-II) or (C-III)
R.sup.7SO.sub.2Cl (C-II) (R.sup.7SO.sub.2).sub.2O (C-III) where
R.sup.7 represents an optionally substituted alkyl group or an
optionally substituted aryl group in the presence of a base to give
a compound of formula (C-IVg) 77where R.sup.7, R.sup.3g and
R.sup.4g have the same meanings as defined above; reacting the
compound of formula (C-IVg) with a compound of formula (C-Vg)
78where R.sup.1g and R.sup.2g have the same meanings as defined
above in the presence of a base and a monovalent or divalent copper
salt to give a compound of formula (G-Ig) 79where R.sup.1g,
R.sup.2g, R.sup.3g and R.sup.4g have the same meanings as defined
above; reacting the compound of formula (G-Ig) with carbon dioxide
in the presence of a base to give a compound of formula (G-IIg)
80where R.sup.1g, R.sup.2g, R.sup.3g and R.sup.4g have the same
meanings as defined above or a salt thereof; reacting the compound
of formula (G-IIg) or salt thereof with a compound of formula
(G-III) R.sup.5R.sup.6NH (G-III) where R.sup.5 and R.sup.6 which
may be the same or different represent a hydrogen atom or an
optionally substituted lower alkyl group to give a compound of
formula (G-Vg) 81where R.sup.1g, R.sup.2g, R.sup.3g, R.sup.4g,
R.sup.5 and R.sup.6 have the same meanings as defined above; or
alternatively reacting the compound of formula 82where R.sup.1g,
R.sup.2g, R.sup.3g and R.sup.4g have the same meanings as defined
above with a compound of formula (G-IVa) 83where R.sup.5 and
R.sup.6, which may be the same or different, represent a hydrogen
atom or an optionally substituted lower alkyl group or a compound
of formula (G-IVb) R.sup.6aNCO (G-IVb) where R.sup.6a represents an
optionally substituted lower alkyl group in the presence of a base
to give a compound of formula (G-Vg) 84where R.sup.1g, R.sup.2g,
R.sup.3g, R.sup.4g, R.sup.5 and R.sup.6 have the same meanings as
defined above; and subjecting the compound of formula (G-Vg) to a
thermal cyclization reaction.
8. A process according to scheme (3) recited in claim 1 for
producing 4-substituted benzopyran derivatives represented by
formula (G-VIh) 85wherein R.sup.1 and R.sup.2 in formula (G-VI),
which may be the same or different, represent a hydrogen atom, an
optionally substituted lower alkyl group, an optionally substituted
lower alkoxy group, an optionally substituted lower alkoxycarbonyl
group, an optionally substituted lower alkylsulfonyl group, an
optionally substituted arylsulfonyl group, a halogen atom, a nitro
group, a cyano group or NY.sub.aY.sub.b where Y.sub.a and Y.sub.b,
which may be the same or different, each represent a hydrogen atom,
an optionally substituted lower alkyl group, an optionally
substituted lower alkoxycarbonyl group, an acyl group, an
optionally substituted lower alkylsulfonyl group or an optionally
substituted arylsulfonyl group or, when taken together, may form a
3- to 8-membered ring); R.sup.3 and R.sup.4 each represent a
fluoromethyl group; and R.sup.5 and R.sup.6, which may be the same
or different, represent a hydrogen atom or an optionally
substituted lower alkyl group.
9. The process according to scheme (3) recited in claim 1 for
producing 4-substituted benzopyran derivatives represented by
formula (G-VIi) 86wherein R.sup.1 in formula (G-VI) represents a
6-trifluoromethyl group or a 6-pentafluoroethyl group; R.sup.2
represents a hydrogen atom; R.sup.3 and R.sup.4 each represent a
fluoromethyl group; and R.sup.5 and R.sup.6, which may be the same
or different, represent a hydrogen atom or an optionally
substituted lower alkyl group.
10. The process according to scheme (3) recited in claim 1 for
producing 4-substituted benzopyran derivatives represented by
formula (G-VIj) 87wherein R.sup.1 in formula (G-VI) represents a
6-trifluoromethyl group or a 6-pentafluoroethyl group; R.sup.2
represents a hydrogen atom; R.sup.3 and R.sup.4 each represent a
fluoromethyl group; and R.sup.5 represents a hydrogen atom and
R.sup.6 represents a 2-cyanoethyl group.
11. A process for producing 4-substituted benzopyran derivatives
represented by formula (G-VIg) 88where R.sup.1g and R.sup.2g, which
may be the same or different, represent a hydrogen atom, an
optionally substituted lower alkyl group, an optionally substituted
lower alkoxy group, an optionally substituted lower alkoxycarbonyl
group, an optionally substituted lower alkylsulfonyl group, an
optionally substituted arylsulfonyl group, a halogen atom, a nitro
group, a cyano group or NY.sub.aY.sub.b where Y.sub.a and Y.sub.b,
which may be the same or different, each represent a hydrogen atom,
an optionally substituted lower alkyl group, an optionally
substituted lower alkoxycarbonyl group, an acyl group, an
optionally substituted lower alkylsulfonyl group or an optionally
substituted arylsulfonyl group or, when taken together with the
nitrogen atom to which they are bound, may form a 3- to 8-membered
ring; R.sup.3g and R.sup.4g, which may be the same or different,
represent a hydrogen atom or an optionally substituted
.alpha.-haloalkyl group, provided that they are not both a hydrogen
atom; R.sup.5 and R.sup.6, which may be the same or different,
represent a hydrogen atom or an optionally substituted lower alkyl
group, wherein a compound represented by formula (G-Vk) 89where
R.sup.1g, R.sup.2g, R.sup.3g, R.sup.4g, R.sup.5 and R.sup.6 have
the same meanings as defined above is subjected to a thermal
cyclization reaction.
12. A process according to claim 11 for producing 4-substituted
benzopyran derivatives represented by formula (G-VII) 90wherein
R.sup.1g and R.sup.2g in formula (G-VIg), which may be the same or
different, represent a hydrogen atom, an optionally substituted
lower alkyl group, an optionally substituted lower alkoxy group, an
optionally substituted lower alkoxycarbonyl group, an optionally
substituted lower alkylsulfonyl group, an optionally substituted
arylsulfonyl group, a halogen atom, a nitro group, a cyano group or
NY.sub.aY.sub.b where Y.sub.a and Y.sub.b, which may be the same or
different, each represent a hydrogen atom, an optionally
substituted lower alkyl group, an optionally substituted lower
alkoxycarbonyl group, an acyl group, an optionally substituted
lower alkylsulfonyl group or an optionally substituted arylsulfonyl
group or, when taken together with the nitrogen atom to which they
are bound, may form a 3- to 8-membered ring; R.sub.3gand R.sup.4g
each represent a fluoromethyl group; R.sup.5 and R.sup.6, which may
be the same or different, represent a hydrogen atom or an
optionally substituted lower alkyl group.
13. A process according to claim 11 for producing 4-substituted
benzopyran derivatives represented by formula (G-VIm) 91wherein
R.sup.1g in formula (G-VIg) represents a 6-trifluoromethyl group or
a 6-pentafluoroethyl group; R.sup.2g represents a hydrogen atom;
R.sup.3g and R.sup.4g each represent a fluoromethyl group; and
R.sup.5 and R.sup.6, which may be the same or different, represent
a hydrogen atom or an optionally substituted lower alkyl group.
14. A process according to claim 11 for producing 4-substituted
benzopyran derivatives represented by formula (G-VIn) 92wherein
R.sup.1g in formula (G-VIg) represents a 6-trifluoromethyl group or
a 6-pentafluoroethyl group; R.sup.2g represents a hydrogen atom;
R.sup.3g and R.sup.4g each represent a fluoromethyl group; and
R.sup.5 represents a hydrogen atom and R.sup.6 represents a
2-cyanoethyl group.
15. A process according to scheme (5) or (6) recited in claim 1 for
producing 4-substituted benzopyran derivatives represented by
formula (Iz) 93where R.sup.1g and R.sup.2g, which may be the same
or different, represent a hydrogen atom, an optionally substituted
lower alkyl group, a halogen atom, an optionally substituted lower
alkoxy group, NY.sub.aY.sub.b (here Y.sub.a and Y.sub.b, which may
be the same or different, each represent a hydrogen atom, an
optionally substituted lower alkyl group, an optionally substituted
lower alkoxycarbonyl group, an acyl group, an optionally
substituted lower alkylsulfonyl group or an optionally substituted
arylsulfonyl group or, when taken together with the nitrogen atom
to which they are bound, may form a 3- to 8-membered ring, a nitro
group, a cyano group, an optionally substituted lower
alkoxycarbonyl group, an optionally substituted lower alkylsulfonyl
group or an optionally substituted arylsulfonyl group; Hal
represents a halogen atom the process comprising: reacting an
alcohol of formula (C-Ia) 94with a compound of formula (C-II) or
(C-III) R.sup.7SO.sub.2Cl (C-II) (R.sup.7SO.sub.2).sub.2O (C-III)
where R.sup.7 represents an optionally substituted lower alkyl
group or an optionally substituted aryl group in the presence of a
base to give a compound of formula (C-IVa) 95where R.sup.7 has the
same meaning as defined above; reacting the compound of formula
(C-IVa) with a compound of formula (C-Vg) 96where R.sup.1g and
R.sup.2g have the same meanings as defined above in the presence of
a base and a monovalent or divalent copper salt to give a compound
of formula (G-VIa) 97where R.sup.1g and R.sup.2g have the same
meanings as defined above; subjecting the compound of formula
(G-VIa) to a halogenation reaction to give a compound of formula
(D-IIa) 98where R.sup.1g, R.sup.2g and Hal have the same meanings
as defined above; and subjecting the compound of formula (D-IIa) to
a thermal cyclization reaction.
16. A process according to scheme (5) or (6) recited in claim 1 for
producing 4-substituted benzopyran derivatives represented by
formula (Iy) 99where R.sup.1 in formula (I) represents a
6-trifluoromethyl group or a 6-pentafluoroethyl group; R.sup.2
represents a hydrogen atom; R.sup.3 and R.sup.4 both represent a
fluoromethyl group; X is a bromine atom, the process comprising:
reacting an alcohol of formula (C-Ia) 100with a compound of formula
(C-II) or (C-III) R.sup.7SO.sub.2Cl (C-II) (R.sup.7SO.sub.2).sub.2O
(C-III) where R.sup.7 represents an optionally substituted lower
alkyl group or an optionally substituted aryl group in the presence
of a base to give a compound of formula (C-IVa) 101where R.sup.7
has the same meaning as defined above; reacting the compound of
formula (C-IVa) with a 4-substituted phenol derivative of formula
(C-Va) 102where R.sup.1e has the same meaning as defined above in
the presence of a base and a monovalent or divalent copper salt to
give a compound of formula (G-VIb) 103where R.sup.1e has the same
meaning as defined above; subjecting the compound of formula
(G-VIb) to bromination reaction to give a compound of formula
(D-IIb) 104where R.sup.1e has the same meaning as defined above;
and subjecting the compound of formula (D-IIb) to a thermal
cyclization reaction.
17. A process according to scheme (5) or (6) recited in claim 1 for
producing 4-substituted benzopyran derivatives represented by
formula (G-VIz) 105wherein R.sup.1 in formula (G-VI) represents a
6-trifluoromethyl group or a 6-pentafluoroethyl group; R.sup.2
represents a hydrogen atom; R.sup.3 and R.sup.4 each represents a
fluoromethyl group; and R.sup.5 and R.sup.6, which may be the same
or different, represent a hydrogen atom or an optionally
substituted lower alkyl group.
18. A process according to scheme (5) or (6) recited in claim 1 for
producing 4-substituted benzopyran derivatives represented by
formula (G-VIy) 106wherein R.sup.1 in formula (G-VI) represents a
6-trifluoromethyl group or a 6-pentafluoroethyl group; R.sup.2
represents a hydrogen atom; R.sup.3 and R.sup.4 each represents a
fluoromethyl group; and R.sup.5 represents a hydrogen atom and
R.sup.6 represents a 2-cyanoethyl group.
19. A process according to scheme (5) or (6) in claim 1, comprising
reacting a compound of formula (C-IVb) 107as obtained by reacting
methanesulfonyl chloride of formula (C-II) where R.sup.7 is a
methyl group with a compound of formula (C-I) where R.sup.3 and
R.sup.4 are each a fluoromethyl group.
20. A process according to scheme (5) or (6) in claim 1, comprising
reacting a compound of formula (C-IVc) 108where Tol represents a
tolyl group that is obtained by reacting p-toluenesulfonyl chloride
of formula (C-II) where R.sup.7 is a p-tolyl group with a compound
of formula (C-I) where R.sup.3 and R.sup.4 are each a fluoromethyl
group in the presence of a base.
21. A process according to scheme (5) or (6) recited in claim 1,
comprising reacting a compound of formula (C-VIb) 109where R.sup.1e
has the same meaning as defined above that is obtained by reacting
a compound of formula (C-Va) 110where R.sup.1e has the same meaning
as defined above; R.sup.1 in formula (C-V) is a 4-trifluoromethyl
group or a 4-pentafluoroethyl group; and R.sup.2 is a hydrogen atom
with a compound of formula (C-IVb) or (C-IVc) 111wherein Tol
represents a p-tolyl group.
22. A process according to scheme (5) or (6) recited in claim 1,
comprising reacting a compound of formula (D-IIb) 112where R.sup.1e
has the same meaning as defined above that is obtained by
brominating a compound of formula (C-VIb) 113where R.sup.1e has the
same meaning as defined above; R.sup.1 in formula (C-VI) is a
4-trifluoromethyl group or a 4-pentafluoroethyl group; R.sup.2 is a
hydrogen atom; and R.sup.3 and R.sup.4 are both a fluoromethyl
group).
23. A process according to scheme (5) or (6) recited in claim 1,
comprising reacting a 4-bromobenzopyran derivative of formula (Iq)
114where R.sup.1e has the same meaning as defined above that is
obtained by subjecting a compound of formula (D-IIb) 115where
R.sup.1e has the same meaning as defined above; R.sup.1 in formula
(D-II) is a 4-trifluoromethyl group or a 4-pentafluoroethyl group;
R.sup.2 is a hydrogen atom; and R.sup.3 and R.sup.4 are both a
fluoromethyl group; and X is a bromine atom to a thermal
cyclization reaction.
24. The process according to claim 2 wherein the leaving group is a
halogen atom, an optionally substituted lower alkylsulfonyloxy
group, or an arylsulfonyloxy group
25. The process according to claim 3 wherein the leaving group is a
halogen atom, an optionally substituted lower alkylsulfonyloxy
group, or an arylsulfonyloxy group
26. The process accdroing to claim 4 wherein the leaving group is a
halogen atom, an optionally substituted lower alkylsulfonyloxy
group, or an arylsulfonyloxy group
27. The process according to claim 5 wherein the leaving group is a
halogen atom, an optionally substituted lower alkylsulfonyloxy
group, or an arylsulfonyloxy group.
28. The process according to scheme (4) recited in claim 1 for
producing 4-substituted benzopyran derivatives represented by
formula (G-VIh) 116wherein R.sup.1 and R.sup.2 in formula (G-VI)
which may be the same or different represent a hydrogen atom, an
optionally substituted lower alkyl group, an optionally substituted
lower alkoxy group, an optionally substituted lower alkoxycarbonyl
group, an optionally substituted lower alkylsulfonyl group, an
optionally substituted arylsulfonyl group, a halogen atom, a nitro
group, a cyano group or NY.sub.aY.sub.b where Y.sub.a and Y.sub.b
which may be the same or different each represent a hydrogen atom,
an optionally substituted lower alkyl group, an optionally
substituted lower alkoxycarbonyl group, an acyl group, an
optionally substituted lower alkylsulfonyl group or an optionally
substituted arylsulfonyl group or, when taken together, may form a
3- to 8-membered ring; R.sup.3 and R.sup.4 each represent a
fluoromethyl group; and R.sup.5 and R.sup.6 which may be the same
or different represent a hydrogen atom or an optionally substituted
lower alkyl group.
29. The process according to claim 7 for producing 4-substituted
benzopyran derivatives represented by formula (G-VIh) 117wherein
R.sup.1 and R.sup.2 in formula (G-VI) which may be the same or
different represent a hydrogen atom, an optionally substituted
lower alkyl group, an optionally substituted lower alkoxy group, an
optionally substituted lower alkoxycarbonyl group, an optionally
substituted lower alkylsulfonyl group, an optionally substituted
arylsulfonyl group, a halogen atom, a nitro group, a cyano group or
NY.sub.aY.sub.b where Y.sub.a and Y.sub.b which may be the same or
different each represent a hydrogen atom, an optionally substituted
lower alkyl group, an optionally substituted lower alkoxycarbonyl
group, an acyl group, an optionally substituted lower alkylsulfonyl
group or an optionally substituted arylsulfonyl group or, when
taken together, may form a 3- to 8-membered ring; R.sup.3 and
R.sup.4 each represent a fluoromethyl group; and R.sup.5 and
R.sup.6 which may be the same or different represent a hydrogen
atom or an optionally substituted lower alkyl group.
30. The process according to scheme (4) recited in claim 1 for
producing 4-substutited benzopyran derivatives represented by
formula (G-VIi) 118wherein R.sup.1 in formula (G-VI) represents a
6-trifluoromethyl group or a 6-pentafluoroethyl group; R.sup.2
represents a hydrogen atom; R.sup.3 and R.sup.4 each represent a
fluoromethyl group; and R.sup.5 and R.sup.6 which may be the same
or different represent a hydrogen atom or an optionally substituted
lower alkyl group.
31. The process according to claim 7 for producing 4-substituted
benzopyran derivatives represented by formula (G-VIi) 119wherein
R.sup.1 in formula (G-VI) represents a 6-trifluoromethyl group or a
6-pentafluoroethyl group; R.sup.2 represents a hydrogen atom;
R.sup.3 and R.sup.4 each represent a fluoromethyl group; and
R.sup.5 and R.sup.6 which may be the same or different represent a
hydrogen atom or an optionally substituted lower alkyl group.
32. The process according to scheme (4) recited in claim 1 for
producing 4-substituted benzopyran derivatives represented by
formula (G-VIj) 120wherein R.sup.1 in formula (G-VI) represents a
6-trifluoromethyl group or a 6-pentafluoroethyl group; R.sup.2
represents a hydrogen atom; R.sup.3 and R.sup.4 each represent a
fluoromethyl group; and R.sup.5 represents a hydrogen atom and
R.sup.6 represents a 2-cyanoethyl group.
33. The process according to claim 7 for producing 4-substituted
benzopyran derivatives represented by formula (G-VIj) 121wherein
R.sup.1 in formula (G-VI) represents a 6-trifluoromethyl group or a
6-pentafluoroethyl group; R.sup.2 represents a hydrogen atom;
R.sup.3 and R.sup.4 each represent a fluoromethyl group; and
R.sup.5 represents a hydrogen atom and R.sup.6 represents a
2-cyanoethyl group.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a divisional of Ser. No.
09/787,673, filed Mar. 21, 2001, which is the national stage of
PCT/JP99/05387, filed Sep. 30, 1999.
TECHNICAL FIELD
[0002] This invention relates to novel processes for producing
4-substituted benzopyran derivatives useful as medicines,
agrichemicals and cosmetics, as well as intermediates for their
synthesis and processes for producing such intermediates.
BACKGROUND ART
[0003] One of the prior art techniques known in the field
contemplated by the invention is a process for synthesizing
4-substituted benzopyran derivatives via 4-bromobenzopyran
drivatives (JPA Hei 7-188210).
[0004] According to JPA Hei 7-188210, a compound represented by the
general formula (XVIII) (the chemical formulae embraced by the
general formula (XVIII) are set forth in the List of Chemical
Formulae at the end of the specification; all the chemical formulae
referred to hereinafter are collectively set forth in the List of
Chemical Formulae at the end of the specification) is reacted with
carbon monoxide and amine in the presence of a palladium catalyst
to give an amide form represented by the general formula
(XXVI).
[0005] A method generally known to be applicable in the synthesis
of benzopyrans is by subjecting a compound of the general formula
(D) to thermal cyclization reaction to give a compound of the
general formula (E) (see, for example, Australian Journal
Chemistry, 1971, Vol. 24, pp. 2347-2354).
[0006] It is also known that the 4-bromobenzopyran derivative
(XVIII) can be produced from a compound of the general formula
(XII) in six steps (JPA Hei 5-294954). According to JPA Hei
5-294954, an acetophenone derivative represened by the general
formula (XII) (where Z.sup.5 and Z.sup.6 which may be the same or
different represent a hydrogen atom, a lower alkyl group, a lower
haloalkyl group, a halogen atom, a lower haloalkoxy group, an amino
group, an acylamino group, a nitro group, a cyano group, an
alkoxycarbonyl group, an optionally substituted lower alkylsulfonyl
group or an arylsulfonyl group or, when taken together, represent a
substituent .dbd.N--O--N.dbd.) is condensed with an acetone
derivative represented by the general formula (XIII) (where Z.sup.7
and Z.sup.8 which may be the same or different represent a hydrogen
atom, a lower alkyl group or a substituted lower alkyl group or,
when taken together, represent a polymethylene group or a
substituent forming a heterocycle) in the presence of a base such
as pyrrolidine to give a benzopyran derivative represented by the
general formula (XIV) (where Z.sup.5, Z.sup.6, Z7 and Z.sup.8 have
the same meanings as defined above). The benzopyran derivative
(XIV) is reduced with a suitable reducing agent such as sodium
borohydride to give a benzopyran derivative represented by the
general formula (XV) (where Z.sup.5, Z.sup.6, Z.sup.7 and Z.sup.8
have the same meanings as defined above). The benzopyran derivative
(XV) is dehydrated with a suitable dehydrating agent such as
p-toluenesulfonic acid to give a benzopyran derivative represented
by the general formula (XVI) (where Z.sup.5, Z.sup.6, Z and Z.sup.8
have the same meanings as defined above) The benzopyran derivative
(XVI) is brominated with a suitable brominating agent such as
bromine to give a 3,4-dibromobenzopyran derivative represented by
the general formula (XVII) (where Z.sup.5, Z.sup.6, Z.sup.7 and
Z.sup.8 have the same meanings as defined above). The
3,4-dibromobenzopyran derivative (XVII) is treated with a suitable
base such as sodium hydroxide to give a 4-bromobenzopyran
derivative represented by the general formula (XVIII) (where
Z.sup.5, Z.sup.6, Z.sup.7 and Z.sup.8 have the same meanings as
defined above).
[0007] Other processes for producing the benzopyran derivative
(XVI) as an intermediate for the general formula (XXVII) have been
reported elsewhere (Tetrahedron Letters, 1993, 34, 1815-1818; The
20th Symposium on Progress in Organic Reactions and Syntheses,
Shizuoka (1994)).
[0008] According to Tetrahedron Letters, 1993, 34, 1815-1818, a
compound (IIf) and trimethylsilyl acetylene are subjected to
cross-coupling reaction in the presence of copper(I) iodide and
tetrakis(triphenylphosph- ine)palladium and the resulting
trimethylsilyl acetylene compound is treated with potassium
carbonate in methanol to give a compound represented by the formula
(XIX) set forth below. This compound is reacted with
hexafluoroacetone using n-butyllithium to give a compound
represented by the formula (XX). This compound is reduced with a
palladium-barium sulfate catalyst under a hydrogen atmosphere to
give a compound represented by the formula (XXI). This compound is
reacted with sodium hydride to give a benzopyran derivative
represented by the formula (XXII).
[0009] According to the 20th Symposium on Progress in Organic
Reactions and Syntheses, Shizuoka (1994), 4-fluoronitrobenzene and
acetylene represented by the general formula (XXIII) (where Z.sup.9
represents a methyl group or a fluoromethyl group) are reacted in
the presence of sodium hydride to give a compound represented by
the general formula (XXIV) (where Z.sup.9 has the same meaning as
defined above). This compound is heated in dichlorobenzene to give
a benzopyran derivative represented by the general formula (XXV)
(where Z.sup.9 has the same meaning as defined above).
[0010] In the production method of the invention, phenylpropargyl
ethers are one of the important intermediates for synthesis and can
be produced by known methods such as those described in Synthetic
Communications, 19, 1255-1259 (1989) and U.S. Pat. No.
5,463,059.
[0011] According to Synthetic Communications, 19, 1255 (1989), a
phenol represented by the general formula (H) and a substituted
propargyl alcohol represented by the general formula (J) are
condensed in benzene in the presence of diethyl azodicarboxylate
and triphenylphosphine to give a compound represented by the
general formula (K).
[0012] According to U.S. Pat. No. 5,463,059, a compound represented
by the general formula (L) and a substituted propargyl alcohol
represented by the general formula (M) (where L represents a
leaving group such as a halogen atom, a trifluoroacetoxy group or
an alkoxycarbonyloxy group) are reacted in acetonitrile in the
presence of an organic base and a catalytic amount of a copper salt
to give a compound represented by the general formula (N).
[0013] Other prior art techniques known in the field contemplated
by the invention are processes for synthesizing 4-substituted
benzopyran derivatives via 4-bromobenzopyran derivatives (XVIII)
(JPA Hei 7-17965, JPA Hei 7-188210 and Tetrahedron Letters, 1995,
36, 87-90). According to JPA Hei 7-17965 and JPA Hei 7-188210, the
general formula (P) (where Z.sup.a and Z.sup.b which may be the
same or different represent a hydrogen atom, a lower alkyl group, a
lower haloalkyl group, a halogen atom, a lower haloalkoxy group, an
amino group, an acylamino group, a nitro group, a cyano group, an
ester group, a lower alkylsulfonyl group or a lower arylsulfonyl
group or, when taken together, represent a substituent
.dbd.N--O--N.dbd.; Z.sup.c and Z.sup.dwhich may be the same or
different represent a hydrogen atom, a lower alkyl group or a
substituted alkyl group or, when taken together, represent a
polymethylene group or a substituent forming a heterocycle) is
reacted with carbon monoxide and amine in the presence of a
palladium catalyst to give an amide form represented by the general
formula (Q).
[0014] However, the reaction for the synthesis of benzopyran having
a bromine-containing group introduced at 4-position involves so
many steps that cumbersome treatment procedures are required. In
particular, the intermediate benzopyran derivative (XIV) is a
labile compound, so large amounts of decomposition products occur
as by-products during the synthesis of the benzopyran and very
cumbersome post-treatment procedures are involved. As a further
problem, due to their labile nature, derivatives having acid- or
base-sensitive functional groups such as a perfluoroalkyl group in
Z.sup.7 and Z.sup.8 cannot be synthesized without suitable
protective groups. Because of these problems, extreme difficulties
have often been encountered in the synthesis of the benzopyran. In
order to produce the compound (XXIV), the presence of a nitro group
in para-position is essential, so the process involving the
formation of this compound as an intermediate does not have
extensive applicability.
[0015] The method of synthesis of 4-halobenzopyrans that is
described in JPA Hei 5-294954 has a long synthesis pathway and is
not satisfactory in terms of yield. It has therefore been desired
to develop a synthesis pathway that is short and yet has a broad
range of applications. The idea of condensing phenol and alcohol
using the Mitsunobu Reaction as described in Synthetic
Communications, 19, 1255-1259 (1989) turned out to be very
inefficient (low yield) when it was applied to the synthesis of the
compounds of the present invention. U.S. Pat. No. 5,463,059 gives
no example of condensation between a dihalomethyl-substituted
propargyl alcohol and phenol and it involves other difficulties
such as the use of expensive anhydrous trifluoroacetic acid and
1,8-diazabicyclo(5.4.0)-7-un- decene.
[0016] Under these circumstances, it has been required to develop a
process for producing 4-substituted benzopyran derivatives that
involves a smaller number of steps, that is economical and which
yet allows for easy post-treatment and purification procedures.
[0017] As a result of their intensive studies, the present
inventors found very useful processes for producing 4-substituted
benzopyran derivatives that were shorter, safe, high in yield and
which yet allowed for easy treatment and purification
procedures.
DISCLOSURE OF THE INVENTION
[0018] The present invention provides the following various
production processes.
[0019] 1. A process for producing 4-substituted benzopyran
derivatives represented by the general formula (G-VI) [where
R.sup.1 and R.sup.2 which may be the same or different represent a
hydrogen atom, an optionally substituted lower alkyl group, an
optionally substituted lower alkoxy group, an optionally
substituted lower alkoxycarbonyl group, an optionally substituted
lower alkylsulfonyl group, an optionally substituted arylsulfonyl
group, a halogen atom, a nitro group, a cyano group or
NY.sub.aY.sub.b (where Y.sub.a and Y.sub.b which may be the same or
different each represent a hydrogen atom, an optionally substituted
lower alkyl group, an optionally substituted lower alkoxycarbonyl
group, an acyl group, an optionally substituted lower alkylsulfonyl
group or an optionally substituted arylsulfonyl group or, when
taken together with the nitrogen atom to which they are bound, may
form a 3- to 8-membered ring) or, when taken together, represent a
substituent .dbd.N.dbd.O--N.dbd.; R.sup.3 and R.sup.4 which may be
the same or different represent a hydrogen atom or an optionally
substituted lower alkyl group or, when taken together with the
carbon atom to which they are bound, represent a polymethylene
group or a substituent forming a heterocycle, provided that R.sup.3
and R.sup.4 are not both a hydrogen atom; R.sup.5 and R.sup.6 which
may be the same or different represent a hydrogen atom or an
optionally substituted lower alkyl group] by any one of the schemes
(1), (2), (3), (4), (5) and (6) containing a plurality of steps as
indicated below, namely,
[0020] (1):
(1-1).fwdarw.(1-2).fwdarw.(1-3).fwdarw.(1-4).fwdarw.(1-5);
[0021] (2):
(2-1).fwdarw.(2-2).fwdarw.(2-3).fwdarw.(2-4).fwdarw.(2-5).fwda-
rw.(1-5);
[0022] (3): (3-1).fwdarw.(3-2);
[0023] (4): (4-1).fwdarw.(4-2);
[0024] (5):
(a-1).fwdarw.(a-2).fwdarw.(b-1).fwdarw.(b-2).fwdarw.(1-5); and
[0025] (6):
(a-1).fwdarw.(a-2).fwdarw.(d-1).fwdarw.(d-2).fwdarw.(d-3);
[0026] (1-1) the step of reacting a compound of the general formula
(II) (where X and Y which may be the same or different represent a
leaving group such as a halogen atom, an optionally substituted
lower alkylsulfonyloxy group or an arylsulfonyloxy group; R.sup.1
and R.sup.2 have the same meanings as defined above) with an olefin
of the general formula (III) (where R.sup.3 and R.sup.4 have the
same meanings as defined above) to give a compound of the general
formula (IV) (where Y, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 have
the same meanings as defined above);
[0027] (1-2) the step of reacting the resulting compound of the
general formula (IV) with a halogenating agent to give a compound
of the general formula (V) (where Y, R.sup.1, R.sup.2, R.sup.3,
R.sup.4 and Hal have the same meanings as defined above);
[0028] (1-3) the step of reacting the resulting compound of the
general formula (V) with a base to give a compound of the general
formula (VI) (where Y, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and Hal
have the same meanings as defined above);
[0029] (1-4) the step of reacting the resulting compound of the
general formula (VI) with a base to give a 4-halobenzopyran of the
general formula (I) (where Y, R.sup.1, R.sup.2, R.sup.3, R.sup.4
and Hal have the same meanings as defined above);
[0030] (1-5) the step of reacting the compound of the general
formula
[0031] (I) with carbon monoxide and a compound of the general
formula (G-III)
R.sup.5R.sup.6NH (G-III)
[0032] (where R.sup.5 and R.sup.6 which may be the same or
different represent a hydrogen atom or an optionally substituted
lower alkyl group) in the presence of a metal to give a
4-substituted benzopyran derivative of the general formula (G-VI)
set forth above;
[0033] (2-1) the step of reacting a compound of the general formula
(III) with acetylene of the general formula (VII) (where R.sup.3
and R.sup.4 have the same meanings as defined above) to give a
compound of the general formula (VIII) (where Y, R.sup.1, R.sup.2,
R.sup.3 and R.sup.4 have the same meanings as defined above);
[0034] (2-2) the step of reacting the resulting compound of the
general formula (VIII) with a reducing agent to give a compound of
the general formula (IX) (where Y, R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 have the same meanings as defined above);
[0035] (2-3) the step of reacting the resulting compound of the
general formula (IX) with a base to give a benzopyran derivative of
the general formula (X) (where R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 have the same meanings as defined above);
[0036] (2-4) the step of reacting the resulting compound of the
general formula (X) with a halogenating agent to give a
3,4-dihalobenzopyran derivative of the general formula (XI) (where
R.sup.1, R.sup.2, R.sup.3, R.sup.4 and Hal have the same meanings
as defined above);
[0037] (2-5) the step of reacting the resulting compound of the
general formula (XI) with a base to give a 4-halobenzopyran
derivative of the general formula (I) (where R.sup.1, R.sup.2,
R.sup.3, R.sup.4 and Hal have the same meanings as defined
above);
[0038] (3-1) the step of reacting a compound of the general formula
(G-I) (where R.sup.1, R.sup.2, R.sup.3 and R.sup.4 have the same
meanings as defined above) with carbon dioxide in the presence of a
base to give a compound of the general formula (G-II) (where
R.sup.1, R.sup.2, R.sup.3 and R.sup.4 have the same meanings as
defined above) or a salt thereof;
[0039] (3-2) the step of reacting the resulting compound of the
general formula (G-II) or salt thereof with a compound of the
genera formula (G-III)
R.sup.5R.sup.6NH (G-III)
[0040] (where R.sup.5 and R.sup.6 which may be the same or
different represent a hydrogen atom or an optionally substituted
lower alkyl group) to give a 4-substituted benzopyran derivative of
the general formula (G-VI) set forth above;
[0041] (4-1) the step of reacting a compound of the general formula
(G-I) (where R.sup.1, R.sup.2, R.sub.3 and R.sup.4 have the same
meanings as defined above) with a compound of the general formula
(G-IVa) (where R.sup.5 and R.sup.6 which may be the same or
different represent a hydrogen atom or an optionally substituted
lower alkyl group) or a compound of the general formula (G-IVb)
R.sup.6aNCO (G-IVb)
[0042] (where R.sup.6a represents an optionally substituted lower
alkyl group) in the presence of a base to give a compound of the
general formula (G-V) (where R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5 and R.sup.6 have the same meanings as defined above);
[0043] (4-2) the step of subjecting the resulting compound of the
general formula (G-V) to thermal cyclization reaction to give a
4-substituted benzoyran derivative of the general formula (G-VI)
set forth above;
[0044] (a-1) the step of reacting an alcohol of the general formula
(C-I) (where R.sup.3 and R.sup.4 have the same meanings as defined
above) with a compound of the general formula (C-II) or (C-III)
R.sup.7SO.sub.2Cl (C-II)
(R.sup.7SO.sub.2).sub.2O (C-III)
[0045] (where R.sup.7 represents an optionally substituted alkyl
group or an optionally substituted aryl group) in the presence of a
base to give a compound of the general formula (C-IV) (where
R.sup.7, R.sup.3 and R.sup.4 have the same meanings as defined
above);
[0046] (a-2) the step of reacting the compound of the general
formula (C-IV) with a compound of the general formula (C-V) (where
R.sup.1 and R.sup.2 have the same meanings as defined above) in the
presence of a base and a monovalent or divalent copper salt to give
a compound of the general formula (C-VI) (where R.sup.1, R.sup.2,
R.sup.3 and R.sup.4 have the same meanings as defined above);
[0047] (b-1) the step of subjecting the compound of the general
formula (C-VI) which is the end product of step (a-2) to
halogenation reaction to give a compound of the general formula
(D-II) (where R.sup.1, R.sup.2, R.sup.3 and R.sup.4 have the same
meanings as defined above and Hal represents a halogen atom);
[0048] (b-2) the step of subjecting the compound of the general
formula (D-II) to thermal cyclization reaction to give a
4-hlobenzopyran derivative of the general formula (I) (where
R.sup.1, R.sup.2, R.sup.3, R.sup.4 and Hal have the same meanings
as defined above);
[0049] (d-1) the step of reacting the compound of the general
formula (C-VI), which is the end product of step (a-2), with a
compound of the general formula (H-II)
O.dbd.C(OR.sup.8).sub.2 (H-II)
[0050] or a compound of the general formula (H-III)
ClC.dbd.O(OR.sup.8) (H-III)
[0051] (where R.sup.8 represents an optionally substituted lower
alkyl group) to give a compound of the general formula (H-IV)
(where R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.8 have the same
meanings as defined above);
[0052] (d-2) the step of subjecting the compound of the general
formula (H-IV) to thermal cyclization reaction to give a compound
of the general formula (H-V) (where R.sup.1, R.sup.2, R.sup.3,
R.sup.4 and R.sup.8 have the same meanings as defined above);
[0053] (d-3) the step of hydrolyzing the resulting compound of the
general formula (H-V) and then subjecting the hydrolyzate to
dehydrative condensation with a compound of the general formula
(G-III)
R.sup.5R.sup.6NH (G-III)
[0054] (where R.sup.5 and R.sup.6 which may be the same or
different represent a hydrogen atom or an optionally substituted
lower alkyl group) to give a 4-substituted benzopyran derivative of
the general formula (G-VI) set forth above.
[0055] 2. A process for producing 4-substituted benzopyran
derivatives represented by the general formula (G-VIa) (where
R.sup.1a represents a lower perfluoroalkyl group, a nitro group or
a cyano group; R.sup.3a and R.sup.4a which may be the same or
different represent a hydrogen atom, an optionally substituted
lower alkyl group or, when taken together with the carbon atom to
which they are bound, represent a polymethylene group or a
substituent forming a heterocycle, provided that R.sup.3a and
R.sup.4a are not both a hydrogen atom; R.sup.5 and R.sup.6 which
may be the same or different represent a hydrogen atom or an
optionally substituted lower alkyl group) by any one of the schemes
(1a) and (2a) containing a plurality of steps as indicated below,
namely,
[0056] (1a)
(1a-1).fwdarw.(1a-2).fwdarw.(1a-3).fwdarw.(1a-4).fwdarw.(1a-5)- ;
and
[0057] (2a)
(2a-1).fwdarw.(2a-2).fwdarw.(2a-3).fwdarw.(2a-4).fwdarw.(2a-5)-
.fwdarw.(1a-5)
[0058] (1a-1) the step of reacting a compound of the general
formula (IIa) (where X and Y which may be the same or different
represent a leaving group such as a halogen atom, an optionally
substituted lower alkylsulfonyloxy group or an arylsulfonyloxy
group; R.sup.1a has the same meaning as defined above) with an
olefin of the general formula (IIIa) (where R.sup.3a and R.sup.4a
have the same meanings as defined above) to give a compound of the
general formula (IVa) (where Y, R.sup.1a, R.sup.3a and R.sup.4a
have the same meanings as defined above);
[0059] (1a-2) the step of reacting the resulting compound of the
general formula (IVa) with a halogenating agent to give a compound
of the general formula (Va) (where Y, R.sup.1a, R.sup.3a and
R.sup.4a have the same meanings as defined above, and Hal
represents a halogen atom);
[0060] (1a-3) the step of reacting the resulting compound of the
general formula (Va) with a base to give a compound of the general
formula (VIa) (where Y, R.sup.1a, R.sup.3a, R.sup.4a and Hal have
the same meanings as defined above);
[0061] (1a-4) the step of reacting the resulting compound of the
general formula (VIa) with a base to give a compound of the general
formula (Ia) (where R.sup.1a, R.sup.3a, R.sup.4a and Hal have the
same meanings as defined above);
[0062] (Ia-5) the step of reacting the resulting compound of the
general formula (Ia) with carbon monoxide and a compound of the
general formula (G-III)
R.sup.5R.sup.6NH (G-III)
[0063] (where R.sup.5 and R.sup.6 which may be the same or
different represent a hydrogen atom or an optionally substituted
lower alkyl group) in the presence of a metal to give a
4-substituted benzopyran derivative of the general formula (G-VIa)
set forth above (where R.sup.1a, R.sup.3a, R.sup.4, R.sup.5 and
R.sup.6 have the same meanings as defined above);
[0064] (2a-1) the step of reacting a compound of the general
formula (IIa) with acetylene of the general formula (VIIa) (where
R.sup.3a and R.sup.4a have the same meanings as defined above) to
give a compound of the general formula (VIIIa) (where Y, R.sup.1a,
R.sup.3a and R.sup.4a have the same meanings as defined above);
[0065] (2a-2) the step of treating the resulting compound of the
general formula (VIIIa) with a reducing agent to give a compound of
the general formula (IXa) (where Y, R.sup.1a, R.sup.3a and R.sup.4a
have the same meanings as defined above);
[0066] (2a-3) the step of reacting the resulting compound of the
general formula (IXa) with a base to give a benzopyran derivative
of the general formula (Xa) (where R.sup.1a, R.sup.3a and R.sup.4a
have the same meanings as defined above);
[0067] (2a-4) the step of reacting the resulting compound of the
general formula (Xa) with a halogenating agent to give a
3,4-dihalobenzopyran derivative of the general formula (XIa) (where
R.sup.1a, R.sup.3a and R.sup.4a have the same meanings as defined
above and Hal represents a halogen atom);
[0068] (2a-5) the step of treating the resulting compound of the
general formula (XIa) with a base to give a 4-halobenzopyran
derivative of the general formula (Ia) set forth above.
[0069] 3. A process for producing 4-substituted benzopyran
derivatives represented by the general formula (G-VIb) (where
R.sup.1b represents a lower perfluoroalkyl group; R.sup.3b and
R.sup.4b which may be the same or different represent a hydrogen
atom, an optionally substituted lower alkyl group or, when taken
together with the carbon atom to which they are bound, represent a
polymethylene group, provided that R.sup.3b and R.sup.4b are not
both a hydrogen atom; R.sup.5 and R.sup.6 which may be the same or
different represent a hydrogen atom or an optionally substituted
lower alkyl group) by any one of the schemes (1b) and (2b)
containing a plurality of steps as indicated below, namely,
[0070] (1b)
(1b-1).fwdarw.(1b-2).fwdarw.(1b-3).fwdarw.(1b-4).fwdarw.(1b-5)- ;
and
[0071] (2b)
(2b-1).fwdarw.(2b-2).fwdarw.(2b-3).fwdarw.(2ba-4).fwdarw.(2b-5-
).fwdarw.(1b-5);
[0072] (1b-1) the step of reacting a compound of the general
formula (IIb) (where X and Y which may be the same or different
represent a leaving group such as a halogen atom, an optionally
substituted lower alkylsulfonyloxy group or an arylsulfonyloxy
group; R.sup.1b has the same meaning as defined above) with an
olefin of the general formula (IIIb) (where R.sup.3b and R.sup.4b
have the same meanings as defined above) to give a compound of the
general formula (IVb) (where Y, R.sup.1b, R.sup.3b and R.sup.4b
have the same meanings as defined above);
[0073] (1b-2) the step of reacting the resulting compound of the
general formula (IVb) with a halogenating agent to give a compound
of the general formula (Vb) (where Y, R.sup.1b, R.sup.3b and
R.sup.4b have the same meanings as defined above, and Hal
represents a halogen atom);
[0074] (1b-3) the step of reacting the resulting compound of the
general formula (Vb) with a base to give a compound of the general
formula (VIb) (where Y, R.sup.1b, R.sup.3b, R.sup.4b and Hal have
the same meanings as defined above);
[0075] (1b-4) the step of reacting the resulting compound of the
general formula (VIb) with a base to give a compound of the general
formula (Ib) (where R.sup.1b, R.sup.3b, R.sup.1b and Hal have the
same meanings as defined above);
[0076] (Ib-5) the step of reacting the resulting compound of the
general formula (Ib) with carbon monoxide and a compound of the
general formula (G-III)
R.sup.5R.sup.6NH (G-III)
[0077] (where R.sup.5 and R.sup.6 which may be the same or
different represent a hydrogen atom or an optionally substituted
lower alkyl group) in the presence of a metal to give a
4-substituted benzopyran derivative of the general formula (G-VIb)
set forth above (where R.sup.1b, R.sup.3b, R.sup.4b, R.sup.5 and
R.sup.6 have the same meanings as defined above);
[0078] (2b-1) the step of reacting a compound of the general
formula (IIb) with acetylene of the general formula (VIIb) (where
R.sup.3b and R.sup.4b have the same meanings as defined above) to
give a compound of the general formula (VIIIb) (where Y, Rb ,
R.sup.3b and R.sup.4b have the same meanings as defined above);
[0079] (2b-2) the step of treating the resulting compound of the
general formula (VIIIb) with a reducing agent to give a compound of
the general formula (IXb) (where Y, R.sup.1b, R.sup.3b and R.sup.4b
have the same meanings as defined above);
[0080] (2b-3) the step of reacting the resulting compound of the
general formula (IXb) with a base to give a benzopyran derivative
of the general formula (Xb) (where R.sup.1b, R.sup.3b and R.sup.4b
have the same meanings as defined above);
[0081] (2b-4) the step of reacting the resulting compound of the
general formula (Xb) with a halogenating agent to give a
3,4-dihalobenzopyran derivative of the general formula (XIb) (where
R.sup.1b, R.sup.3b, R.sup.1b and Hal have the same meanings as
defined above);
[0082] (2b-5) the step of treating the resulting compound of the
general formula (XIb) with a base to give a 4-halobenzopyran
derivative of the general formula (Ib) set forth above.
[0083] 4. A process for producing 4-substituted benzopyran
derivatives represented by the general formula (G-VIc) (where
R.sup.1b represents a lower perfluoroalkyl group; R.sup.3c and
R.sup.4c which are the same represent a lower alkyl group or a
lower fluoroalkyl group; R.sup.5c represents a hydrogen atom and
R.sup.6 represents an optionally substituted lower alkyl group) by
any one of the schemes (1c) and (2c) containing a plurality of
steps as indicated below, namely,
[0084] (1c)
(1c-1).fwdarw.(1c-2).fwdarw.(1c-3).fwdarw.(1c-4).fwdarw.(1c-5)- ;
and
[0085] (2c)
(2c-1).fwdarw.(2c-2).fwdarw.(2c-3).fwdarw.(2c-4).fwdarw.(2c-5)-
.fwdarw.(1c-5);
[0086] (1c-1) the step of reacting a compound of the general
formula (IIb) (where X and Y which may be the same or different
represent a leaving group such as a halogen atom, an optionally
substituted lower alkylsulfonyloxy group or an arylsulfonyloxy
group; R.sup.1b has the same meaning as defined above) with an
olefin of the general formula (IIIc) (where R.sup.3c and R.sup.4c
have the same meanings as defined above) to give a compound of the
general formula (IVc) (where Y, R.sup.1b, R.sup.3c and R.sup.4c
have the same meanings as defined above);
[0087] (1c-2) the step of reacting the resulting compound of the
general formula (IVc) with a halogenating agent to give a compound
of the general formula (Vc) (where Y, R.sup.1b, R.sup.3c and
R.sup.4c have the same meanings as defined above, and Hal
represents a halogen atom);
[0088] (1c-3) the step of reacting the resulting compound of the
general formula (Vc) with a base to give a compound of the general
formula (VIc) (where Y, R.sup.1b, R.sup.3c and R.sup.4c have the
same meanings as defined above, and Hal represents a halogen
atom);
[0089] (1c-4) the step of reacting the resulting compound of the
general formula (VIc) with a base to give a compound of the general
formula (Ic) (where R.sup.1b, R.sup.3c, R.sup.4c and Hal have the
same meanings as defined above);
[0090] (Ic-5) the step of reacting the resulting compound of the
general formula (Ic) with carbon monoxide and a compound of the
general formula (G-IIIc)
R.sup.5cR.sup.6aNH (G-IIIc)
[0091] (where R.sup.5c represents a hydrogen atom and R.sup.6a
represents an optionally substituted lower alkyl group) in the
presence of a metal to give a 4-substituted benzopyran derivative
of the general formula (G-VIc) set forth above;
[0092] (2c-1) the step of reacting a compound of the general
formula (IIb) with acetylene of the general formula (VIIc) (where
R.sup.3c and R.sup.4c have the same meanings as defined above) to
give a compound of the general formula (VIIIc) (where Y, R.sup.1b,
R.sup.3c and R.sup.4c have the same meanings as defined above);
[0093] (2c-2) the step of treating the resulting compound of the
general formula (VIIIc) with a reducing agent to give a compound of
the general formula (IXc) (where Y, R.sup.1b, R.sup.3c and R.sup.4c
have the same meanings as defined above);
[0094] (2c-3) the step of reacting the resulting compound of the
general formula (IXc) with a base to give a benzopyran derivative
of the general formula (Xc) (where R.sup.1b, R.sup.3c and R.sup.4c
have the same meanings as defined above);
[0095] (2c-4) the step of reacting the resulting compound of the
general formula (Xc) with a halogenating agent to give a
3,4-dihalobenzopyran derivative of the general formula (XIc) (where
R.sup.1b, R.sup.3c, R.sup.4c and Hal have the same meanings as
defined above);
[0096] (2c-5) the step of treating the resulting compound of the
general formula (XIc) with a base to give a 4-halobenzopyran
derivative of the general formula (Ic) set forth above.
[0097] 5. A process for producing 4-substituted benzopyran
derivatives represented by the general formula (G-VId) (where
R.sup.1b represents a lower perfluoroalkyl group; R.sup.5c
represents a hydrogen atom; and R.sup.6b represents a lower alkyl
group which may optionally have a cyano group) by any one of the
schemes (1d) and (2d) containing a plurality of steps as indicated
below, namely,
[0098] (1d)
(1d-1).fwdarw.(1d-2).fwdarw.(1d-3).fwdarw.(1d-4).fwdarw.(1d-5)- ;
and
[0099] (2d)
(2d-1).fwdarw.(2d-2).fwdarw.(2d-3).fwdarw.(2d-4).fwdarw.(2d-5)-
.fwdarw.(1d-5);
[0100] (1d-1) the step of reacting a compound of the general
formula (IId) (where X and Y which may be the same or different
represent a leaving group such as a halogen atom, an optionally
substituted lower alkylsulfonyloxy group or an arylsulfonyloxy
group; R.sup.1b has the same meaning as defined above) with an
olefin of the general formula (IIId) set forth below to give a
compound of the general formula (IVd) (where Y and R.sup.1b have
the same meanings as defined above);
[0101] (1d-2) the step of reacting the resulting compound of the
general formula (IVd) with a halogenating agent to give a compound
of the general formula (Vd) (where Y and R.sup.1b have the same
meanings as defined above, and Hal represents a halogen atom);
[0102] (1d-3) the step of reacting the resulting compound of the
general formula (Vd) with a base to give a compound of the general
formula (VId) (where Y, R.sup.1b and Hal have the same meanings as
defined above);
[0103] (1d-4) the step of reacting the resulting compound of the
general formula (VId) with a base to give a 4-halobenzopyran
derivative of the general formula (Id) (where R.sup.1b and Hal have
the same meanings as defined above);
[0104] (1d-5) the step of reacting the resulting compound of the
general formula (Id) with carbon monoxide and a compound of the
general formula (G-IIId)
R.sup.5cR.sup.6NH (G-IIId)
[0105] (where R.sup.5c represents a hydrogen atom and R.sup.6b
represents a lower alkyl group which may optionally have a cyano
group) in the presence of a metal to give a 4-substituted
benzopyran derivative of the general formula (G-VId) set forth
above;
[0106] (2d-1) the step of reacting a compound of the general
formula (IId) with acetylene of the general formula (VIId) to give
a compound of the general formula (VIIId) (where Y and R.sup.1b
have the same meanings as defined above);
[0107] (2d-2) the step of treating the resulting compound of the
general formula (VIIId) with a reducing agent to give a compound of
the general formula (IXd) (where Y and R.sup.1b have the same
meanings as defined above);
[0108] (2d-3) the step of reacting the resulting compound of the
general formula (IXd) with a base to give a benzopyran derivative
of the general formula (Xd) (where R.sup.1b has the same meaning as
defined above);
[0109] (2d-4) the step of reacting the resulting compound of the
general formula (Xd) with a halogenating agent to give a
3,4-dihalobenzopyran derivative of the general formula (XId) (where
R.sup.1b and Hal have the same meanings as defined above);
[0110] (2d-5) the step of treating the resulting compound of the
general formula (XId) with a base to give a 4-halobenzopyran
derivative of the general formula (Id) (where R.sup.1b and Hal have
the same meanings as defined above).
[0111] 6. A process for producing 4-substituted benzopyran
derivatives represented by the general formula (G-VIe) (where
R.sup.1e represents a trifluoromethyl group or a pentafluoroethyl
group; R.sup.5c represents a hydrogen atom; R.sup.6d represents a
cyanoethyl group) by any one of the schemes (1e) and (2e)
containing a plurality of steps as indicated below, namely,
[0112] (1e)
(1e-1).fwdarw.(1e-2).fwdarw.(1e-3).fwdarw.(1e-4).fwdarw.(1e-5)- ;
and
[0113] (2e)
(2e-1).fwdarw.(2e-2).fwdarw.(2e-3).fwdarw.(2e-4).fwdarw.(2e-5)-
.fwdarw.(1e-5);
[0114] (1e-1) the step of reacting a compound of the general
formula (IIe) (where R.sup.1c has the same meaning as defined
above) with an olefin of the general formula (IIId) set forth below
to give a compound of the general formula (IVe) (where R.sup.1e has
the same meaning as defined above);
[0115] (1e-2) the step of reacting the resulting compound of the
general formula (IVe) with a halogenating agent to give a compound
of the general formula (Ve) (where R.sup.1e has the same meaning as
defined above; Hal represents a halogen atom);
[0116] (1e-3) the step of reacting the resulting compound of the
general formula (Ve) with a base to give a compound of the general
formula (VIe) (where R.sup.1e and Hal have the same meanings as
defined above);
[0117] (1e-4) the step of reacting the resulting compound of the
general formula (VIe) with a base to give a 4-halobenzopyran
derivative of the general formula (Ie) (where R.sup.1e and Hal have
the same meanings as defined above);
[0118] (Ie-5) the step of reacting the resulting compound of the
general formula (Ie) with carbon monoxide and a compound of the
general formula (G-IIIe)
R.sup.5cR.sup.6dNH (G-IIIe)
[0119] (where R.sup.5c represents a hydrogen atom and R.sup.6d
represents a cyanoethyl group) in the presence of a metal to give a
4-substituted benzopyran derivative of the general formula (G-VIe)
set forth above;
[0120] (2e-1) the step of reacting a compound of the general
formula (IIe2) (where R.sup.1e has the same meaning as defined
above) with acetylene of the general formula (VIId) set forth below
to give a compound of the general formula (VIIIe) (where R.sup.1e
has the same meaning as defined above);
[0121] (2e-2) the step of treating the resulting compound of the
general formula (VIIIe) with a reducing agent to give a compound of
the general formula (IXe) (where R.sup.1e has the same meaning as
defined above);
[0122] (2e-3) the step of reacting the resulting compound of the
general formula (IXe) with a base to give a benzopyran derivative
of the general formula (Xd) (where R.sup.1d has the same meaning as
defined above);
[0123] (2e-4) the step of reacting the resulting compound of the
general formula (Xd) with a halogenating agent to give a
3,4-dihalobenzopyran derivative of the general formula (XIe) (where
R.sup.1e and Hal have the same meanings as defined above);
[0124] (2e-5) the step of treating the resulting compound of the
general formula (XIe) with a base to give a 4-halobenzopyran
derivative of the general formula (Ie) set forth above.
[0125] 7. A process according to scheme (3) or (4) in Process 1 for
producing 4-substituted benzopyran derivatives represented by the
general formula (G-VIg) [where R.sup.1g and R.sup.2g which may be
the same or different represent a hydrogen atom, an optionally
substituted lower alkyl group, an optionally substituted lower
alkoxy group, an optionally substituted lower alkoxycarbonyl group,
an optionally substituted lower alkylsulfonyl group, an optionally
substituted arylsulfonyl group, a halogen atom, a nitro group, a
cyano group or NY.sub.aY.sub.b (where Y.sub.a and Y.sub.b which may
be the same or different each represent a hydrogen atom, an
optionally substituted lower alkyl group, an optionally substituted
lower alkoxycarbonyl group, an acyl group, an optionally
substituted lower alkylsulfonyl group or an optionally substituted
arylsulfonyl group or, when taken together with the nitrogen atom
to which they are bound, may form a 3- to 8-membered ring);
R.sup.3g and R.sup.4g which may be the same or different represent
a hydrogen atom or an optionally substituted .alpha.-haloalkyl
group, provided that they are not both a hydrogen atom; R.sup.5 and
R.sup.6 which may be the same or different represent a hydrogen
atom or an optionally substituted lower alkyl group] by the steps
of:
[0126] reacting an alcohol of the general formula (C-Ig) (where
R.sup.3g and R.sup.4g have the same meanings as defined above) with
a compound of the general formula (C-II) or (C-III)
R.sup.7SO.sub.2Cl (C-II)
(R.sup.7SO.sub.2).sub.2O (C-III)
[0127] (where R.sup.7 represents an optionally substituted alkyl
group or an optionally substituted aryl group) in the presence of a
base to give a compound of the general formula (C-IVg) (where
R.sup.7, R.sup.3g and R.sup.4g have the same meanings as defined
above);
[0128] reacting the compound of the general formula (C-IVg) with a
compound of the general formula (C-Vg) (where R.sup.1g and R.sup.2g
have the same meanings as defined above) in the presence of a base
and a monovalent or divalent copper salt to give a compound of the
general formula (G-Ig) (where R.sup.1g, R.sup.2g, R.sup.3g and
R.sup.4g have the same meanings as defined above);
[0129] reacting the compound of the general formula (G-Ig) with
carbon dioxide in the presence of a base to give a compound of the
general formula (G-IIg) (where R.sup.1g, R.sup.2g, R.sup.3g and
R.sup.4g have the same meanings as defined above) or a salt
thereof;
[0130] reacting the compound of the general formula (G-IIg) or salt
thereof with a compound of the general formula (G-III)
R.sup.5R.sup.6NH (G-III)
[0131] (where R.sup.5 and R.sup.6 which may be the same or
different represent a hydrogen atom or an optionally substituted
lower alkyl group) to give a compound of the general formula (G-Vg)
(where R.sup.1g, R.sup.2g, R.sup.3g, R.sup.4g, R.sup.5 and R.sup.6
have the same meanings as defined above); or alternatively reacting
the compound of the general formula (G-Ig) (where R.sup.1g,
R.sup.2g, R.sup.3g and R.sup.4g have the same meanings as defined
above) with a compound of the general formula (G-IVa) (where
R.sup.5 and R.sup.6 which may be the same or different represent a
hydrogen atom or an optionally substituted lower alkyl group) or a
compound of the general formula (G-IVb)
R.sup.6aNCO (G-IVb)
[0132] (where R.sup.6a represents an optionally substituted lower
alkyl group) in the presence of a base to give a compound of the
general formula (G-Vg) (where R.sup.1g, R.sup.2g, R.sup.3g,
R.sup.4g, R.sup.5 and R.sup.6have the same meanings as defined
above); and
[0133] subjecting the compound of the general formula (G-Vg) to
thermal cyclization reaction.
[0134] 8. A process according to scheme (3) or (4) in Process 1 or
a process according to Process 7 for producing 4-substituted
benzopyran derivatives represented by the general formula (G-VIh)
set forth below, wherein R.sup.1and R.sup.2 in the general formula
(G-VI) which may be the same or different represent a hydrogen
atom, an optionally substituted lower alkyl group, an optionally
substituted lower alkoxy group, an optionally substituted lower
alkoxycarbonyl group, an optionally substituted lower alkylsulfonyl
group, an optionally substituted arylsulfonyl group, a halogen
atom, a nitro group, a cyano group or NY.sub.aY.sub.b (where
Y.sub.a and Y.sub.b which may be the same or different each
represent a hydrogen atom, an optionally substituted lower alkyl
group, an optionally substituted lower alkoxycarbonyl group, an
acyl group, an optionally substituted lower alkylsulfonyl group or
an optionally substituted arylsulfonyl group or, when taken
together, may form a 3- to 8-membered ring); R.sup.3 and R.sup.4
each represent a fluoromethyl group; and R.sup.5 and R.sup.6 which
may be the same or different represent a hydrogen atom or an
optionally substituted lower alkyl group.
[0135] 9. A process according to scheme (3) or (4) in Process 1 or
a process according to Process 7 for producing 4-substituted
benzopyran derivatives represented by the general formula (G-VIi)
set forth below, wherein R.sup.1 in the general formula (G-VI)
represents a 6-trifluoromethyl group or a 6-pentafluoroethyl group;
R.sup.2 represents a hydrogen atom; R.sup.3 and R.sup.4 each
represent a fluoromethyl group; and R.sup.5 and R.sup.6 which may
be the same or different represent a hydrogen atom or an optionally
substituted lower alkyl group.
[0136] 10. A process according to scheme (3) or (4) in Process 1 or
a process according to Process 7 for producing 4-substituted
benzopyran derivatives represented by the general formula (G-VIj)
set forth below, wherein R.sup.1 in the general formula (G-VI)
represents a 6-trifluoromethyl group or a 6-pentafluoroethyl group;
R.sup.2 represents a hydrogen atom; R.sup.3 and R.sup.4 each
represent a fluoromethyl group; and R.sup.5 represents a hydrogen
atom and R.sup.6 represents a 2-cyanoethyl group.
[0137] 11. A process for producing 4-substituted benzopyran
derivatives represented by the general formula (G-VIg) [where
R.sup.1g and R.sup.2g which may be the same or different represent
a hydrogen atom, an optionally substituted lower alkyl group, an
optionally substituted lower alkoxy group, an optionally
substituted lower alkoxycarbonyl group, an optionally substituted
lower alkylsulfonyl group, an optionally substituted arylsulfonyl
group, a halogen atom, a nitro group, a cyano group or
NY.sub.aY.sub.b (where Y.sub.a and Y.sub.b which may be the same or
different each represent a hydrogen atom, an optionally substituted
lower alkyl group, an optionally substituted lower alkoxycarbonyl
group, an acyl group, an optionally substituted lower alkylsulfonyl
group or an optionally substituted arylsulfonyl group or, when
taken together with the nitrogen atom to which they are bound, may
form a 3- to 8-membered ring); R.sup.3g and R.sup.4g which may be
the same or different represent a hydrogen atom or an optionally
substituted .alpha.-haloalkyl group, provided that they are not
both a hydrogen atom; R.sup.5 and R.sup.6 which may be the same or
different represent a hydrogen atom or an optionally substituted
lower alkyl group], wherein a compound represented by the general
formula (G-VIg) (where R.sup.1g, R.sup.2g, R.sup.3g, R.sup.4g,
R.sup.5 and R.sup.6 have the same meanings as defined above).
[0138] 12. A process according to Process 11 for producing
4-substituted benzopyran derivatives represented by the general
formula (G-VIl) set forth below, wherein R.sup.1g and R.sup.2g in
the general formula (G-VIg) which may be the same or different
represent a hydrogen atom, an optionally substituted lower alkyl
group, an optionally substituted lower alkoxy group, an optionally
substituted lower alkoxycarbonyl group, an optionally substituted
lower alkylsulfonyl group, an optionally substituted arylsulfonyl
group, a halogen atom, a nitro group, a cyano group or
NY.sub.aY.sub.b (where Y.sub.a and Y.sub.b which may be the same or
different each represent a hydrogen atom, an optionally substituted
lower alkyl group, an optionally substituted lower alkoxycarbonyl
group, an acyl group, an optionally substituted lower alkylsulfonyl
group or an optionally substituted arylsulfonyl group or, when
taken together with the nitrogen atom to which they are bound, may
form a 3- to 8-membered ring); R.sup.3g and R.sup.4g each represent
a fluoromethyl group; R.sup.5 and R.sup.6 which may be the same or
different represent a hydrogen atom or an optionally substituted
lower alkyl group.
[0139] 13. A process according to Process 11 for producing
4-substituted benzopyran derivatives represented by the general
formula (G-VIm) set forth below, wherein R.sup.1g in the general
formula (G-VIg) represents a 6-trifluoromethyl group or a
6-pentafluoroethyl group; R.sup.2g represents a hydrogen atom;
R.sup.3g and R.sup.4g each represent a fluoromethyl group; and
R.sup.5 and R.sup.6 which may be the same or different represent a
hydrogen atom or an optionally substituted lower alkyl group.
[0140] 14. A process according to Process 11 for producing
4-substituted benzopyran derivatives represented by the general
formula (G-VIn) set forth below, wherein R.sup.1g in the general
formula (G-VIg) represents a 6-trifluoromethyl group or a
6-pentafluoroethyl group; R.sup.2g represents a hydrogen atom;
R.sup.3g and R.sup.4g each represent a fluoromethyl group; and
R.sup.5 represetns a hydrogen atom and R.sup.6 represents a
2-cyanoethyl group.
[0141] 15. A process according to scheme (5) or (6) in Process 1
for producing 4-substituted benzopyran derivatives represented by
the general formula (Iz) set forth below [where R.sup.1g and
R.sup.2g, which may be the same or different represent a hydrogen
atom, an optionally substituted lower alkyl group, a halogen atom,
an optionally substituted lower alkoxy group, NY.sub.aY.sub.b
(where Y.sub.a and Y.sub.b which may be the same or different each
represent a hydrogen atom, an optionally substituted lower alkyl
group, an optionally substituted lower alkoxycarbonyl group, an
acyl group, an optionally substituted lower alkylsulfonyl group or
an optionally substituted arylsulfonyl group or, when taken
together with the nitrogen atom to which they are bound, may form a
3- to 8-membered ring), a nitro group, a cyano group, an optionally
substituted lower alkoxycarbonyl group, an optionally substituted
lower alkylsulfonyl group or an optionally substituted arylsulfonyl
group; Hal represents a halogen atom] by the steps of:
[0142] reacting an alcohol of the general formula (C-Ia) with a
compound of the general formula (C-II) or (C-III)
R.sup.7SO.sub.2Cl (C-II)
(R.sup.7SO.sub.2).sub.2O (C-III)
[0143] (where R.sup.7 represents an optionally substituted lower
alkyl group or an optionally substituted aryl group) in the
presence of a base to give a compound of the general formula
(C-IVa) (where R.sup.7 has the same meaning as defined above);
[0144] reacting the compound of the general formula (C-IVa) with a
compound of the general formula (C-Vg) (where R.sup.1g and R.sup.2g
have the same meanings as defined above) in the presence of a base
and a monovalent or divalent copper salt to give a compound of the
general formula (G-VIa) (where R.sup.1g and R.sup.2g have the same
meanings as defined above);
[0145] subjecting the compound of the general formula (G-VIa) to
halogenation reaction to give a compound of the general formula
(D-IIa) (where R.sup.1g, R.sup.2g and Hal have the same meanings as
defined above); and
[0146] subjecting the compound of the general formula (D-IIa) to
thermal cyclization reaction.
[0147] 16. A process according to scheme (5) or (6) in Process 1
for producing 4-substituted benzopyran derivatives represented by
the general formula (Iy) set forth below (where R.sup.1 in the
general formula (I) represents a 6-trifluoromethyl group or a
6-pentafluoroethyl group; R.sup.2 represents a hydrogen atom;
R.sup.3 and R.sup.4 both represent a fluoromethyl group; X is a
bromine atom) by
[0148] the steps of:
[0149] reacting an alcohol of the general formula (C-Ia) with a
compound of the general formula (C-II) or (C-III)
R.sup.7SO.sub.2Cl (C-II)
(R.sup.7SO.sub.2).sub.2O (C-III)
[0150] (where R.sup.7 represents an optionally substituted lower
alkyl group or an optionally substituted aryl group) in the
presence of a base to give a compound of the general formula
(C-IVa) (where R.sup.7 has the same meaning as defined above);
[0151] reacting the compound of the general formula (C-IVa) with a
4-substituted phenol derivative of the general formula (C-Va)
(where R.sup.1e has the same meaning as defined above) in the
presence of a base and a monovalent or divalent copper salt to give
a compound of the general formula (G-VIb) (where R.sup.1e has the
same meaning as defined above);
[0152] subjecting the compound of the general formula (G-VIb) to
bromination reaction to give a compound of the general formula
(D-IIb) (where R.sup.1e has the same meaning as defined above);
and
[0153] subjecting the compound of the general formula (G-IIb) to
thermal cyclization reaction.
[0154] 17. A process according to scheme (5) or (6) in Process 1
for producing 4-substituted benzopyran derivatives represented by
the general formula (G-VIz) set forth below, wherein R.sup.1 in the
general formula (G-VI) represents a 6-trifluoromethyl group or a
6-pentafluoroethyl group; R.sup.2 represents a hydrogen atom;
R.sup.3 and R.sup.4 each represent a fluoromethyl group; and
R.sup.5 and R.sup.6 which may be the same or different represent a
hydrogen atom or an optionally substituted lower alkyl group.
[0155] 18. A process according to scheme (5) or (6) in Process 1
for producing 4-substituted benzopyran derivatives represented by
the general formula (G-VIy) set forth below, wherein R.sup.1 in the
general formula (G-VI) represents a 6-trifluoromethyl group or a
6-pentafluoroethyl group; R.sup.2 represents a hydrogen atom;
R.sup.3 and R.sup.4 each represent a fluoromethyl group; and
R.sup.5 represents a hydrogen atom and R.sup.6 represents a
2-cyanoethyl group.
[0156] 19. A process according to scheme (5) or (6) in Process 1,
which uses a compound of the general formula (C-IVb) as obtained by
reacting methanesulfonyl chloride of the general formula (C-II)
where R.sup.7 is a methyl group with a compound of the general
formula (C-I) where R.sup.3 and R.sup.4 are each a fluoromethyl
group.
[0157] 20. A process according to scheme (5) or (6) in Process 1,
which uses a compound of the general formula (C-IVc) (where Tol
represents a tolyl group) that is obtained by reacting
p-toluenesulfonyl chloride of the general formula (C-II) where
R.sup.7 is a p-tolyl group with a compound of the general formula
(C-I) where R.sup.3 and R.sup.4 are each a fluoromethyl group in
the presence of a base.
[0158] 21. A process according to scheme (5) or (6) in Process 1,
which uses a compound of the general formula (C-VIb) (where
R.sup.1e has the same meaning as defined above) that is obtained by
reacting a compound of the general formula (C-Va) set forth below
(where R.sup.1e has the same meaning as defined above; R.sup.1 in
the general formula (C-V) is a 4-trifluoromethyl group or a
4-pentafluoroethyl group and R.sup.2 is a hydrogen atom) with a
compound of the general formula (C-IVb) or (C-IVc) set forth below,
wherein Tol represents a p-tolyl group.
[0159] 22. A process according to scheme (5) or (6) in Process 1,
which uses a compound of the general formula (D-IIb) (where
R.sup.1e has the same meaning as defined above) that is obtained by
brominating a compound of the general formula (C-VIb) set forth
below (where R.sup.1e has the same meaning as defined above;
R.sup.1 in the general formula (C-VI) is a 4-trifluoromethyl group
or a 4-pentafluoroethyl group; R.sup.2 is a hydrogen atom; R.sup.3
and R.sup.4 are both a fluoromethyl group).
[0160] 23. A process according to scheme (5) or (6) in Process 1,
which uses a 4-bromobenzopyran derivative of the general formula
(Iq) (where R.sup.1e has the same meaning as defined above) that is
obtained by subjecting a compound of the general formula (D-IIb)
set forth below (where R.sup.1e has the same meaning as defined
above; R.sup.1 in the general formula (D-II) is a 4-trifluoromethyl
group or a 4-pentafluoroethyl group; R.sup.2 is a hydrogen atom;
R.sup.3 and R.sup.4 are both a fluoromethyl group; X is a bromine
atom) to thermal cyclization reaction.
[0161] The general formula (G-1) and the general formula (C-VI)
represent substantially the same compound. R.sup.1 and R.sup.1g
represent substantially the same group, so do R.sup.2 and
R.sup.2g.
[0162] The general formula (C-V) and the general formula (C-Vg)
represent substantially the same compound.
[0163] The general formulae (C-VIe), (C-VIj) and (C-VIy) represent
substantially the same compound.
BEST MODE FOR CARRYING OUT THE INVENTION
[0164] As mentioned above, the present invention relates to a
process for producing 4-substituted benzopyran derivatives
represented by the general formula (G-VI) [where R.sup.1and R.sup.2
which may be the same or different represent a hydrogen atom, an
optionally substituted lower alkyl group, an optionally substituted
lower alkoxy group, an optionally substituted lower alkoxycarbonyl
group, an optionally substituted lower alkylsulfonyl group, an
optionally substituted arylsulfonyl group, a halogen atom, a nitro
group, a cyano group or NY.sub.aY.sub.b (where Y.sub.a and Y.sub.b
which may be the same or different each represent a hydrogen atom,
an optionally substituted lower alkyl group, an optionally
substituted lower alkoxycarbonyl group, an acyl group, an
optionally substituted lower alkylsulfonyl group or an optionally
substituted arylsulfonyl group or, when taken together with the
nitrogen atom to which they are bound, may form a 3- to 8-membered
ring) or, when taken together, represent a substituent
.dbd.N.dbd.O--N.dbd.; R.sup.3 and R.sup.4 which may be the same or
different represent a hydrogen atom or an optionally substituted
lower alkyl group or, when taken together with the carbon atom to
which they are bound, represent a polymethylene group or a
substituent forming a heterocycle, provided that R.sup.3 and
R.sup.4 are not both a hydrogen atom; R.sup.5 and R.sup.6 which may
be the same or different represent a hydrogen atom or an optionally
substituted lower alkyl group] by any one of the schemes (1), (2),
(3), (4), (5) and (6) containing a plurality of steps as indicated
below, namely,
[0165] (1):
(1-1).fwdarw.(1-2).fwdarw.(1-3).fwdarw.(1-4).fwdarw.(1-5);
[0166] (2):
(2-1).fwdarw.(2-2).fwdarw.(2-3).fwdarw.(2-4).fwdarw.(2-5).fwda-
rw.(1-5);
[0167] (3): (3-1).fwdarw.(3-2);
[0168] (4): (4-1).fwdarw.(4-2);
[0169] (5):
(a-1).fwdarw.(a-2).fwdarw.(b-1).fwdarw.(b-2).fwdarw.(1-5); and
[0170] (6):
(a-1).fwdarw.(a-2).fwdarw.(d-1).fwdarw.(d-2).fwdarw.(d-3).
[0171] Referring to the 4-substituted benzopyran derivatives
represented by the general formula (G-VI), examples of the
optionally substituted lower alkyl group as R.sup.1 and R.sup.2
include a lower alkyl group, a lower haloalkyl group, a lower
perfluoroalkyl group, a lower alkyl group having a halogen atom as
a substituent, and an .alpha.-haloalkyl group; examples of the
optionally substituted lower alkoxy group as and R.sup.2 include a
lower alkoxy group and a lower haloalkoxy group; examples of
NY.sub.aY.sub.b as R.sup.1 and R.sup.2 include an amino group and
an acylamino group.
[0172] Examples of the optionally substituted lower alkyl group as
R.sup.3 and R.sup.4 include a lower alkyl group, a substituted
lower alkyl group, a lower fluoroalkyl group, a lower alkyl group
having a halogen atom as a substituent, and an .alpha.-haloalkyl
group.
[0173] On the pages that follow, the practice of the present
invention is described for six different schemes grouped in three,
the first consisting of schemes (1) and (2), the second being
schemes (3) and (4), and the third being schemes (5) and (6).
[0174] A. Schemes (1) and (2):
[0175] Speaking of the process according to schemes (1) and (2),
the preferred substituents in the 4-substituted benzopyran
derivatives of the general formula (G-VI) are exemplified by the
following.
[0176] Preferably, R.sup.1 and R.sup.2 which may be the same or
different represent a hydrogen atom, a lower alkyl group, a lower
haloalkyl group, a halogen atom, a lower haloalkoxy group, an amino
group, an acylamino group, a nitro group, a cyano group, an
alkoxycarbonyl group, an optionally substituted lower alkylsulfonyl
group, an arylsulfonyl group or, when taken together, represent a
substituent .dbd.N--O--N.dbd..
[0177] Preferably, R.sup.3 and R.sup.4 which may be the same or
different represent a hydrogen atom or an optionally substituted
lower alkyl group or, when taken together with the carbon atom to
which they are bound, represent a polymethylene group or a
substituent forming a heterocycle, provided that R.sup.3 and
R.sup.4 are not both a hydrogen atom.
[0178] Preferably, R.sup.5 and R.sup.6 which may be the same or
different represent a hydrogen atom or an optionally substituted
lower alkyl group.
[0179] In schemes (1) and (2), the term "halogen atom" means a
fluorine atom, a chlorine atom, a bromine atom or an iodine
atom.
[0180] In schemes (1) and (2), the lower alkyl group means a
straight-chained or branched alkyl group having 1-4 carbon atoms or
a cyclic alkyl group having 3-6 carbon atoms; examples include a
methyl group, an ethyl group, an n-propyl group, an n-butyl group,
an i-propyl group, an i-butyl group, a sec-butyl group, a
tert-butyl group, a cyclopropyl group, a cyclobutyl group, a
cyclopentyl group and a cyclohexyl group.
[0181] In schemes (1) and (2), the lower alkoxy group means a
straight-chained or branched alkoxy group having 1-4 carbon atoms
or a cyclic alkoxy group having 3-6 carbon atoms; examples include
a methoxy group, an ethoxy group, an n-propoxy group, an n-butoxy
group, an i-propoxy group, an i-butoxy group, a sec-butoxy group, a
tert-butoxy group, a cyclopropoxy group, a cyclobutoxy group, a
cyclopentoxy group and a cyclohexoxy group.
[0182] The lower haloalkyl group as R.sup.1 and R.sup.2 means a
straight-chained or branched alkyl group having 1-4 carbon atoms or
a cyclic alkyl group having 3-6 carbon atoms, in which at least one
hydrogen atom is replaced by a halogen atom; examples include a
fluoromethyl group, a difluoromethyl group, a trifluoromethyl
group, a fluoroethyl group, a difluoroethyl group, a trifluoroethyl
group, a tetrafluoroethyl group, a pentafluoroethyl group, an
n-fluoropropyl group, an n-difluoropropyl group, an
n-trifluoropropyl group, an n-tetrafluoropropyl group, an
n-pentafluoropropyl group, an n-hexafluoropropyl group, an
n-heptafluoropropyl group, an n-fluorobutyl group, an
n-difluorobutyl group, an n-trifluorobutyl group, an
n-tetrafluorobutyl group, an n-pentafluorobutyl group, an
n-hexafluorobutyl group, an n-heptafluorobutyl group, an
n-octafluorobutyl group, an n-nonafluorobutyl group, an
i-fluoropropyl group, an i-difluoropropyl group, an
i-trifluoropropyl group, an i-tetrafluoropropyl group, an
i-pentafluoropropyl group, an i-hexafluoropropyl group, an
i-heptafluoropropyl group, an i-fluorobutyl group, an
i-difluorobutyl group, an i-trifluorobutyl group, an
i-tetrafluorobutyl group, an i-pentafluorobutyl group, an
i-hexafluorobutyl group, an i-heptafluorobutyl group, an
i-octafluorobutyl group, an i-nonafluorobutyl group, a
sec-fluorobutyl group, a sec-difluorobutyl group, a
sec-trifluorobutyl group, a sec-tetrafluorobutyl group, a
sec-pentafluorobutyl group, a sec-hexafluorobutyl group, a
sec-heptafluorobutyl group, a sec-octafluorobutyl group, a
sec-nonafluorobutyl group, a tert-fluorobutyl group, a
tert-difluorobutyl group, a tert-trifluorobutyl group, a
tert-tetrafluorobutyl group, a tert-pentafluorobutyl group, a
tert-hexafluorobutyl group, a tert-heptafluorobutyl group, a
tert-octafluorobutyl group, a tert-nonafluorobutyl group, a
fluorocyclopropyl group, a difluorocyclopropyl group, a
trifluorocyclopropyl group, a tetrafluorocyclopropyl group, a
pentafluorocyclopropyl group, a fluorocyclobutyl group, a
difluorocyclobutyl group, a trifluorocyclobutyl group, a
tetrafluorocyclobutyl group, a pentafluorocyclobutyl group, a
hexafluorocyclobutyl group, a heptafluorocyclobutyl group, a
fluorocyclopentyl group, a difluorocyclopentyl group, a
trifluorocyclopentyl group, a tetrafluorocyclopentyl group, a
pentafluorocyclopentyl group, a hexafluorocyclopentyl group, a
heptafluorocyclopentyl group, an octafluorocyclopentyl group, a
nonafluorocyclopentyl group, a fluorocyclohexyl group, a
difluorocyclohexyl group, a trifluorocyclohexyl group, a
tetrafluorocyclohexyl group, a pentafluorocyclohexyl group, a
hexafluorocyclohexyl group, a heptafluorocyclohexyl group, an
octafluorocyclohexyl group, a nonafluorocyclohexyl group, a
decafluorocyclohexyl group, and an undecafluorocyclohexyl
group.
[0183] The lower perfluoroalkyl group as R.sup.1 means a
straight-chained or branched perfluoroalkyl group having 1-4 carbon
atoms or a cyclic perfluoroalkyl group having 3-6 carbon atoms;
examples include a trifluoromethyl group, a pentafluoroethyl group,
an n-heptafluoropropyl group, an n-nonafluorobutyl group, an
i-heptafluoropropyl group, an i-nonafluorobutyl group, a
sec-nonafluorobutyl group, a tert-nonafluorobutyl group, a
pentafluorocyclopropyl group, a heptafluorocyclobutyl group, a
nonafluorocyclopentyl group and an undecafluorocyclohexyl
group.
[0184] Examples of the optionally substituted lower
alkylsulfonyloxy group as X and Y include a methanesulfonyloxy
group and a trifluoromethanesulfonyloxy group.
[0185] Examples of the arylsulfonyloxy group as X and Y include a
benzenesulfonyloxy group and a p-toluenesulfonyloxy group.
[0186] The lower haloalkoxy group as R.sup.1and R.sup.2 means a
straight-chained or branched alkoxy group having 1-4 carbon atoms
or a cyclic alkoxy group having 3-6 carbon atoms, in which at least
one hydrogen atom is replaced by a halogen atom; examples include a
trifluoromethoxy group, a fluoroethoxy group, a difluoroethoxy
group, a trifluoroethoxy group, a tetrafluoroethoxy group, a
pentafluoroethoxy group, an n-fluoropropoxy group, an
n-difluoropropoxy group, an n-trifluoropropoxy group, an
n-tetrafluoropropoxy group, an n-pentafluoropropoxy group, an
n-hexafluoropropoxy group, an n-heptafluoropropoxy group, an
n-fluorobutoxy group, an n-difluorobutoxy group, an
n-trifluorobutoxy group, an n-tetrafluorobutoxy group, an
n-pentafluorobutoxy group, an n-hexafluorobutoxy group, an
n-heptafluorobutoxy group, an n-octafluorobutoxy group, an
n-nonafluorobutoxy group, an i-fluoropropoxy group, an
i-difluoropropoxy group, an i-trifluoropropoxy group, an
i-tetrafluoropropoxy group, an i-pentafluoropropoxy group, an
i-hexafluoropropoxy group, an i-heptafluoropropoxy group, an
i-fluorobutoxy group, an i-difluorobutoxy group, an
i-trifluorobutoxy group, an i-tetrafluorobutoxy group, an
i-pentafluorobutoxy group, an i-hexafluorobutoxy group, an
i-heptafluorobutoxy group, an i-octafluorobutoxy group, an
i-nonafluorobutoxy group, a sec-fluorobutoxy group, a
sec-difluorobutoxy group, a sec-trifluorobutoxy group, a
sec-tetrafluorobutoxy group, a sec-pentafluorobutoxy group, a
sec-hexafluorobutoxy group, a sec-heptafluorobutoxy group, a
sec-octafluorobutoxy group, a sec-nonafluorobutoxy group, a
tert-fluorobutoxy group, a tert-difluorobutoxy group, a
tert-trifluorobutoxy group, a tert-tetrafluorobutoxy group, a
tert-pentafluorobutoxy group, a tert-hexafluorobutoxy group, a
tert-heptafluorobutoxy group, a tert-octafluorobuoxty group, a
tert-nonafluorobutoxy group, a fluorocyclopropoxy group, a
difluorocyclopropoxy group, a trifluorocyclopropoxy group, a
tetrafluorocyclopropoxy group, a pentafluorocyclopropoxy group, a
fluorocyclobutoxy group, a difluorocyclobutoxy group, a
trifluorocyclobutoxy group, a tetrafluorocyclobutoxy group, a
pentafluorocyclobutoxy group, a hexafluorocyclobutoxy group, a
heptafluorocyclobutoxy group, a fluorocyclopentoxy group, a
difluorocyclopentoxy group, a trifluorocyclopentoxy group, a
tetrafluorocyclopentoxy group, a pentafluorocyclopentoxy group, a
hexafluorocyclopentoxy group, a heptafluorocyclopentoxy group, an
octafluorocyclopentoxy group, a nonafluorocyclopentoxy group, a
fluorocyclohexoxy group, a difluorocyclohexoxy group, a
trifluorocyclohexoxy group, a tetrafluorocyclohexoxy group, a
pentafluorocyclohexoxy group, a hexafluorocyclohexoxy group, a
heptafluorocyclohexoxy group, an octafluorocyclohexoxy group, a
nonafluorocyclohexoxy group, a decafluorocyclohexoxy group, and an
undecafluorocyclohexoxy group.
[0187] The acylamino group as R.sup.1and R.sup.2 means an amino
group in which one of the hydrogen atoms present is replaced by an
acyl group and exemplary acyl groups include a formyl group, an
acetyl group, a trifluoroacetyl group, a propanoyl group, an
n-butanoyl group, an i-butanoyl group, a pivaloyl group, a benzoyl
group, an anisoyl group, and a nitrobenzoyl group.
[0188] Examples of the alkoxycarbonyl group as R.sup.1 and R.sup.2
include a methoxycarbonyl group, an ethoxycarbonyl group, a
tert-butoxycarbonyl group, a benzyloxycarbonyl group, a
methoxybenzylcarbonyl group and a nitrobenzylcarbonyl group.
[0189] Examples of the optionally substituted lower alkylsulfonyl
group as R.sup.1 and R.sup.2 include a methanesulfonyl group and a
trifluoromethanesulfonyl group.
[0190] Examples of the arylsulfonyl group as R.sup.1 and R.sup.2
include a benzenesulfonyl group and a p-toluenesulfonyl group.
[0191] Examples of the substituent in the optionally substituted
lower alkyl group as R.sup.3 and R.sup.4 include a halogen atom, a
phenyl group, a hydroxyl group, a lower alkoxy group optionally
substituted by a halogen atom or a phenyl group, and a lower
alkylthio group optionally substituted by a halogen atom or a
phenyl group. Preferred are halogen atoms, among which a fluorine
atom is particularly preferred.
[0192] Examples of the optionally substituted lower alkyl group as
R.sup.3 and R.sup.4 include a fluoromethyl group, a difluoromethyl
group, a trifluoromethyl group, a fluoroethyl group, a
difluoroethyl group, a trifluoroethyl group, a tetrafluoroethyl
group, a pentafluoroethyl group, an n-fluoropropyl group, an
n-difluoropropyl group, an n-trifluoropropyl group, an
n-tetrafluoropropyl group, an n-pentafluoropropyl group, an
n-hexafluoropropyl group, an n-heptafluoropropyl group, an
n-fluorobutyl group, an n-difluorobutyl group, an n-trifluorobutyl
group, an n-tetrafluorobutyl group, an n-pentafluorobutyl group, an
n-hexafluorobutyl group, an n-heptafluorobutyl group, an
n-octafluorobutyl group, an n-nonafluorobutyl group, an
i-fluoropropyl group, an i-difluoropropyl group, an
i-trifluoropropyl group, an i-tetrafluoropropyl group, an
i-pentafluoropropyl group, an i-hexafluoropropyl group, an
i-heptafluoropropyl group, an i-fluorobutyl group, an
i-difluorobutyl group, an i-trifluorobutyl group, an
i-tetrafluorobutyl group, an i-pentafluorobutyl group, an
i-hexafluorobutyl group, an i-heptafluorobutyl group, an
i-octafluorobutyl group, an i-nonafluorobutyl group, a
sec-fluorobutyl group, a sec-difluorobutyl group, a
sec-trifluorobutyl group, a sec-tetrafluorobutyl group, a
sec-pentafluorobutyl group, a sec-hexafluorobutyl group, a
sec-heptafluorobutyl group, a sec-octafluorobutyl group, a
sec-nonafluorobutyl group, a tert-fluorobutyl group, a
tert-difluorobutyl group, a tert-trifluorobutyl group, a
tert-tetrafluorobutyl group, a tert-pentafluorobutyl group, a
tert-hexafluorobutyl group, a tert-heptafluorobutyl group, a
tert-octafluorobutyl group, a tert-nonafluorobutyl group, a benzyl
group, a methoxymethyl group, an ethoxymethyl group, a
trifluoromethoxymethyl group, a benzyloxymethyl group, a
methylthiomethyl group, an ethylthiomethyl group, and a
methoxycarbonylmethyl group.
[0193] The lower fluoroalkyl group as R.sup.3 and R.sup.4 means a
straight-chained or branched alkoxy group having 1-4 carbon atoms
in which at least one hydrogen atom is replaced by a fluorine atom;
examples include a fluoromethyl group, a difluoromethyl group, a
trifluoromethyl group, a fluoroethyl group, a difluoroethyl group,
a trifluoroethyl group, a tetrafluoroethyl group, a
pentafluoroethyl group, an n-fluoropropyl group, an
n-difluoropropyl group, an n-trifluoropropyl group, an
n-tetrafluoropropyl group, an n-pentafluoropropyl group, an
n-hexafluoropropyl group, an n-heptafluoropropyl group, an
n-fluorobutyl group, an n-difluorobutyl group, an n-trifluorobutyl
group, an n-tetrafluorobutyl group, an n-pentafluorobutyl group, an
n-hexafluorobutyl group, an n-heptafluorobutyl group, an
n-octafluorobutyl group, an n-nonafluorobutyl group, an
i-fluoropropyl group, an i-difluoropropyl group, an
i-trifluoropropyl group, an i-tetrafluoropropyl group, an
i-pentafluoropropyl group, an i-hexafluoropropyl group, an
i-heptafluoropropyl group, an i-fluorobutyl group, an
i-difluorobutyl group, an i-trifluorobutyl group, an
i-tetrafluorobutyl group, an i-pentafluorobutyl group, an
i-hexafluorobutyl group, an i-heptafluorobutyl group, an
i-octafluorobutyl group, an i-nonafluorobutyl group, a
sec-fluorobutyl group, a sec-difluorobutyl group, a
sec-trifluorobutyl group, a sec-tetrafluorobutyl group, a
sec-pentafluorobutyl group, a sec-hexafluorobutyl group, a
sec-heptafluorobutyl group, a sec-octafluorobutyl group, a
sec-nonafluorobutyl group, a tert-fluorobutyl group, a
tert-difluorobutyl group, a tert-trifluorobutyl group, a
tert-tetrafluorobutyl group, a tert-pentafluorobutyl group, a
tert-hexafluorobutyl group, a tert-heptafluorobutyl group, a
tert-octafluorobutyl group, and a tert-nonafluorobutyl group.
[0194] If R.sup.3 and R.sup.4 represent substituents which, when
taken together with the carbon atom to which they are bound, form a
polymethylene group, they are saturated spiro rings having 3-7
carbon atoms, as exemplified by a cyclopropane ring, a cyclobutane
ring, a cyclopentane ring, a cyclohexane ring and a cycloheptane
ring.
[0195] If R.sup.3 and R.sup.4 represent substituents which, when
taken together with the carbon atom to which they are bound, form a
heterocycle, they are saturated spiro heterocycles having 3-7
carbon atoms which contain a hetero atom, as exemplified by an
azetidine ring, pyrrolidine ring, a piperidine ring, an oxetane
ring, a tetrahydrofuran ring, a tetrahydropyran ring, a
tetrahydrothiophene ring, and a tetrahydrothiopyran ring.
[0196] Preferred examples of X are an iodine atom, a bromine atom
and a trifluoromethanesulfonyloxy group.
[0197] Preferred examples of Y include a fluorine atom, a chlorine
atom, a methanesulfonyloxy group, a benzenesulfonyloxy group and a
p-toluenesulfonyl group; among these, a fluorine atom and a
chlorine atom are particularly preferred.
[0198] While X and Y may be the same or different, they are
preferably different.
[0199] There are two preferred combinations of X and Y; in one
combination, X is a bromine atom and Y is a chlorine atom and in
the other combination, X is an iodine atom and Y is a chlorine
atom.
[0200] Preferred examples of R.sup.1 are a lower perfluoroalkyl
group, a nitro group and a cyano group; among these, lower
perfluoroalkyl groups are preferred, with a trifluoromethyl group
and a pentafluoroethyl group being particularly preferred.
[0201] The preferred position of substitution by R.sup.1 is in
6-position on the benzopyran ring.
[0202] The preferred example of R.sup.2 is a hydrogen atom.
[0203] It is preferred that R.sup.3 and R.sup.4 are the same; more
preferably, they both are a lower alkyl group or a lower
fluoroalkyl group; most preferably, they both are a fluoromethyl
group.
[0204] Examples of the optionally substituted lower alkyl group as
R.sup.5 and R.sup.6 include a methyl group, a benzyl group, a
cyclopropylmethyl group, an ethyl group, a 2-cyanoethyl group, a
2-fluoroethyl group and an n-propyl group.
[0205] Preferably, R.sup.5 is a hydrogen atom and R.sup.6 is an
optionally substituted lower alkyl group; more preferably, R.sup.5
is a hydrogen atom and R.sup.6 is a lower alkyl group optionally
having a cyano group; most preferably, R.sup.5 is a hydrogen atom
and R.sup.6 is a 2-cyanoethyl group or a 2-cyanomethyl group.
[0206] A compound represented by the general formula (II) (where X
and Y have the same meanings as defined above; R.sup.1and R.sup.2
have the same meanings as defined above) is reacted with an olefin
represented by the general formula (III) (where R.sup.3 and R.sup.4
have the same meanings as defined above) in a suitable solvent in
the presence of a suitable metal catalyst, a suitable base and a
suitable quaternary ammonium salt under an inert atomosphere at a
suitable temperature to give a compound represented by the general
formula (IV) (where Y, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 have
the same meanings as defined above). The suitable metal catalyst as
used herein means a palladium or a nickel catalyst and examples
include palladium acetate, palladium chloride, palladium carbon,
bis(triphenylphosphine)palladium acetate,
bis(triphenylphosphine)palladium chloride,
tris(dibenzylideneacetone)dipa- lladium,
bis(dibenzylideneacetone)palladium, tetrakis(triphenylphosphine)p-
alladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium chloride,
allyl palladium chloride, bis(acetonitrile)palladium chloride,
nickel acetate, nickel chloride, bis(1,5-octadiene)nickel,
bis(triphenylphosphine)nickel chloride, dicyclopentadienyl nickel,
and nickel acetoacetonate; among these, palladium acetate is
preferred. Examples of the suitable base include diethylamine,
triethylamine, diisopropylethylamine, sodium hydrogencarbonate,
sodium carbonate, potassium hydrogencarbonate, potassium carbonate,
dipotassium hydrogenphosphate, potassium phosphate, sodium
hydroxide and potassium hydroxide; among these, potassium carbonate
is preferred. Examples of the suitable quaternary ammonium salt
include tetrabutylammonium iodide, tetrabutylammonium bromide,
tetrabutylammonium chloride, benzyltriethylammonium chloride and
benzyltrimethylammonium hydroxide; among these, tetrabutylammonium
bromide is preferred. Examples of the suitable solvent include
N,N-dimethylformamide, N,N-dimethylacetamide, toluene, xylene,
acetonitrile and dioxane; among these, N,N-dimethylacetamide is
preferred. An example of the suitable temperature is between room
temperature and 130.degree. C., preferably between 75.degree. C.
and 85.degree. C. Examples of the inert gas are nitrogen and
argon.
[0207] The resulting compound of the general formula (IV) is
reacted with a halogenating agent (e.g. bromine) in a suitable
solvent at a suitable temperature to give a compound represented by
the general formula (V) (where Y, R.sup.1, R.sup.2, R.sup.3,
R.sup.4 and Hal have the same meanings as defined above). Examples
of the suitable solvent include dichloromethane, chloroform, carbon
tetrachloride, 1,2-dichloroethane, diethyl ether, tert-butyl methyl
ether, tert-butyl alcohol, tert-amyl alcohol, 3-methyl-3-pentanol
and 3-ethyl-3-pentanol; among these, tert-amyl alcohol is
preferred. An example of the suitable temperature is between
-78.degree. C. and 80.degree. C., preferably between -15.degree. C.
and -5.degree. C.
[0208] The resulting compound of the general formula (V) is reacted
with a suitable base in a suitable solvent at a suitable
temperature to give a compound represented by the general formula
(VI) (where Y, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and Hal have the
same meanings as defined above). Examples of the suitable base
include diethylamine, triethylamine, diisopropylethylamine, sodium
hydride, potassium hydride, potassium tert-butoxide, sodium
methoxide, sodium ethoxide, sodium bis(trimethylsilyl)amide,
potassium bis(trimethylsilyl)amide, sodium hydrogencarbonate,
sodium carbonate, potassium hydrogencarbonate, potassium carbonate,
dipotassium hydrogenphosphate, potassium phosphate, sodium
hydroxide and potassium hydroxide; among these, sodium hydride and
potassium carbonate are preferred. Examples of the suitable solvent
include dichloromethane, chloroform, carbon tetrachloride,
1,2-dichloroethane, tert-butyl alcohol, tert-amyl alcohol,
3-methyl-3-pentanol, 3-ethyl-3-pentanol, tetrahydrofuran, dioxane,
N,N-dimethylformamide, N,N-dimethylacetamide, toluene and xylene;
among these, toluene and tert-amyl alcohol are preferred. An
example of the suitable temperature is between -78.degree. C. and
80.degree. C., preferably between 30.degree. C. and 60.degree.
C.
[0209] The resulting compound of the general formula (VI) is
reacted with a suitable base in a suitable solvent at a suitable
temperature to give a compound represented by the general formula
(I) (where R.sup.1, R.sup.2, R.sup.3, R.sup.4 and Hal have the same
meanings as defined above). Examples of the suitable base include
sodium hydride, potassium hydride, potassium tert-butoxide, sodium
bis(trimethylsilyl)amide and potassium bis(trimethylsilyl)amide;
among these, sodium hydride and potassium bis(trimethylsilyl)amide
are preferred. Examples of the preferred suitable solvent include
tetrahydrofuran, dioxane, N,N-dimethylformamide,
N,N-dimethylacetamide, toluene and xylene; among these, toluene and
tetrahydrofuran are preferred. An example of the suitable
temperature is between -78.degree. C. and 80.degree. C., preferably
between -15.degree. C. and -5.degree. C.
[0210] The compound of the general formula (I) can also be prepared
by the following scheme. Namely, a compound represented by the
general formula (II) (where X, Y, R.sup.1 and R.sup.2 have the same
meanings as defined above) is reacted with acetylene represented by
the general formula (VII) (where R.sup.3 and R.sup.4 have the same
meanings as defined above) in a suitable solvent in the presence of
a suitable metal catalyst, a suitable ligand, a suitable copper
salt and a suitable base in an inert atmosphere at a suitable
temperature to give a compound represented by the general formula
((VIII) (where Y, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 have the
same meanings as defined above). The suitable metal catalyst as
used herein means a palladium or a nickel catalyst and examples
include palladium acetate, palladium chloride, palladium carbon,
nickel acetate and nickel chloride; alternatively, the metal
catalyst is a complex with a ligand, as exemplified by
bis(triphenylphosphine)palladium acetate,
bis(triphenylphosphine)palladium chloride,
tris(dibenzylideneacetone)dipa- lladium,
bis(dibenzylideneacetone)palladium, tetrakis(triphenylphosphine)p-
alladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium chloride,
allyl palladium chloride, bis(acetonitrile)palladium chloride,
bis(1,5-octadiene)nickel, bis(triphenylphosphine)nickel chloride,
dicyclopentadienyl nickel and nickel acetoacetonate. Examples of
the suitable ligand include triphenylphosphine,
tris(o-tolyl)phosphine, 1,1'-bis(diphenylphosphino)ferrocene and
dibenzylidene acetone; among these bis(triphenylphosphine)palladium
chloride is preferred. Examples of the suitable copper salt include
a copper(O) powder, cuprous chloride, cuprous bromide, cuprous
iodide and cuprous acetate; among these, cuprous iodide is
preferred. Examples of the suitable base include diethylamine,
triethylamine, diisopropylethylamine, sodium hydrogencarbonate,
sodium carbonate, potassium hydrogencarbonate, potassium carbonate,
dipotassium hydrogenphosphate, potassium phosphate, sodium
hydroxide and potassium hydroxide; among these, triethylamine being
preferred. Examples of the suitable solvent include triethylamine,
N,N-dimethylformamide, N,N-dimethylacetamide, toluene, xylene,
acetonitrile and dioxane; among these, N,N-dimethylformamide is
preferred. An example of the preferred temperature is between room
temperature and 130.degree. C., preferably between 75.degree. C.
and 85.degree. C. Examples of the inert gas include nitrogen and
argon.
[0211] The resulting compound of the general formula (VIII) is
subjected to reaction under a hydrogen atmosphere in the presence
of a suitable catalyst and a suitable solvent at a suitable
temperature to give a compound represented by the general formula
(IX) (where Y, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 have the same
meanings as defined above). Examples of the suitable catalyst
include a Lindlar catalyst, developed Raney nickel, barium
carbonate-palladium and barium sulfate-palladium, with 5%
palladium-barium carbonate being preferred. Examples of the
suitable solvent include methanol, ethanol, ethyl acetate and
methanol-pyridine, with 5% pyridine-methanol and ethyl acetate
being preferred. An example of the suitable temperature is between
room temperature and 60.degree. C., preferably room
temperature.
[0212] The resulting compound of the general formula (IX) is
reacted with a suitable base in a suitable solvent at a suitable
temperature to give a compound represented by the general formula
(X) (where R.sup.1, R.sup.2, R.sup.3 and R.sup.4 have the same
meanings as defined above). Examples of the suitable base include
sodium hydride, potassium hydride, potassium tert-butoxide, sodium
bis(trimethylsilyl)amide and potassium bis(trimethylsilyl)amide,
with potassium tert-butoxide being preferred. Examples of the
suitable solvent include tetrahydrofuran, dioxane,
N,N-dimethylformamide, N,N-dimethylacetamide,
1,3-dimethylimidazolidin-2-- one, N-methylpyrrolidone, sulfolane,
toluene and xylene, with N,N-dimethylformamide being preferred. An
example of the suitable temperature is between -78.degree. C. and
80.degree. C., preferably between 55.degree. C. and 65.degree.
C.
[0213] The resulting compound of the general formula (X) is reacted
with a halogenating agent (e.g. bromine) in a suitable solvent at a
suitable temperature to give a compound represented by the general
formula (XI) (where R.sup.1, R.sup.2, R.sup.3, R.sup.4 and Hal have
the same meanings as defined above). Examples of the suitable
solvent include dichloromethane, chloroform, carbon tetrachloride,
1,2-dichloroethane, diethyl ether and tert-butyl methyl ether, with
chloroform and tert-butyl methyl ether being preferred. An example
of the preferred temperature is between -78.degree. C. and room
temperature, preferably between -10.degree. C. and room
temperature.
[0214] The resulting compound of the general formula (XI) is
reacted with a suitable base in a suitable solvent at a suitable
temperature to give a compound represented by the general formula
(I) (where R.sup.1, R.sup.2, R.sup.3, R.sup.4 and Hal have the same
meanings as defined above). Examples of the suitable base include
sodium hydride, potassium hydride, potassium tert-butoxide, sodium
hydrogencarbonate, sodium carbonate, potassium hydrogencarbonate,
potassium carbonate, dipotassium hydrogenphosphate, potassium
phosphate, sodium hydroxide and potassium hydroxide, with potassium
hydroxide being preferred. Examples of the suitable solvent include
water, tetrahydrofuran, dioxane, N,N-dimethylformamide,
N,N-dimethylacetamide, toluene, xylene, methanol and ethanol, with
water-dioxane and ethanol being preferred. An example of the
suitable temperature is between -78.degree. C. and 80.degree. C.,
preferably between room temperature and 80.degree. C.
[0215] The resulting compound of the general formula (I) is
converted to a compound of the general formula (G-VI) by a method
that involves a carbon monoxide inserting cross-coupling reaction
as a key reaction that uses a metal as a catalyst. To be specific,
the compound of the general formula (I) (where R.sup.1, R.sup.2,
R.sup.3, R.sup.4 and Hal have the same meanings as defined above)
is subjected to a cross-coupling reaction with a compound of the
general formula (G-III)
HNR.sup.5R.sup.6 (G-III)
[0216] (where R.sup.5 and R.sup.6 have the same meanings as defined
above) under a carbon monoxide gas at atmospheric or
superatmospheric pressure from a CO gas container, preferably at
atmospheric pressure, at a reaction temperature between -78.degree.
C. and 150.degree. C., preferably between room temperature and
130.degree. C., for a reaction time of from 1 hour to 3 days,
preferably from 3 hours to 1 day, in the presence of a zero-valence
or divalent metal catalyst such as palladium, nickel, copper, zinc,
tin or magnesium, preferably, 1-5 mol % of zero-valence or divalent
palladium such as bis(triphenylphosphine)palladi- um acetate,
palladium acetate and triphenylphosphine,
bis(triphenylphosphine)palladium chloride,
[1,1'-bis(diphenylphosphino)fe- rrocene]palladium chloride
dichloromethane adduct, tetrakis(triphenylphosp- hine)palladium,
tris(dibenzylideneacetone)dipalladium chloroform adduct and
triphenylphosphine, and tris(dibenzylideneacetone)dipalladium
chloroform adduct in a solvent such as N,N-dimethylformamide,
tetrahydrofuran, dioxane, ether, acetonitrile, toluene, benzene or
water, preferably N,N-dimethylformamide, thereby giving a
4-substituted benzopyran derivative represented by the general
formula (G-VI) (where R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5
and R.sup.6 have the same meanings as defined above).
[0217] B. Schemes (3) and (4):
[0218] Speaking of the process according to schemes (3) and (4),
the preferred substituents in the 4-substituted benzopyran
derivatives of the general formula (G-VI) are exemplified by the
following.
[0219] Preferably, R.sup.1 and R.sup.2 which may be the same or
different represent a hydrogen atom, an optionally substituted
lower alkyl group, an optionally substituted lower alkoxy group, an
optionally substituted lower alkoxycarbonyl group, an optionally
substituted lower alkylsulfonyl group, an optionally substituted
arylsulfonyl group, a halogen atom, a nitro group, a cyano group or
NY.sub.aY.sub.b (where Y.sub.a and Y.sub.b which may be the same or
different each represent a hydrogen atom, an optionally substituted
lower alkyl group, an optionally substituted lower alkoxycarbonyl
group, an acyl group, an optionally substituted lower alkylsulfonyl
group or an optionally substituted arylsulfonyl group or, when
taken together with the nitrogen atom to which they are bound, may
form a 3- to 8-membered ring).
[0220] Preferably, R.sup.3 and R.sup.4 which may be the same or
different represent a hydrogen atom or an optionally substituted
.alpha.-haloalkyl group, provided that they are not both a hydrogen
atom.
[0221] Preferably, R.sup.5 and R.sup.6 which may be the same or
different represent a hydrogen atom or an optionally substituted
lower alkyl group.
[0222] In schemes (3) and (4), unless otherwise noted, the
following definitions hold:
[0223] the lower alkyl group means a straight-chained alkyl group
having 1-6 carbon atoms or a branched or cyclic alkyl group having
3-8 carbon atoms; examples include a methyl group, an ethyl group,
an n-propyl group, an n-butyl group, an n-pentyl group, an n-hexyl
group, an i-propyl group, an i-butyl group, a sec-butyl group, a
tert-butyl group, an i-pentyl group, a neopentyl group, a
tert-pentyl group, an i-hexyl group, a cyclopropyl group, a
cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a
cycloheptyl group and a cyclooctyl group;
[0224] the halogen atom means a fluorine atom, a chlorine atom, a
bromine atom or an iodine atom;
[0225] the lower alkoxy group means a straight-chained alkoxy group
having 1-6 carbon atoms or a branched or cyclic alkoxy group having
3-8 carbon atoms; examples include a methoxy group, an ethoxy
group, an n-propoxy group, an n-butoxy group, an n-pentoxy group,
an n-hexoxy group, an i-propoxy group, an i-butoxy group, a
sec-butoxy group, a tert-butoxy group, an i-pentoxy group, a
neopentoxy group, a tert-pentoxy group, an i-hexoxy group, a
cyclopropoxy group, a cyclobutoxy group, a cyclopentoxy group, a
cyclohexoxy group, a cycloheptoxy group and a cyclooctoxy
group.
[0226] the lower alkoxycarbonyl group means an alkoxycarbonyl group
whose alkyl portion is a straight-chained alkyl group having 1-6
carbon atoms or an alkoxycarbonyl group whose alkyl portion is a
branched or cyclic alkyl group having 3-8 carbon atoms, and
examples include a methoxycarbonyl group, an ethoxycarbonyl group,
an n-propoxycarbonyl group, an n-butoxycarbonyl group, an
n-pentoxycarbonyl group, an n-hexoxycarbonyl group, an
i-propoxycarbonyl group, an i-butoxycarbonyl group, a
sec-butoxycarbonyl group, a tert-butoxycarbonyl group, an
i-pentoxycarbonyl group, a neopentoxycarbonyl group, a
tert-pentoxycarbonyl group, an 1-hexoxycarbonyl group, a
cyclopropoxycarbonyl group, a cyclobutoxycarbonyl group, a
cyclopentoxycarbonyl group, a cyclohexoxycarbonyl group, a
cycloheptoxycarbonyl group and a cyclooctoxycarbonyl group;
[0227] the lower alkylsulfonyl group means an alkylsulfonyl group
having 1-8 carbon atoms whose alkyl portion is a straight-chained
alkyl group or an alkylsulfonyl group having 3-8 carbon atoms whose
alkyl portion is a branched or cyclic alkyl group, and examples
include a methylsulfonyl group, an ethylsulfonyl group, a
propylsulfonyl group, an isopropylsulfonyl group, a butylsulfonyl
group and an isobutylsulfonyl group.
[0228] the arylsulfonyl group means an aromatic sulfonyl group and
examples include a phenylsulfonyl group, a p-tolylsulfonyl group, a
p-chlorophenylsulfonyl group, a 2-furylsulfonyl group, a
3-furylsulfonyl group, a 2-thienylsulfonyl group, a
3-thienylsulfonyl group, a 2-pyridylsulfonyl group, a
3-pyridylsulfonyl group and a 4-pyridylsulfonyl group.
[0229] Y.sub.a and Y.sub.b in NY.sub.aY.sub.b which may be the same
or different each represent a hydrogen atom, an optionally
substituted lower alkyl group, an optionally substituted lower
alkoxycarbonyl group, an acyl group, an optionally substituted
lower alkylsulfonyl group or an optionally substituted arylsulfonyl
group or, when taken together with the nitrogen atom to which they
are bound, may form a 3- to 8-membered ring.
[0230] The acyl group as used herein means a formyl group or an
alkylcarbonyl group having 1-8 carbon atoms whose alkyl portion is
an optionally substituted straight-chained alkyl group, an
alkylcarbonyl group having 3-8 carbon atoms whose alkyl portion is
an optionally substituted branched or cyclic alkyl group, or an
arylcarbonyl group, and examples include a formyl group, an acetyl
group, a trifluoroacetyl group, a propionyl group, a butyryl group,
a valeryl group, an isobutyryl group, an isovaleryl group, a
pivaloyl group, a benzoyl group, a phthaloyl group and a toluoyl
group.
[0231] When either one of Y.sub.a and Y.sub.b is a hydrogen atom
and the other is an acyl group, NY.sub.aY.sub.b represents an
acylamino group.
[0232] When both Y.sub.a and Y.sub.b are a hydrogen atom,
NY.sub.aY.sub.b represents an amino group.
[0233] If R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 or R.sup.6
represents an optionally substituted lower alkyl group, an
optionally substituted lower alkoxy group, an optionally
substituted lower alkoxycarbonyl group or an optionally substituted
lower alkylsulfonyl group, the optionally present substituent may
be exemplified by a halogen atom, a phenyl group, a hydroxy group,
a nitro group, a cyano group, a cyclic alkyl group having 3-8
carbon atoms, a lower alkoxy group optionally substituted by a
halogen atom or a phenyl group, a lower alkoxycarbonyl group, a
carboxyl group and NY.sub.cY.sub.d; Y.sub.c and Y.sub.d which may
be the same or different each represent a hydrogen atom, a lower
alkyl group, a lower alkoxycarbonyl group, an acyl group, a lower
alkylsulfonyl group or an optionally substituted arylsulfonyl group
or, when taken together with the nitrogen atom to which they are
bonded, may form a 3- to 8-numbered ring.
[0234] When taken together with the nitrogen atom to which they are
bound, Y.sub.a and Y.sub.b, Y.sub.c and Y.sub.d, or Y.sub.e and
Y.sub.f may form a 3-to 8-membered ring and the ring has 2-7 carbon
atoms, with any carbon atom on the ring being optionally replaced
by a nitrogen atom, an oxygen atom or a sulfur atom. Specific
examples include an aziridine ring, an azetidine ring, a pyrrole
ring, a pyrrolidine ring, a pyridine ring, a 3,4-dihydro-2H-azepine
ring, a 3,4,5,6-tetrahydro-2H-azepine ring, an azocine ring, a
5,6-dihydro-azocine ring, a 5,6,7,8-tetrahydroazocine ring, an
oxazoline ring, an isoxazoline ring, a thioxazoline ring, a
piperazine ring, a morpholine ring and a thiomorpholine ring.
[0235] The .alpha.-haloalkyl group as R.sup.3 and R.sup.4 means a
straight-chained alkyl group having 1-6 carbon atoms or a branched
or cyclic alkyl group having 3-8 carbon atoms that have 1-3 halogen
atoms in 1-position and which may further possess a substituent,
and examples include a fluoromethyl group, a difluoromethyl group,
a trifluoromethyl group, a 1-fluoroethyl group, a 1,1-difluoroethyl
group, a 1-fluoropropyl group, a 1,1-difluoropropyl group, a
1-fluorocyclopropyl group, a 1-fluorobutyl group, a
1,1-difluorobutyl group, a chloromethyl group, a dichloromethyl
group, a trichloromethyl group, a 1-chloroethyl group, a
1,1-dichloroethyl group, a 1-chloropropyl group, a 1,1-chloropropyl
group, a 1-chlorocyclopropyl group, a 1-chlorobutyl group, a
1,1-dichlorobutyl group, a bromomethyl group, a dibromomethyl
group, a tribromomethyl group, a 1-bromoethyl group, a
1,1-dibromoethyl group, a 1-bromopropyl group, a 1,1-dibromopropyl
group, a 1-bromocyclopropyl group, a 1-bromobutyl group, a
1,1-dibromobutyl group, an iodomethyl group, a diodomethyl group, a
triiodomethyl group, a 1-iodoethyl group, a 1,1-diiodoethyl group,
a 1-iodopropyl group, a 1,1-diiodopropyl group, a 1-iodocyclopropyl
group, a 1-iodobutyl group and a 1,1-diiodobutyl group.
[0236] If R.sup.1 or R.sup.2 represents an optionally substituted
arylsulfonyl group or an optionally substituted aryl group, the
optionally present substituent may be exemplified by a halogen
atom, a phenyl group, a hydroxy group, a nitro group, a cyano
group, a straight-chained alkyl group having 1-6 carbon atoms, a
branched or cyclic alkyl group having 3-8 carbon atoms, a lower
alkoxy group optionally substituted by a halogen atom or a phenyl
group, a lower alkylthio group optionally substituted by a halogen
atom or a phenyl group, a lower alkoxycarbonyl group, a carboxyl
group and NY.sub.eY.sub.f; Y.sub.e and Y.sub.f which may be the
same or different each represent a hydrogen atom, an optionally
substituted lower alkyl group, an optionally substituted lower
alkoxycarbonyl group, an acyl group, an optionally substituted
lower alkylsulfonyl group or an arylsulfonyl group or, when taken
together, may form a 3- to 8-numbered ring.
[0237] Examples of the optionally substituted lower alkyl group as
R.sup.1 and R.sup.2 include a methyl group, a fluoromethyl group, a
trifluoromethyl group, a pentafluoroethyl group, a benzyl group, a
nitromethyl group, a cyclopropylmethyl group, a methoxymethyl
group, an ethoxymethyl group, a benzyloxymethyl group, a
methylthiomethyl group, an ethylthiomethyl group, a
methoxycarbonylmethyl group, a dimethylaminomethyl group, an ethyl
group, a 2-fluoroethyl group, a n-propyl group, an i-propyl group,
a 1-methylthiopropyl group and an n-butyl group.
[0238] Examples of the optionally substituted lower alkyl group as
R.sup.5, R.sup.6 and R.sup.6a, include a methyl group, a benzyl
group, a cyclopropylmethyl group, an ethyl group, a 2-cyanoethyl
group, a 2-fluoroethyl group and an n-propyl group.
[0239] Speaking of R.sup.5 and R.sup.6, a preferred case is where
R.sup.5 is a hydrogen atom and R.sup.6 is an optionally substituted
lower alkyl group; a more preferred case is where R.sup.5 is a
hydrogen atom and R.sup.6 is a lower alkyl group optionally having
a cyano group, and a particularly preferred case is where R.sup.5
is a hydrogen atom and R.sup.6 is a 2-cyanoethyl group or a
2-cyanomethyl group.
[0240] A preferred example of R.sup.6a is a lower alkyl group
optionally having a cyano group; more preferred examples are a
2-cyanoethyl group and a 2-cyanomethyl group, with a 2-cyanoethyl
group being particularly preferred.
[0241] Examples of the optionally substituted lower alkoxy group as
R.sup.1 and R.sup.2 include a methoxy group, a trifluoromethoxy
group, a benzyloxy group, a cyclopropylmethoxy group, an ethoxy
group and a n-propoxy group.
[0242] Examples of the optionally substituted lower alkoxycarbonyl
group as R.sup.1and R.sup.2 include a methoxycarbonyl group, a
trifluoromethoxycarbonyl group, a benzyloxycarbonyl group, a
cyclopropylmethoxycarbonyl group, an ethoxycarbonyl group, an
n-propoxycarbonyl group and a tert-butoxycarbonyl group.
[0243] The preferred position of substitution by R.sup.1 is in
6-position on the benzopyran ring. Preferred examples of R.sup.1
include an optionally substituted lower alkyl group, an optionally
substituted alkylsulfonyl group, an optionally substituted
arylsulfonyl group, a nitro group and a cyano group; among these,
lower alkyl groups having a fluorine atom as a substituent are
preferred, with a 6-trifluoromethyl group and a 6-pentafluoroethyl
group being particularly preferred.
[0244] The preferred example of R.sup.2 is a hydrogen atom.
[0245] Speaking of R.sup.3 and R.sup.4, they are preferably the
same; more preferably, they both are an optionally substituted
.alpha.-haloalkyl group; most preferably, they both are a
fluoromethyl group.
[0246] Examples of the optionally substituted alkyl group as
R.sup.7 include a methyl group, an ethyl group and a propyl group.
Examples of the optionally substituted aryl group as R.sup.7
include a phenyl group, a p-tolyl group and a p-chlorophenyl group;
among these, a p-tolyl group and a methyl group are preferred, with
a p-tolyl group being particularly preferred.
[0247] Examples of the above-mentioned NY.sub.aY.sub.b,
NY.sub.cY.sub.d and NY.sub.eY.sub.f include an amino group, a
methylamino group, a benzylamino group, an ethylamino group, a
dimethylamino group, an ethylmethylamino group, a pyrrolidinyl
group, a piperidino group, a morpholino group, an acetamido group,
a benzamido group, an N-methylacetamido group, a
tert-butoxycarbonylamino group, an
N-methyl-tert-butoxycarbonylamino group, a methylsulfonylamino
group, an ethylsulfonylamino group, a propylsulfonylamino group, an
isopropylsulfonylamino group, a butylsulfonylamino group, an
isobutylsulfonylamino group, a phenylsulfonylamino group, a
p-tolylsulfonylamino group and a p-chlorophenylsulfonylamino
group.
[0248] For synthesis of the compound represented by the general
formula (G-II), the compound represented by the general formula
(G-I) is used as an intermediate and this compound, being
undocumented and novel, constituents the present invention. To give
the compound of the general formula (G-I), a sulfonate ester
represented by the general formula (C-IV) (where R.sup.7, R.sup.3
and R.sup.4 have the same meanings as defined above) may be reacted
with a phenol represented by the general formula (C-V) (where
R.sup.1 and R.sup.2 have the same meanings as defined above) in an
inert solvent such as acetonitrile that does not affect the
reaction, in the presence of a suitable base and a catalytic amount
of a suitable copper salt at a temperature between -78.degree. C.
and room temperature, preferably between 0.degree. C. and room
temperature. Examples of the suitable base that can be used in the
reaction include organic strong bases such as
1,8-diazabicyclo(5.4.0)-7-u- ndecene and
1,5-diazabicyclo(4.3.0)-5-nonene, and tertiary amines such as
triethylamine, tributylamine and N,N-diisopropylethylamine, with
N,N-diisopropylethylamine being preferred. Exampples of the
suitable copper base that can be used in the reaction include
cuprous salts such as copper(I) acetate, copper(I)
trifluoroacetate, cuprous chloride, cuprous bromide, cuprous iodide
and cuprous cyanide, and cupric salts such as cupric chloride and
cupric bromide, with cupric chloride and cupric bromide being
preferred.
[0249] For synthesis of the compound of the general formula (G-I),
the compound represented by the general formula (C-IV) is used as
an intermediate and this compound, being undocumented and novel,
constitutes the present invention. To prepare the compound of the
general formula (C-IV), an alcohol represented by the general
formula (C-I) (where R.sup.3 and R.sup.1 have the same meanings as
defined above) may be reacted with a compound of the general
formula (C-II) or (C-III)
R.sup.7SO.sub.2Cl (C-II)
(R.sup.7SO.sub.2).sub.2O (C-III)
[0250] (where R.sup.7 represents an optionally substituted alkyl
group or an optionally substituted aryl group) either after
reacting the alcohol with a suitable base in a suitable solvent to
be converted to an alkoxide or directly in a suitable solvent in
the presence of a suitable base at a temperature between
-78.degree. C. and room temperature, preferably between 0.degree.
C. and room temperature. In this reaction, a suitable catalyst such
as N,N-dimethylaminopyridine may be used. The suitable solvent that
can be used in this reaction is an inert solvent that does not
affect the reaction, as exemplified by diethyl ether, diisopropyl
ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, diglyme,
acetone, N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl
sulfide, with tetrahydrofuran and tert-butyl methyl ether being
preferred. Examples of the suitable base that can be used in the
reaction include alkali metal hydrides such as potassium hydride,
sodium hydride and lithium hydride, or carbonates such as potassium
carbonate and sodium carbonate, bicarbonates such as potassium
hydrogencarbonate and sodium hydrogencarbonate, organic strong
bases such as 1,8-diazabicyclo(5.4.0)-7- -undecene and
1,5-diazabicyclo(4.3.0)--S-nonene, tertiary amines such as
triethylamine, tributylamine and N,N-diisopropylethylamine; among
these, sodium hydride and triethylamine are preferred.
[0251] The compound of the invention which is represented by the
general formula (G-VI) may be synthesized by the following
procedure:
[0252] a compound represented by the general formula (G-I) (where
R.sup.1, R.sup.2, R.sup.3 and R.sup.4 have the same meanings as
defined above) is reacted in an inert solvent such as hexane,
toluene, diethyl ether, diisopropyl ether, tert-butyl methyl ether,
tetrahydrofuran, dioxane or tert-butanol, preferably in tert-butyl
methyl ether, tetrahydrofuran or diethyl ether, at a temperature
between -78.degree. C. and the boiling point of the reaction
mixture, preferably between -40.degree. C. and room temperature,
with an alkali metal such as lithium, sodium or potassium,
alkyllithium such as methyllithium, ethyllithium, n-propyllithium,
i-propyllithium, n-butyllithium, sec-butyllithium or
tert-butyllithium, or a Grignard reagent such as methylmagnesium
chloride, methylmagnesium bromide, methylmagnesium iodide,
ethylmagnesium chloride, ethylmagnesium bromide, ethylmagnesium
iodide, n-propylmagnesium chloride, n-propylmagnesium bromide,
n-propylmagnesium iodide, i-propylmagnesium chloride,
i-propylmagnesium bromide, i-propylmagnesium iodide,
n-butylmagnesium chloride, n-butylmagnesium bromide,
n-butylmagnesium iodide, sec-butylmagnesium chloride,
sec-butylmagnesium bromide, sec-butylmagnesium iodide,
tert-butylmagnesium chloride, tert-butylmagnesium bromide or
tert-butylmagnesium iodide, or a reagent selected from among
lithium hydride, sodium hydride, potassium hydride,
tert-butoxypotassium, lithium amide, sodium amide, potassium amide,
lithium diisopropylamide, sodium diisopropylamide, potassium
diisopropylamide, sodium bis(trimethylsilyl)amide and potassium
bis(trimethylsilyl)amide, preferably reacted with n-butyllithium or
tert-butylmagnesium chloride; then, reaction with carbon dioxide
follows to give a compound represented by the general formula
(G-II) (where R.sup.1, R.sup.2, R.sup.3 and R.sup.4 have the same
meanings as defined above); subsequently, the compound represented
by the general formula (G-VI) (where R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5 and R.sup.6 have the same meanings as defined
above) is obtained by performing amidation reaction on the compound
of the general formula (G-II) in the usual manner. Amidation
reaction typically involves reaction with a suitable condensing
agent and an amine of the general formula (G-III)
R.sup.5R.sup.6NH (G-III)
[0253] (where R.sup.5 and R.sup.6 which may be the same or
different represent a hydrogen atom or an optionally substituted
lower alkyl group) in an inert solvent in the presence or absence
of an organic base or an inorganic base (preferably, in their
absence).
[0254] The condensing agent is a reagent selected from among
commonly used condensing agents such as hydrochlorides of
dicyclohexylcarbodiimide, diisopropylcarbodiimide and
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide- , and methyl
chloroformate, ethyl chloroformate and isopropyl chloroformate,
with a hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)c-
arbodiimide and ethyl chloroformate being preferred.
[0255] Exemplary organic bases include pyridine and triethylamine.
Exemplary inorganic bases include sodium hydroxide, sodium
alkoxide, potassium alkoxide, alkyllithium, potassium carbonate,
sodium carbonate and potassium hydroxide.
[0256] Useful reaction solvents are inert solvents such as toluene,
diethyl ether, diisopropyl ether, tert-butyl methyl ether,
tetrahydrofuran, dioxane, dichloromethane, dichloroethane,
chloroform and ethyl acetate, or mixtures of solvents selected from
among these solvents; preferably, tert-butyl methyl ether, ethyl
acetate and dichloromethane are used. The reaction temperature is
between -78.degree. C. and the boiling point of the reaction
mixture, preferably between -40.degree. C. and room
temperature.
[0257] The compound which is represented by the general formula
(G-V) (where R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and
R.sup.6 have the same meanings as defined above) can also be
obtained by the following procedure:
[0258] a compound represented by the general formula (G-I) (where
R.sup.1, R.sup.2, R.sup.3 and R.sup.4 have the same meanings as
defined above) is reacted in an inert solvent such as hexane,
toluene, diethyl ether, diisopropyl ether, tert-butyl methyl ether,
tetrahydrofuran or dioxane, preferably in tert-butyl methyl ether,
tetrahydrofuran or diethyl ether, at a temperature between
-78.degree. C. and the boiling point of the reaction mixture,
preferably between -40.degree. C. and room temperature, with an
alkali metal such as lithium, sodium or potassium, alkyllithium
such as methyllithium, ethyllithium, n-propyllithium,
i-propyllithium, n-butyllithium, sec-butyllithium or
tert-butyllithium, or a Grignard reagent such as methylmagnesium
chloride, methylmagnesium bromide, methylmagnesium iodide,
ethylmagnesium chloride, ethylmagnesium bromide, ethylmagnesium
iodide, n-propylmagnesium chloride, n-propylmagnesium bromide,
n-propylmagnesium iodide, i-propylmagnesium chloride,
i-propylmagnesium bromide, i-propylmagnesium iodide,
n-butylmagnesium chloride, n-butylmagnesium bromide,
n-butylmagnesium iodide, sec-butylmagnesium chloride,
sec-butylmagnesium bromide, sec-butylmagnesium iodide,
tert-butylmagnesium chloride, tert-butylmagnesium bromide or
tert-butylmagnesium iodide, or a reagent selected from among
lithium hydride, sodium hydride, potassium hydride,
tert-butoxypotassium, lithium amide, sodium amide, potassium amide,
lithium diisopropylamide, sodium diisopropylamide, potassium
diisopropylamide, sodium bis(trimethylsilyl)amide and potassium
bis(trimethylsilyl)amide, preferably reacted with n-butyllithium or
tert-butylmagnesium chloride; subsequently, reaction is performed
with a compound represented by the general formula (G-IVa) (where
R.sup.5 and R.sup.6 which may be the same or different represent a
hydrogen atom or an optionally substituted lower alkyl group) or a
compound represented by the general formula (G-IVb)
R.sup.6aNCO (G-IVb)
[0259] (where R.sup.6a represents an optionally substituted lower
alkyl group).
[0260] If the resulting compound of the general formula (G-V) is
heated in an inert solvent such as a saturated hydrocarbon (e.g.
decane, undecane, dodecane, tridecane, tetradecane, cis-decalin or
trans-decalin), an aromatic hydrocarbon (e.g. toluene, xylene,
dichlorobenzene, tetralin or biphenyl), an ether-containing
hydrocarbon (e.g. diglyme, triglyme, tetraglyme or diphenyl ether),
a sulfolane-containing hyrocarbon (e.g. sulfolane) or a mixture
thereof, preferably, undecane, dodecane, cis-decalin,
trans-decalin, tetralin or a mixture thereof, at 100-300.degree.
C., preferably at 160-250.degree. C., there is produced a
4-substituted benzopyran derivative represented by the general
formula (G-VI) (where R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5
and R.sup.6 have the same meanings as defined above). During this
thermal cyclization reaction, a benzofuran derivative represented
by the general formula (G-VII) forms as a by-product. It was found
that the yield ratio between the end product 4-substituted
benzopyran derivative and the by-product benzofuran derivative
depends largely upon the reaction solvent and the reaction
temperature; when diethylaniline, a common conventional solvent for
the thermal cyclization reaction, was used as the reaction solvent,
benzopyran derivatives were not obtained at all but only benzofuran
derivatives occurred.
[0261] The compound of the general formula (G-II) can also be
obtained in salt form; specific examples of its salt include a
lithium salt, a sodium salt, a potassium salt and a magnesium salt,
with a sodium salt and a potassium salt being preferred.
[0262] If a compound of the general formula (G-IVb) is used,
R.sup.5 in the compound of the general formula (G-VI) is a hydrogen
atom.
[0263] C. Schemes (5) and (6):
[0264] For schemes (5) and (6), preferred examples of R.sup.1 and
R.sup.2 which may be the same or different include a hydrogen atom,
an optionally substituted lower alkyl group, a halogen atom, an
optionally substituted lower alkoxy group, NY.sub.aY.sub.b (where
Y.sub.a and Y.sub.b which may be the same or different each
represent a hydrogen atom, an optionally substituted lower alkyl
group, an optionally substituted lower alkoxycarbonyl group, an
acyl group, an optionally substituted lower alkylsulfonyl group or
an optionally substituted arylsulfonyl group or, when taken
together with the nitrogen atom to which they are bound, may form a
3- to 8-membered ring), a nitro group, a cyano group, an optionally
substituted lower alkoxycarbonyl group, an optionally substituted
lower alkylsulfonyl group, and an optionally substituted
arylsulfonyl group. These groups correspond to R.sup.1g and
R.sup.2g as defined in the general formula (Iz).
[0265] Preferably, R.sup.5 and R.sup.6 which may be the same or
different are a hydrogen atom or an optionally substituted lower
alkyl group.
[0266] In schemes (5) and (6), unless otherwise noted, the
following definitions hold:
[0267] the lower alkyl group means a straight-chained alkyl group
having 1-6 carbon atoms or a branched or cyclic alkyl group having
3-8 carbon atoms; examples include a methyl group, an ethyl group,
an n-propyl group, an n-butyl group, an n-pentyl group, an n-hexyl
group, an i-propyl group, an i-butyl group, a sec-butyl group, a
tert-butyl group, an i-pentyl group, a neopentyl group, a
tert-pentyl group, an i-hexyl group, a cyclopropyl group, a
cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a
cycloheptyl group and a cyclooctyl group;
[0268] the halogen atom means a fluorine atom, a chlorine atom, a
bromine atom or an iodine atom;
[0269] the lower alkoxy group means a straight-chained alkoxy group
having 1-6 carbon atoms or a branched or cyclic alkoxy group having
3-8 carbon atoms; examples include a methoxy group, an ethoxy
group, an n-propoxy group, an n-butoxy group, an n-pentoxy group,
an n-hexoxy group, an i-propoxy group, an i-butoxy group, a
sec-butoxy group, a tert-butoxy group, an i-pentoxy group, a
neopentoxy group, a tert-pentoxy group, an i-hexoxy group, a
cyclopropoxy group, a cyclobutoxy group, a cyclopentoxy group, a
cyclohexoxy group, a cycloheptoxy group and a cyclooctoxy
group.
[0270] the lower alkoxycarbonyl group means an alkoxycarbonyl group
whose alkyl portion is a straight-chained alkyl group having 1-6
carbon atoms or an alkoxycarbonyl group whose alkyl portion is a
branched or cyclic alkyl group having 3-8 carbon atoms, and
examples include a methoxycarbonyl group, an ethoxycarbonyl group,
an n-propoxycarbonyl group, an n-butoxycarbonyl group, an
n-pentoxycarbonyl group, an n-hexoxycarbonyl group, an
i-propoxycarbonyl group, an i-butoxycarbonyl group, a
sec-butoxycarbonyl group, a tert-butoxycarbonyl group, an
i-pentoxycarbonyl group, a neopentoxycarbonyl group, a
tert-pentoxycarbonyl group, an i-hexoxycarbonyl group, a
cyclopropoxycarbonyl group, a cyclobutoxycarbonyl group, a
cyclopentoxycarbonyl group, a cyclohexoxycarbonyl group, a
cycloheptoxycarbonyl group and a cyclooctoxycarbonyl group;
[0271] the lower alkylsulfonyl group means an alkylsulfonyl group
having 1-8 carbon atoms whose alkyl portion is a straight-chained
alkyl group or an alkylsulfonyl group having 3-8 carbon atoms whose
alkyl portion is a branched or cyclic alkyl group, and examples
include a methylsulfonyl group, an ethylsulfonyl group, a
propylsulfonyl group, an isopropylsulfonyl group, a butylsulfonyl
group and an isobutylsulfonyl group.
[0272] the arylsulfonyl group means an aromatic sulfonyl group and
examples include a phenylsulfonyl group, a p-tolylsulfonyl group, a
p-chlorophenylsulfonyl group, a 2-furylsulfonyl group, a
3-furylsulfonyl group, a 2-thienylsulfonyl group, a
3-thienylsulfonyl group, a 2-pyridylsulfonyl group, a
3-pyridylsulfonyl group and a 4-pyridylsulfonyl group.
[0273] Y.sub.a and Y.sub.b in NY.sub.aY.sub.b which may be the same
or different each represent a hydrogen atom, an optionally
substituted lower alkyl group, an optionally substituted lower
alkoxycarbonyl group, an acyl group, an optionally substituted
lower alkylsulfonyl group or an optionally substituted arylsulfonyl
group or, when taken together with the nitrogen atom to which they
are bound, may form a 3- to 8-membered ring. The acyl group as used
herein means a formyl group or an alkylcarbonyl group having 1-8
carbon atoms whose alkyl portion is an optionally substituted
straight-chained alkyl group, an alkylcarbonyl group having 3-8
carbon atoms whose alkyl portion is an optionally substituted
branched or cyclic alkyl group, or an arylcarbonyl group, and
examples include a formyl group, an acetyl group, a trifluoroacetyl
group, a propionyl group, a butyryl group, a valeryl group, an
isobutyryl group, an isovaleryl group, a pivaloyl group, a benzoyl
group, a phthaloyl group and a toluoyl group.
[0274] If R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7 or R.sup.8 represents an optionally substituted lower alkyl
group, an optionally substituted lower alkoxy group, an optionally
substituted lower alkoxycarbonyl group or an optionally substituted
lower alkylsulfonyl group, the optionally present substituent may
be exemplified by a halogen atom, a phenyl group, a hydroxy group,
a nitro group, a cyano group, a cyclic alkyl group having 3-8
carbon atoms, a lower alkoxy group optionally substituted by a
halogen atom or a phenyl group, a lower alkoxycarbonyl group, a
carboxyl group and NY.sub.cY.sub.d; Y.sub.c and Y.sub.d which may
be the same or different each represent a hydrogen atom, a lower
alkyl group, a lower alkoxycarbonyl group, an acyl group, a lower
alkylsulfonyl group or an optionally substituted arylsulfonyl group
or, when taken together with the nitrogen atom to which they are
bonded, may form a 3- to 8-numbered ring.
[0275] In the case where R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7 or R.sup.8 represents a lower alkyl
having a halogen atom as a substituent, an .alpha.-haloalkyl group
may be mentioned as an example. The .alpha.-haloalkyl group means a
straight-chained alkyl group having 1-6 carbon atoms or a branched
or cyclic alkyl group having 3-8 carbon atoms that have 1-3 halogen
atoms in 1-position and which may further possess a substituent,
and examples include a fluoromethyl group, a difluoromethyl group,
a trifluoromethyl group, a 1-fluoroethyl group, a 1,1-difluoroethyl
group, a 1-fluoropropyl group, a 1,1-difluoropropyl group, a
1-fluorocyclopropyl group, a 1-fluorobutyl group, a
1,1-difluorobutyl group, a chloromethyl group, a dichloromethyl
group, a trichloromethyl group, a 1-chloroethyl group, a
1,1-dichloroethyl group, a 1-chloropropyl group, a 1,1-chloropropyl
group, a 1-chlorocyclopropyl group, a 1-chlorobutyl group, a
1,1-dichlorobutyl group, a bromomethyl group, a dibromomethyl
group, a tribromomethyl group, a 1-bromoethyl group, a
1,1-dibromoethyl group, a 1-bromopropyl group, a 1,1-dibromopropyl
group, a 1-bromocyclopropyl group, a 1-bromobutyl group, a
1,1-dibromobutyl group, an iodomethyl group, a diodomethyl group, a
triiodomethyl group, a 1-iodoethyl group, a 1,1-diiodoethyl group,
a 1-iodopropyl group, a 1,1-diiodopropyl group, a 1-iodocyclopropyl
group, a 1-iodobutyl group and a 1,1-diiodobutyl group.
[0276] If R.sup.1, R.sup.2, R.sup.5, R.sup.6 or R.sup.7 represents
an optionally substituted arylsulfonyl group or an optionally
substituted aryl group, the optionally present substituent may be
exemplified by a halogen atom, a phenyl group, a hydroxy group, a
nitro group, a cyano group, a straight-chained alkyl group having
1-6 carbon atoms, a branched or cyclic alkyl group having 3-8
carbon atoms, a lower alkoxy group optionally substituted by a
halogen atom or a phenyl group, a lower alkylthio group optionally
substituted by a halogen atom or a phenyl group, a lower
alkoxycarbonyl group, a carboxyl group and NY.sub.eY.sub.f; Y.sub.e
and Y.sub.f which may be the same or different each represent a
hydrogen atom, an optionally substituted lower alkyl group, an
optionally substituted lower alkoxycarbonyl group, an acyl group,
an optionally substituted lower alkylsulfonyl group or an
arylsulfonyl group or, when taken together, may form a 3- to
8-numbered ring.
[0277] Examples of the optionally substituted lower alkyl group as
R.sup.1 and R.sup.2 include a methyl group, a fluoromethyl group, a
trifluoromethyl group, a pentafluoroethyl group, a benzyl group, a
nitromethyl group, a cyclopropylmethyl group, a methoxymethyl
group, an ethoxymethyl group, a benzyloxymethyl group, a
methylthiomethyl group, an ethylthiomethyl group, a
methoxycarbonylmethyl group, a dimethylaminomethyl group, an ethyl
group, a 2-fluoroethyl group, an n-propyl group, an i-propyl group,
a 1-methylthiopropyl group and an n-butyl group.
[0278] Examples of the optionally substituted lower alkyl group as
R.sup.3 and R.sup.4 include a methyl group, an ethyl group, an
n-propyl group, an n-butyl group, a fluoromethyl group, a
trifluoromethyl group, a benzyl group, a cyclopropylmethyl group, a
1-fluoroethyl group and a 1,1-difluoroethyl group.
[0279] Examples of the optionally substituted lower alkyl group as
R.sup.5 and R.sup.6 include a methyl group, a benzyl group, a
cyclopropylmethyl group, an ethyl group, a 2-cyanoethyl group, a
2-fluoroethyl group and a n-propyl group.
[0280] Examples of the optionally substituted lower alkoxy group as
R.sup.1 and R.sup.2 include a methoxy group, a trifluoromethoxy
group, a benzyloxy group, a cyclopropylmethoxy group, an ethoxy
group and a n-propoxy group.
[0281] Examples of the optionally substituted lower alkoxycarbonyl
group as R.sup.1and R.sup.2 include a methoxycarbonyl group, a
trifluoromethoxycarbonyl group, a benzyloxycarbonyl group, a
cyclopropylmethoxycarbonyl group, an ethoxycarbonyl group, an
n-propoxycarbonyl group and a tert-butoxycarbonyl group.
[0282] Examples of the above-mentioned NY.sub.aY.sub.b,
NY.sub.cY.sub.d and NY.sub.eY.sub.f include an amino group, a
methylamino group, a benzylamino group, an ethylamino group, a
dimethylamino group, an ethylmethylamino group, a pyrrolidinyl
group, a piperidino group, a morpholino group, an acetamido group,
a benzamido group, an N-methylacetamido group, a
tert-butoxycarbonylamino group, an
N-methyl-tert-butoxycarbonylamino group, a methylsulfonylamino
group, an ethylsulfonylamino group, a propylsulfonylamino group, an
isopropylsulfonylamino group, a butylsulfonylamino group, an
isobutylsulfonylamino group, a phenylsulfonylamino group, a
p-tolylsulfonylamino group and a p-chlorophenylsulfonylamino
group.
[0283] When taken together with the nitrogen atom to which they are
bound, Y.sub.a and Y.sub.b, Y.sub.c and Y.sub.d, or Y.sub.e and
Y.sub.f may form a 3-to 8-membered ring and the ring has 2-7 carbon
atoms, with any carbon atom on the ring being optionally replaced
by a nitrogen atom, an oxygen atom or a sulfur atom. Specific
examples include an aziridine ring, an azetidine ring, a pyrrole
ring, a pyrrolidine ring, a pyridine ring, a 3,4-dihydro-2H-azepine
ring, a 3,4,5,6-tetrahydro-2H-azepine ring, an azocine ring, a
5,6-dihydro-azocine ring, a 5,6,7,8-tetrahydroazocine ring, an
oxazoline ring, an isoxazoline ring, a thioxazoline ring, a
piperazine ring, a morpholine ring and a thiomorpholine ring.
[0284] The preferred position of substitution by R.sup.1 is in
6-position on the benzopyran ring.
[0285] Preferred examples of R.sup.1 include an optionally
substituted lower alkyl group, an optionally substituted
alkylsulfonyl group, an optionally substituted arylsulfonyl group,
a nitro group and a cyano group; among these, lower alkyl groups
having a fluorine atom as a substituent are preferred, with a
6-trifluoromethyl group and a 6-pentafluoroethyl group being
particularly preferred.
[0286] The preferred example of R.sup.2 is a hydrogen atom.
[0287] Speaking of R.sup.3 and R.sup.4, they are preferably the
same; more preferably, they both are an optionally substituted
.alpha.-haloalkyl group; most preferably, they both are a
fluoromethyl group.
[0288] Examples of the optionally substituted lower alkyl group as
R.sup.5 and R.sup.6 include a methyl group, a benzyl group, a
cyclopropylmethyl group, an ethyl group, a 2-cyanoethyl group, a
2-fluoroethyl group and an n-propyl group.
[0289] Speaking of R.sup.5 and R.sup.6, a preferred case is where
R.sup.5 is a hydrogen atom and R.sup.6 is an optionally substituted
lower alkyl group; a more preferred case is where R.sup.5 is a
hydrogen atom and R.sup.6 is a lower alkyl group optionally having
a cyano group, and a particularly preferred case is where R.sup.5
is a hydrogen atom and R.sup.6 is a 2-cyanoethyl group or a
2-cyanomethyl group.
[0290] Examples of the optionally substituted alkyl group as
R.sup.7 include a methyl group, an ethyl group and a propyl group.
Examples of the optionally substituted aryl group as R.sup.7
include a phenyl group, a p-tolyl group and a p-chlorophenyl group;
among these, a p-tolyl group and a methyl group are preferred, with
a p-tolyl group being particularly preferred.
[0291] Speaking of R.sup.8, it represents an optionally substituted
lower alkyl group; it is preferably an unsubstituted alkyl group,
with a methyl group and an ethyl group being particularly
preferred.
[0292] The compound of the general formula (I) (where R.sup.1,
R.sup.2, R.sup.3, R.sup.4 and Hal have the same meanings as defined
above) may be synthesized by the following procedure. Stated
specifically, the compound can be obtained by heating a compound of
the general formula (D-II) (where R.sup.1, R.sup.2, R.sup.3,
R.sup.4 and Hal have the same meanings as defined above) either
with or without a solvent, preferably in a suitable solvent for
smooth progress of the reaction, at a temperature between
130.degree. C. and the boiling point of the solvent, preferably at
150-200.degree. C. The suitable solvent to be used in the reaction
is an inert high-boiling point solvent that does not affect the
reaction and examples are solvent naphtha, xylene, o-xylene,
m-xylene, p-xylene, mesitylene, o-chlorotoluene, m-chlorotoluene,
p-chlorotoluene, o-dichlorobenzene, dodecane, tetralin, decalin and
diphenyl ether, with solvent naphtha and o-xylene being
preferred.
[0293] A compound of the general formula (G-VI) (where R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 have the same
meanings as defined above) can typically be synthesized by
conversion from the compound of the general formula (I) by a method
that involves a carbon monoxide inserting cross-coupling reaction
as a key reaction that uses a metal as a catalyst. To be specific,
the compound of the general formula (I) (where R.sup.1, R.sup.2,
R.sup.3, R.sup.4 and Hal have the same meanings as defined above)
is subjected to a cross-coupling reaction with a compound of the
general formula (G-III)
HNR.sup.5R.sup.6 (G-III)
[0294] (where R.sup.5 and R.sup.6 have the same meanings as defined
above) in a carbon monoxide stream at atmospheric or subatmospheric
pressure from a CO.sub.2 gas container, preferably at atmospheric
pressure, at a reaction temperature between -78.degree. C. and
150.degree. C., preferably between room temperature and 130.degree.
C., for a reaction time of from 1 hour to 3 days, preferably from 3
hours to 1 day, in the presence of a zero-valence or divalent metal
catalyst such as palladium, nickel, copper, zinc, tin or magnesium,
preferably, 1-5 mol % of zero-valence or divalent palladium such as
bis(triphenylphosphine)palladi- um acetate, palladium acetate and
triphenylphosphine, bis(triphenylphosphine)palladium chloride,
[1,1'-bis(diphenylphosphino)fe- rrocene]palladium chloride
dichloromethane adduct, tetrakis (triphenylphosphine) palladium,
tris(dibenzylideneacetone)dipalladium chloroform adduct and
triphenylphosphine, or tris(dibenzylideneacetone)di- palladium
chloroform adduct in a solvent such as N,N-dimethylformamide,
tetrahydrofuran, dioxane, ether, acetonitrile, toluene, benzene or
water, preferably N,N-dimethylformamide, thereby giving a
4-substituted benzopyran derivative represented by the general
formula (G-VI) (where R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5
and R.sup.6 have the same meanings as defined above).
[0295] For synthesis of the compound represented by the general
formula (I), the compound represented by the general formula (D-II)
is used as an intermediate and this compound, being undocumented
and novel, constitutes the present invention. To give the compound
of the general formula (D-II), a compound represented by the
general formula (C-VI) (where R.sup.1, R.sup.2, R.sup.3 and R.sup.4
have the same meanings as defined above) is reacted with a suitable
base in a suitable solvent at a temperature between -78.degree. C.
and the boiling point of the reaction mixture, preferably between
-40.degree. C. and room temperature, and without subsequent
isolation, reaction is performed with a halogen (preferably
bromine). The suitable solvent to be used in this reaction is an
inert solvent that does not affect the reaction and may be
exemplified by hexane, toluene, diethyl ether, diisopropyl ether,
tert-butyl methyl ether, tetrahydrofuran and dioxane, with
tetrahydrofuran and diethyl ether being preferred. The suitable
base to be used in this reaction is exemplified by alkyllithium
such as methyllithium, ethyllithium, n-propyllithium,
i-propyllithium, n-butyllithium, sec-butyllithium or
tert-butyllithium, alkoxides such as potassium t-butoxide, sodium
methoxide and sodium ethoxide, or Grignard reagents such as
methylmagnesium chloride, methylmagnesium bromide, methylmagnesium
iodide, ethylmagnesium chloride, ethylmagnesium bromide,
ethylmagnesium iodide, n-propylmagnesium chloride,
n-propylmagnesium bromide, n-propylmagnesium iodide,
i-propylmagnesium chloride, i-propylmagnesium bromide,
i-propylmagnesium iodide, n-butylmagnesium chloride,
n-butylmagnesium bromide, n-butylmagnesium iodide,
sec-butylmagnesium chloride, sec-butylmagnesium bromide,
sec-butylmagnesium iodide, tert-butylmagnesium chloride,
tert-butylmagnesium bromide and tert-butylmagnesium iodide; among
these, n-butyllithium and ethylmagnesium bromide are preferred.
[0296] The compound of the general formula (D-II) can also be
obtained by reacting a compound of the general formula (C-VI)
(where R.sup.1, R.sup.2, R.sup.3 and R.sup.4 have the same meanings
as defined above) with a halogen (preferably bromine) in a suitable
solvent in the presence of a suitable base at a temperature between
-40.degree. C. and room temperature, preferably between 0.degree.
C. and room temperature. The suitable solvent to be used in this
invention may be selected from among alcohols such as methanol,
ethanol, n-propyl alcohol, i-propyl alcohol, n-butyl alcohol,
i-butyl alcohol, sec-butyl alcohol and tert-butyl alcohol, mixtures
of these alcohols with inert solvents that do not affect the
reaction such as diethyl ether, diisopropyl ether, tert-butyl
methyl ether, tetrahydrofuran and dioxane; among these, a mixture
of tert-butyl methyl ether and tert-butyl alcohol is a preferred
solvent system. The suitable base to be used in this reaction is an
alkoxide such as potassium tert-butoxide, sodium methoxide or
sodium ethoxide, with potassium tert-butoxide being preferred.
[0297] For synthesis of the compound represented by the general
formula (D-II), the compound represented by the general formula
(C-VI) is used as an intermediate and this compound, being
undocumented and novel, constitutes the present invention. To give
the compound of the general formula (C-VI), a sulfonate ester
represented by the general formula (C-IV) (where R.sup.7, R.sup.3
and R.sup.4 have the same meanings as defined above) may be reacted
with a phenol represented by the general formula (C-V) (where
R.sup.1 and R.sup.2 have the same meanings as defined above) in an
inert solvent such as acetonitrile that does not affect the
reaction, in the presence of a suitable base and a catalytic amount
of a suitable copper salt at a temperature between -78.degree. C.
and room temperature, preferably between 0.degree. C. and room
temperature. Examples of the suitable base that can be used in the
reaction include organic strong bases such as
1,8-diazabicyclo(5.4.0)-7-u- ndecene and
1,5-diazabicyclo(4.3.0)-5-nonene, and tertiary amines such as
triethylamine, tributylamine and N,N-diisopropylethylamine, with
N,N-diisopropylethylamine being preferred. Examples of the suitable
copper salt that can be used in the reaction include cuprous salts
such as copper(I) acetate, copper(I) trifluoroacetate, cuprous
chloride, cuprous bromide, cuprous iodide and cuprous cyanide, and
cupric salts such as cupric chloride and cupric bromide, with
cupric chloride and cupric bromide being preferred.
[0298] For synthesis of the compound of the general formula (C-VI),
the compound represented by the general formula (C-IV) is used as
an intermediate and this compound, being undocumented and novel,
constitutes the present invention. To prepare the compound of the
general formula (C-IV), an alcohol represented by the general
formula (C-I) (where R.sup.3 and R.sup.4 have the same meanings as
defined above) may be reacted with a compound of the general
formula (C-TI) or (C-III)
R.sup.7SO.sub.2Cl (C-II)
(R.sup.7SO.sub.2).sub.2O (C-III)
[0299] (where R.sup.7 represents an optionally substituted alkyl
group or an optionally substituted aryl group) either after
reacting the alcohol with a suitable base in a suitable solvent to
be converted to an alkoxide or directly in a suitable solvent in
the presence of a suitable base at a temperature between
-78.degree. C. and room temperature, preferably between 0.degree.
C. and room temperature. In this reaction, a suitable catalyst such
as N,N-dimethylaminopyridine may be used. The suitable solvent that
can be used in this reaction is an inert solvent that does not
affect the reaction, as exemplified by diethyl ether, diisopropyl
ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, diglyme,
acetone, N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl
sulfide, with tetrahydrofuran and tert-butyl methyl ether being
preferred. Examples of the suitable base that can be used in the
reaction include alkali metal hydrides such as potassium hydride,
sodium hydride and lithium hydride, or carbonates such as potassium
carbonate and sodium carbonate, bicarbonates such as potassium
hydrogencarbonate and sodium hydrogencarbonate, organic strong
bases such as 1,8-diazabicyclo(5.4.0)-7- -undecene and
1,5-diazabicyclo(4.3.0)-5-nonene, tertiary amines such as
triethylamine, tributylamine and N,N-diisopropylethylamine; among
these, sodium hydride and triethylamine are preferred.
[0300] Among the compounds represented by the general formula
(H-V), a compound in which R.sup.3 and R.sup.4 are a
trifluoromethyl group (--CH.sub.2F) is an undocumented novel
compound and constitutes the present invention. To give the
compound of the general formula (H-V), a compound represented by
the general formula (H-IV) (where R.sup.1, R.sup.2, R.sup.3,
R.sup.4 and R.sup.8 have the same meanings as defined above) may be
rapidly heated to a temperature between 180.degree. C. and
250.degree. C., preferably between 180.degree. C. and 200.degree.
C., either with or without a solvent, preferably in a suitable
solvent for smooth progress of the reaction, either at atmospheric
or superatmospheric pressure. The suitable solvent to be used in
this reaction is a high-boiling point solvent that does not affect
the reaction and may be exemplified by mesitylene, dichlorobenzene,
dodecane, tetralin, decalin and diphenyl ether, with
1,2-dichlorobenzene being preferred.
[0301] For synthesis of the compound represented by the general
formula (H-V), the compound represented by the general formula
(H-IV) is used as an intermediate. Among the compounds represented
by the general formula (H-IV), a compound in which R.sup.3 and
R.sup.4 are a trifluoromethyl group (--CH.sub.2F) is an
undocumented novel compound and constitutes the present invention.
To give the compound of the general formula (H-IV), a compound
represented by the general formula (C-VI) (where R.sup.1, R.sup.2,
R.sup.3 and R.sup.4 have the same meanings as defined above) is
reacted with a suitable base in a suitable solvent at a temperature
between -78.degree. C. and the boiling point of the reaction
mixture, preferably between -40.degree. C. and room temperature,
and without subsequent isolation, reaction is performed with a
compound represented by the general formula (H-II)
OC(OR.sup.8).sub.2 (H-II)
or the general formula (H-III)
ClC(O)R.sup.8 (H-III)
[0302] (where R.sup.8 represents an optionally substituted lower
alkyl group). The suitable solvent to be used in this reaction is
an inert solvent that does not affect the reaction and may be
exemplified by hexane, toluene, diethyl ether, diisopropyl ether,
tert-butyl methyl ether, tetrahydrofuran and dioxane, with
tetrahydrofuran and diethyl ether being preferred. The suitable
base to be used in this reaction is exemplified by alkyllithium
such as methyllithium, ethyllithium, n-propyllithium,
i-propyllithium, n-butyllithium, sec-butyllithium or
tert-butyllithium, or Grignard reagents such as methylmagnesium
chloride, methylmagnesium bromide, methylmagnesium iodide,
ethylmagnesium chloride, ethylmagnesium bromide, ethylmagnesium
iodide, n-propylmagnesium chloride, n-propylmagnesium bromide,
n-propylmagnesium iodide, i-propylmagnesium chloride,
i-propylmagnesium bromide, i-propylmagnesium iodide,
n-butylmagnesium chloride, n-butylmagnesium bromide,
n-butylmagnesium iodide, sec-butylmagnesium chloride,
sec-butylmagnesium bromide, sec-butylmagnesium iodide,
tert-butylmagnesium chloride, tert-butylmagnesium bromide and
tert-butylmagnesium iodide, and alkoxides such as potassium
t-butoxide, sodium methoxide and sodium ethoxide; among these,
n-butyllithium and ethylmagnesium bromide are preferred.
[0303] The compound represented by the general formula (G-VI) can
be obtained by conversion from the compound of the general formula
(H-V) in the following manner. To be specific, the compound
represented by the general formula (H-V) (where R.sup.1, R.sup.2,
R.sup.3, R.sup.4 and R.sup.8 have the same meanings as defined
above) is reacted with a suitable reagent in a suitable solvent at
a temperature between 0.degree. C. and the boiling point of the
solvent, preferably between room temperature and 80.degree. C., to
effect hydrolysis (conversion from --COOR.sup.8 to --COOH);
thereafter, the carboxylate is reacted with a compound represented
by the general formula (G-III)
HNR.sup.5R.sup.6 (G-III)
[0304] (where R.sup.5 and R.sup.6 have the same meanings as defined
above) and a suitable reagent to effect dehydrative condensation in
a suitable solvent at a temperature between 0.degree. C. and the
boiling point of the solvent, preferably at room temperature,
thereby producing the general formula (G-VI) (where R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 have the same
meanings as defined above).
[0305] The suitable solvent for use in hydrolysis is an inert
solvent that does not affect the reaction, as exemplified by water,
methanol, ethanol, isopropanol, hydrous methanol, hydrous ethanol,
hydrous isopropanol, hydrous tetrahydrofuran, hydrous dioxane,
benzene and toluene, with ethanol being preferred. The suitable
reagent for use in hydrolysis is a base such as lithium hydroxide,
sodium hydroxide, potassium hydroxide, barium hydroxide, lithium
carbonate, sodium carbonate or potassium carbonate, or an acid such
as hydrochloric acid, hydrobromic acid, acetic acid or sulfuric
acid, with potassium hydroxide being preferred.
[0306] The suitable solvent for use in dehydrative condensation is
an inert solvent that does not affect the reaction, as exemplified
by tetrahydrofuran, dichloromethane, chloroform, carbon
tetrachloride, acetonitrile, benzene, toluene,
N,N-dimethylformamide and dimethyl sulfoxide, with tetrahydrofuran
being preferred. The suitable reagent for use in dehydrative
condensation may be selected from among reagents such as
N,N'-carbonyldiimidazole, 1,3-dicyclohexylcarbodiimide,
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, 2,2'-pyridine
sulfide and triphenylphosphine,
2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, thionyl chloride,
phosphorus pentachloride and phosphorus oxychloride; among these,
N,N'-carbonyldiimidazole is preferred.
EXAMPLES
[0307] The following examples are provided for the purpose of
further illustrating the present invention. The term "room
temperature" as used hereinafter means a temperature between
10.degree. C. and 30.degree. C.
[0308] A. Examples for Schemes (1) and (2):
Example A1
[0309] Preparation of
4-bromo-2,2-bis(fluoromethyl)-6-trifluoromethyl-2H-1-
-benzopyran
[0310] 1) 1-fluoro-2-fluoromethyl-3-buten-2-ol
[0311] To a 1 M vinylmagnesium bromide-tetrahydrofuran solution (1
L), 1,3-difluoroacetone (105 g) was added dropwise at -30.degree.
C. and the mixture was stirred at the same temperature for 1 hour.
To the reaction mixture, a saturated aqueous solution of ammonium
chloride was added and following extraction with hexane and washing
with a saturated aqueous solution of sodium chloride, the mixture
was dried with anhydrous sodium sulfate and concentrated at
atmospheric pressure; the resulting residue was purified by
distillation to give l-fluoro-2-fluoromethyl-3-buten-2-ol (105 g)
having a boiling point of 78-81.degree. C./106 mm Hg.
[0312] 1H-NMR (CDCl.sub.3) .delta.:2.50-2.55(1H,m),
4.26-4.55(4H,m), 5.40(1H,dd,J=10.9, 1.3 Hz), 5.56(1H,dd,J=17.5, 1.3
Hz), 5.91(1H,dd,J=17.5, 10.9 Hz).
[0313] 2)
4-(2-chloro-5-trifluoromethylphenyl)-1-fluoro-2-fluoromethyl-3-t-
rans-buten-2-ol
[0314] A mixture of 3-bromo-4-chlorobenzotrifluoride (1.50 g),
1-fluoro-2-fluoromethyl-3-buten-2-ol (0.80 g), potassium carbonate
(2.10 g), tetrabutylammonium bromide (325 mg), palladium acetate
(56 mg) and N,N-dimethylacetamide (10 ml) was stirred under a
nitrogen atmosphere at 80.degree. C. for 14 hours. To the reaction
mixture, 1 N HCl was added followed by extraction with a
hexane/ethyl acetate mixed (1/1) solvent; the resulting organic
layers were combined and washed with a saturated aqueous solution
of sodium thiosulfate and a saturated aqueous solution of sodium
chloride; the mixture was dried with anhydrous sodium sulfate and
concentrated under reduced pressure; the resulting residue was
subjected to silica gel column chromatography (eluent; hexane/ethyl
acetate=10/1) to give
4-(2-chloro-5-trifluoromethylphenyl)-1-fluoro-2-flu-
oromethyl-3-trans-buten-2-ol (1.53 g) having a melting point of
61-62.degree. C.
[0315] 1H-NMR (CDCl.sub.3) .delta.:2.76(1H,s), 4.41-4.61(4H,m),
6.31(1H,d,J=16.2 Hz), 7.30(1H,d,J=1.6.2 HZ), 7.42-7.51(2H,m),
7.75(1H,d,J=1.3 Hz).
[0316] 3)
3,4-dibromo-4-(2-chloro-5-trifluoromethylphenyl)-1-fluoro-2-(flu-
oromethyl)butan-2-ol
[0317] A mixture of
4-(2-chloro-5-trifluoromethylphenyl)-1-fluoro-2-fluoro-
methyl-3-trans-buten-2-ol (11.3 g) and tert-amyl alcohol (75 ml)
was stirred at -10.degree. C. and, after dropwise addition of
bromine (3.88 ml), further stirred at -10.degree. C. for an
additional 3 hours. To the reaction mixture, a hexane/ethyl acetate
mixed solvent (1/1) was added and the mixture was washed with a
saturated aqueous solution of sodium thiosulfate and a saturated
aqueous solution of sodium chloride, dried with anhydrous sodium
sulfate and concentrated under reduced pressure to give
3,4-dibromo-4-(2-chloro-5-trifluoromethylphenyl)-1-fluoro-2-(fluorom-
ethyl)butan-2-ol (17.3 g).
[0318] 1H-NMR (CDCl.sub.3) .delta.:2.70-3.20(1H,m),
4.57-5.10(5H,m), 5.90-6.20(1H,m), 7.50-7.60(2H,m), 7.80-8.20(1H,m).
4)
3-(2-chloro-5-trifluoromethylphenyl)bromomethyl-2,2-bis(fluoromethyl)oxir-
ane
[0319] A mixture of
3,4-dibromo-4-(2-chloro-5-trifluoromethylphenyl)-1-flu-
oro-2-(fluoromethyl)butan-2-ol (0.46 g), sodium hydride (48 mg) and
toluene (10 ml) was stirred at 60.degree. C. for 30 minutes. To the
reaction mixture, 2 N HCl was added; after extraction with a
hexane/ethyl acetate mixed solvent (5/1), the mixture was washed
with a saturated aqueous solution of sodium chloride, dried with
anhydrous sodium sulfate and concentrated under reduced pressure;
the resulting residue was subjected to silica gel column
chromatography to give
3-(2-chloro-5-trifluoromethylphenyl)bromomethyl-2,2-bis(fluoromethyl)oxir-
ane (0.37 g) having a melting point of 54-55.degree. C.
[0320] 1H-NMR (CDCl.sub.3) .delta.:3.96(1H,dd,J=9.2, 2.3 Hz),
4.38-4.76(4H,m), 5.29(1H,d,J=9.2 Hz), 7.56-7.57(2H,m),
7.83(1H,s).
[0321] 5)
4-bromo-2,2-bis(fluoromethyl)-6-trifluoromethyl-2H-1-benzopyran
[0322] A mixture of
3-(2-chloro-5-trifluoromethylphenyl)bromomethyl-2,2-bi-
s(fluoromethyl)oxirane (9.59 g) and tetrahydrofuran (80 ml) was
stirred at -10.degree. C. and, following dropwise addition of 0.5 M
potassium bis(trimethylsilyl)amide in toluene (50 ml), further
stirred at -10.degree. C. for an additional 1.5 hours. To the
reaction mixture, 2 N HCl was added, followed by extraction with a
hexane/ethyl acetate mixed solvent (1/1); the resulting organic
layers were combined, washed with a saturated aqueous solution of
sodium chloride, dried with anhydrous sodium sulfate and
concentrated under reduced pressure; the resulting residue was
purified by distillation to give 4-bromo-2,2-bis(fluoromethyl-
)-6-trifluoromethyl-2H-1-benzopyran (6.0 g) having a boiling point
of 122-123.degree. C./5 mmHg.
[0323] 1H-NMR (CDCl.sub.3) .delta.:4.41-4.71(4H,m), 6.14(1H,s),
6.95(1H,d,J=8.6 Hz), 7.50(1H,dd,J=8.6, 2.0 Hz), 7.71(1H,d,J=2.0
Hz).
Example A2
[0324] Preparation of
4-bromo-2,2-bis(fluoromethyl)-6-trifluoromethyl-2H-1- -benzopyran
via 2,2-bisfluoromethyl-6-trifluoromethyl-2H-1-benzopyran
(Alternative Method for Preparing the End Compound of Example
A1)
[0325] 1)
4-(2-chloro-5-trifluoromethylphenyl)-1-fluoro-2-fluoromethyl-3-b-
utyn-2-ol
[0326] A mixture of 4-chloro-3-iodobenzotrifluoride (63.3 g),
1-fluoro-2-fluoromethyl-3-butyn-2-ol (28.8 g), triethylamine (26.2
g), cuprous iodide (0.38 g), bis(triphenylphosphine)palladium
chloride (1.40 g) and N,N-dimethylformamide (100 ml) was stirred
under a nitrogen atmosphere under heating at 80.degree. C. for 1.5
hours. To the reaction mixture, 2 N HCl and a hexane/ethyl acetate
mixed solvent (3/1) were added and the insoluble matter was
filtered off with Celite; following extraction with a hexane/ethyl
acetate mixed solvent (3/1), the resulting organic layers were
combined, washed with a saturated aqueous solution of sodium
chloride, dried with anhydrous sodium sulfate and concentrated
under reduced pressure; the resulting residue was purified by
distillation to give
4-(2-chloro-5-trifluoromethylphenyl)-1-fluoro-2-fluo-
romethyl-3-butyn-2-ol (44.5 g) having a boiling point of
105-107.degree. C./1 mmHg.
[0327] 1H-NMR (CDCl.sub.3) .delta.:2.70-3.00(1H,m),
4.52-4.71(4H,m), 7.54-7.56(2H,m), 7.76(1H,t,J=0.7 Hz)
[0328] 2)
4-(2-chloro-5-trifluoromethylphenyl)-1-fluoro-2-fluoromethyl-3-c-
is-buten-2-ol
[0329] A mixture of
4-(2-chloro-5-trifluoromethylphenyl)-1-fluoro-2-fluoro-
methyl-3-butyn-2-ol (44.5 g), 5% palladium-barium carbonate (6.6
g), pyridine (2.3 g) and ethyl acetate (500 ml) was stirred under a
hydrogen atmosphere at room temperature for 10 days. The catalyst
was filtered off from the reaction mixture; subsequent
concentrating under reduced pressure gave
4-(2-chloro-5-trifluoromethylphenyl)-1-fluoro-2-fluoromethy-
l-3-cis-buten-2-ol (44.0 g).
[0330] 1H-NMR (CDCl.sub.3) .delta.:2.00-2.20(1H,m),
4.24-4.52(4H,m), 5.83(1H,dt,J=12.5, 1.3 Hz), 6.74(1H,d,J=12.5 Hz),
7.48(1H,d,J=1Hz), 7.70(1H,s).
[0331] 3)
2,2-bis(fluoromethyl)-6-trifluoromethyl-2H-1-benzopyran
[0332] A mixture of
4-(2-chloro-5-trifluoromethylphenyl)-1-fluoro-2-fluoro-
methyl-3-cis-buten-2-ol (8.80 g), potassium tert-butoxide (3.50 g)
and N,N-dimethylformamide (60 ml) was stirred at 60.degree. C. for
40 minutes. To the reaction mixture, 2 N HCl was added, followed by
extraction with ethyl acetate; the resulting organic layers were
combined, washed with a saturated aqueous solution of sodium
bicarbonate and a saturated aqueous solution of sodium chloride,
dried with anhydrous sodium sulfate and concentrated under reduced
pressure to give
2,2-bis(fluoromethyl)-6-trifluoromethyl-2H-1-benzopyran (7.0
g).
[0333] 1H-NMR (CDCl.sub.3) .delta.:4.38-4.72(4H,m), 5.72(1H,d,J=9.9
Hz), 6.65(1H,d,J=9.9 Hz), 6.94(1H,d,J=8.6 Hz), 7.27-7.28(2H,m),
7.42(1H,dd,J=8.6, 2.0 Hz).
[0334] 4)
3,4-dibromo-2,2-bis(fluoromethyl)-6-trifluoromethyl-3,4-dihydro--
2H-1-benzopyran
[0335] A mixture of
2,2-bis(fluoromethyl)-6-trifluoromethyl-2H-1-benzopyra- n (6.68 g),
bromine (2 ml) and chloroform (150 ml) was stirred at -10.degree.
C. for 20 minutes. The reaction mixture was concentrated under
reduced pressure to give
3,4-dibromo-2,2-bis(fluoromethyl)-6-triflu-
oromethyl-3,4-dihydro-2H-1-benzopyran (10.72 g).
[0336] 1H-NMR (CDCl.sub.3) .delta.:4.62-5.25(5H,m), 5.66(1H,d,J=4.6
Hz), 7.07(1H,d,J=8.6 Hz), 7.53(1H,dd,J=8.6, 1.6 Hz), 7.73 (1H, d,
J=i. 6 Hz).
[0337] 5)
4-bromo-2,2-bis(fluoromethyl)-6-trifluoromethyl-2H-1-benzopyran
[0338] A mixture of
3,4-dibromo-2,2-bis(fluoromethyl)-6-trifluoromethyl-3,-
4-dihydro-2H-1-benzopyran (10.72 g), a 2 N aqueous solution of
sodium hydroxide (60 ml) and dioxane (100 ml) was stirred at room
temperature for 2 hours. To the reaction mixture, 2 N HCl was
added, followed by extraction with ethyl acetate; the resulting
organic layers were combined, washed with a saturated aqueous
solution of sodium chloride, dried with anhydrous sodium sulfate
and concentrated under reduced pressure; the resulting residue was
subjected to silica gel column chromatography (eluent; hexane/ethyl
acetate=10/1) to give
4-bromo-2,2-bis(fluoromethyl)-6-trifluoromethyl-2H-1-benzopyran
(8.18 g).
[0339] 1H-NMR (CDCl.sub.3) .delta.:4.41-4.71(4H,m), 6.14(1H,s),
6.95(1H,d,J=8.6 Hz), 7.50(1H,dd,J=8.6, 2.0 Hz), 7.71(1H,d,J=2.0
Hz).
Example A3
[0340] Preparation of
N-(2-cyanoethyl)-2,2-bis(fluoromethyl)-6-trifluorome-
thyl-2H-1-benzopyran-4-carboxamide
[0341] A mixture of
4-bromo-2,2-bis(fluoromethyl)-6-trifluoromethyl-2H-1-b- enzopyran
(1.73 g), 2-cyanoethylamine (1.44 g), potassium iodide (0.86 g),
triphenylphosphine (26 mg), palladium acetate (11 mg) and
N,N-dimethylacetamide (10 ml) was stirred under a CO atmosphere at
100.degree. C. for 3 hours. To the reaction mixture, 2 N HCl was
added and the precipitating crystals were recovered by filtration.
To the recovered crystals, ethyl acetate was added and the
insoluble matter was filtered off; the filtrate was washed with a
saturated aqueous solution of sodium thiosulfate and a saturated
aqueous solution of sodium chloride, dried with anhydrous sodium
sulfate and concentrated under reduced pressure; the resulting
residue was recrystallized with an ethanol/water mixed solvent,
thereby giving N-(2-cyanoethyl)-2,2-bis(fluo-
romethyl)-6-trifluoromethyl-2H-1-benzopyran-4-carboxamide (1.46 g)
having a melting point of 129-131.degree. C.
[0342] 1H-NMR (DMSO-d.sub.6) .delta.:2.77(2H,t,J=6.3 Hz),
3.47(2H,q,J=6.3 Hz), 4.53-4.82(4H,m), 6.14(1H,s), 7.11(1H,d,J=8.6
Hz), 7.59(1H,dd,J=8.6, 2.0 Hz), 7.83(1H,d,J=2.0 Hz),
8.85-9.00(1H,m). MSm/z:360(M.sup.+)
Example A4
[0343] Preparation of
N-(2-cyanoethyl)-2,2-bis(fluoromethyl)-6-trifluorome-
thyl-2H-1-benzopyran-4-carboxamide via
2,2-bis(fluoromethyl)-6-trifluorome-
thyl-2H-1-benzopyran-4-carboxylic acid (Alternative Method for
Preparing the End Compound of Example A3)
[0344] 1)
2,2-bis(fluoromethyl)-6-trifluoromethyl-2H-1-benzopyran-4-carbox-
ylic acid
[0345] A mixture of
4-bromo-2,2-bis(fluoromethyl)-6-trifluoromethyl-2H-1-b- enzopyran
(1.72 g), potassium acetate (2.00 g), potassium iodide (0.85 g),
triphenylphosphine (27 mg), palladium acetate (11 mg) and
N,N-dimethylacetamide (10 ml) was stirred under a CO atmosphere at
120.degree. C. for 9 hours. To the reaction mixture, 2 N HCl was
added and the precipitating crystals were recovered by filtration.
To the recovered crystals, ethyl acetate was added and the
insoluble matter was filtered off; the filtrate was washed with a
saturated aqueous solution of sodium thiosulfate and a saturated
aqueous solution of sodium chloride, dried with anhydrous sodium
sulfate and concentrated under reduced pressure; the resulting
residue was dissolved in a saturated aqueous solution of sodium
hydrogencarbonate and washed with dichloromethane; to the resulting
aqueous layer, concentrated HCl was added to render it acidic and
the precipitating crystals were recovered by filtration. The
recovered crystals were dissolved in ethyl acetate, dried with
anhydrous magnesium sulfate and concentrated under reduced
pressure; the resulting residue was recrystallized with an ethyl
acetate/hexane mixed solvent to give
2,2-bis(fluoromethyl)-6-trifluoromet-
hyl-2H-1-benzopyran-4-carboxylic acid (1.25 g) having a melting
point of 162-163.degree. C.
[0346] 1H-NMR (DMSO-d.sub.6) .delta.:4.56-4.85(4H,m), 6.81(1H,s),
7.08(1H,d,J=8.6 Hz), 7.60(1H,dd,J=8.6, 2.0 Hz), 7.83(1H,d,J=2.0
Hz), 8.86(1H,d,J=2.0 Hz), 13.45-13.70(1H,m). MSm/z:308(M.sup.+)
[0347] 2)
N-(2-cyanoethyl)-2,2-bis(fluoromethyl)-6-trifluoromethyl-2H-1-be-
nzopyran-4-carboxamide
[0348] A mixture of
2,2-bis(fluoromethyl)-6-trifluoromethyl-2H-1-benzopyra-
n-4-carboxylic acid (1.55 g), thionyl chloride (0.51 ml) and
toluene (5 ml) was stirred at 80.degree. C. for 5 hours. The
reaction mixture was concentrated under reduced pressure; to the
resulting residue, a mixture of 2-cyanoethylamine (0.42 g) and
acetonitrile (5 ml) was added over an ice bath; further, a mixture
of triethylamine (2.52 g) and acetonitrile (5 ml) was added and the
resulting mixture was stirred first over an ice bath for 10
minutes, then at room temperature for 1 hour. To the reaction
mixture, 2 N HCl was added and the precipitating crystals were
recovered by filtration. The recovered crystals were dissolved in
ethyl acetate, washed with a saturated aqueous solution of sodium
chloride, dried with anhydrous sodium sulfate and concentrated
under reduced pressure; the resulting residue was recrystallized
with an ethanol/water mixed solvent to give
N-(2-cyanoethyl)-2,2-bis(fluoromethyl)-6-trifluoromethyl-2H-1-ben-
zopyran-4-carboxamide (1.61 g) having a melting point of
129-131.degree. C.
[0349] 1H-NMR (DMSO-d.sub.6) .delta.:2.77(2H,t,J=6.3 Hz),
3.47(2H,q,J=6.3 Hz), 4.53-4.82(4H,m), 6.14(1H,s), 7.11(1H,d,J=8.6
Hz), 7.59(1H,dd,J=8.6, 2.0 Hz), 7.83(1H,d,J=2.0 Hz),
8.85-9.00(1H,m). MSm/z:360(M.sup.+)
Example A5
[0350]
N-(2-cyanoethyl)-6-pentafluoroethyl-2,2-bis(fluoromethyl)-2H-1-benz-
opyran-4-carboxamide
[0351] A mixture of
4-bromo-6-pentafluoroethyl-2,2-bis(fluoromethyl)-2H-1-- benzopyran
(0.40 g), bis(triphenylphosphine)palladium chloride (28 mg),
2-cyanoethylamine (0.28 g), potassium iodide (0.17 g) and
N,N-dimethylformamide (5 ml) was stirred under a CO atmosphere at
80.degree. C. for 2 hours. To the reaction mixture, 2N HCl was
added, followed by extraction with ethyl acetate; the extract was
dried with sodium sulfate and subjected to silica gel column
chromatography (eluent; hexane/ethyl acetate=1/1) to give the
titled compound (0.33 g) having a melting point of 144-145.degree.
C.
[0352] 1H-NMR (CDCl.sub.3) .delta.:2.73(2H,t,J=6.3 Hz),
3.67(2H,q,J=6.3 Hz), 4.44-4.73(4H,m), 6.08(1H,s), 6.40-6.60(1H,m),
7.03(1H,d,J=8.6 Hz), 7.47(1H,dd,J=8.6, 2.0 Hz), 7.81(1H,d,J=2.0
Hz). MSm/z:410(M.sup.+)
[0353] B. Examples for Schemes (3) and (4):
Example B1
[0354] Preparation of 1-fluoro-2-fluoromethyl-3-butyn-2-yl
p-toluenesulfonate
[0355] An amount (6.6 g) of 1-fluoro-2-fluoromethyl-3-butyn-2-ol
and p-toluenesulfonyl chloride (9.5 g) were dissolved in
tetrahydrofuran (100 ml); to the solution under cooling with ice,
60% oily sodium hydride (2.4 g) was added under a nitrogen
atmosphere. After the end of the addition, the mixture was stirred
for 5 hours while its temperature was raised to room temperature.
To the reaction mixture, water was added followed by extraction
with ether. The extract was washed with water and a saturated
aqueous solution of sodium chloride, dried with anhydrous sodium
sulfate and concentrated under reduced pressure. The resulting
residue was subjected to silica gel column chromatography (eluent;
hexane/methylene chloride=1/1) to give the titled compound (11.1
g).
[0356] 1H-NMR (CDCl.sub.3) .delta.:2.45(3H,s), 2.74(1H,s),
4.53-4.87(4H,m), 7.34(2H,d,J=8.3 Hz), 7.83(2H,d,J=8.3 Hz).
Example B2
[0357] Preparation of 1-fluoro-2-fluoromethyl-3-butyn-2-yl
methanesulfonate
[0358] (A) An amount (1.2 g) of
1-fluoro-2-fluoromethyl-3-butyn-2-ol was dissolved in
tetrahydrofuran (10 ml); to the solution under cooling with ice,
60% oily sodium hydride (0.48 g) was added under a nitrogen
atmosphere. The solution was stirred for 30 minutes under cooling
with ice and then methanesulfonyl chloride (1.1 ml) was added
dropwise. The solution was stirred for 2.5 hours while its
temperature was raised to room temperature. To the reaction
mixture, ether was added, followed by extraction with diethyl
ether. The extract was washed with water and a saturated aqueous
solution of sodium chloride, and dried with anhydrous sodium
sulfate and concentrated under reduced pressure. The resulting
residue was subjected to silica gel column chromatography (eluent;
30% ethyl acetate/hexane) to give the titled compound (1.6 g).
[0359] 1H-NMR (CDCl.sub.3) .delta.:2.98(1H,s), 3.22(3H,s),
4.57-4.89(4H,m).
[0360] (B) An amount (1.2 g) of
1-fluoro-2-fluoromethyl-3-butyn-2-ol and methanesulfonyl chloride
(0.85 ml) were dissolved in tert-butyl methyl ether (15 ml); to the
solution under cooling with ice, triethylamine (1.5 ml) was added
dropwise in a nitrogen atmosphere. After the end of the dropwise
addition, the solution was stirred for 1.5 hours under cooling with
ice. To the reaction mixture, tert-butyl methyl ether was added,
followed by washing with water and a saturated aqueous solution of
sodium chloride. The mixture was dried with anhydrous sodium
sulfate and concentrated under reduced pressure to give the titled
compound (1.9 g).
[0361] 1H-NMR (CDCl.sub.3) .delta.:2.98(1H,s), 3.22(3H,s),
4.57-4.89(4H,m)
Example B3
[0362] Preparation of 1-fluoro-2-fluoromethyl-3-butyn-2-yl
4-trifluoromethylphenyl ether
[0363] (A) An amount (18.6 g) of
1-fluoro-2-fluoromethyl-3-butyn-2-yl methanesulfonate and
4-hydroxybenzotrifluoride (19.8 g) were dissolved in acetonitrile
(200 ml). To the solution under cooling with ice, cupric chloride
dihydrate (3 mg) was added under a nitrogen atmosphere and then
diisopropylethylamine (12.3 g) as dissolved in acetonitrile (100
ml) was added dropwise. After the end of the dropwise addition, the
solution was stirred overnight while its temperature was raised to
room temperature. The acetonitrile was distilled off under reduced
pressure and, after addition of hexane, the residue was washed with
water, an aqueous solution of sodium hydroxide, dilute hydrochloric
acid, aqueous sodium bicarbonate and a saturated aqueous solution
of sodium chloride. The residue was dried with anhydrous sodium
sulfate and concentrated under reduced pressure. The resulting
residue was distilled under reduced pressure to give the titled
compound (13.9 g).
[0364] 1H-NMR (CDCl.sub.3) .delta.:2.77(1H,s), 4.52-4.80(4H,m),
7.32(2H,d,J=8.6 Hz), 7.59(2H,d,J=8.6 Hz).
[0365] (B) An amount (24.8 g) of
1-fluoro-2-fluoromethyl-3-butyn-1-yl p-toluenesulfonate and
4-hydroxybenzotrifluoride (16.2 g) were dissolved in acetonitrile
(400 ml). To the solution under cooling with ice, cupric chloride
dihydrate (5 mg) was added in a nitrogen atmosphere and then
diisopropylethylamine (11.7 g) as dissolved in acetonitrile (100
ml) was added dropwise. After the end of the dropwise addition, the
mixture was stirred for 6 hours while its temperature was raised to
room temperature. The acetonitrile was distilled off under reduced
pressure and, following the addition of hexane, the residue was
washed with water, an aqueous solution of sodium hydroxide, dilute
hydrochloric acid, aqueous bicarbonate and a saturated aqueous
solution of sodium chloride. The residue was dried with anhydrous
sodium sulfate and concentrated under reduced pressure; the
resulting residue was distilled under reduced pressure to give the
titled compound (11.9 g).
Example B4
[0366] Preparation of
5-fluoro-4-fluoromethyl-4-(4-trifluoromethylphenoxy)- -2-pentynoic
acid
[0367] A portion (1.32 g) of the
1-fluoro-2-fluoromethyl-3-butyn-2-yl 4-trifluoromethylphenyl ether
obtained in Example B3 was dissolved in t-butyl methyl ether (20
ml); to the solution, 1.63 M n-butyllithium (2.913 ml) was added at
-70.degree. C. under a nitrogen atmosphere and the mixture was
stirred for 15 minutes. Subsequently, carbon dioxide gas was
bubbled into the reaction mixture for 10 minutes, followed by
addition of 0.1 N HCl and extraction with ethyl acetate; the
resulting organic layer was washed with a saturated aqueous
solution of sodium chloride, dried with anhydrous sodium sulfate
and concentrated under reduced pressure to give the titled compound
(1.45 g) as a colorless oil.
[0368] 1H-NMR (CDCl.sub.3) .delta.:4.70(4H,dddd,J=47.2,13.2,9.9,2.0
Hz), 7.31(2H,d,J=8.6 Hz), 7.63(2H,d,J=8.6 Hz), 9.20(1H,br s)
Example B5
[0369] Preparation of
N-(2-cyanoethyl)-5-fluoro-4-fluoromethyl-4-(4-triflu-
oromethylphenoxy)-2-pentynamide
[0370] (A) An amount (1.1 g) of
5-fluoro-4-fluoromethyl-4-(4-trifluorometh- ylphenoxy)-2-pentynoic
acid and triethylamine (903 mg) were dissolved in dichloromethane
(20 ml); to the solution under stirring at -10.degree. C., ethyl
chloroformate (464 mg) was added dropwise and the mixture was
stirred at -10.degree. C. for another one hour. Subsequently,
3-aminopropionitrile (500 mg) was added to the reaction mixture,
followed by stirring at room temperature for 2 hours. To the
reaction mixture, a hexane/ethyl acetate mixed solvent (1/1) was
added and the resulting mixture was washed with 0.1 N HCl, a
saturated aqueous solution of sodium hydrogencarbonate and a
saturated aqueous solution of sodium chloride, dried with anhydrous
sodium sulfate and concentrated under reduced pressure; the
resulting residue was subjected to silica gel column chromatography
(eluent; hexane/ethyl acetate=3/2) to give the titled compound (1.2
g) as a colorless oil.
[0371] 1H-NMR (CDCl.sub.3) .delta.:2.64(2H,t,J=6.3 Hz),
3.55(2H,dt,J=6.3, 5.9 Hz), 4.68(4H,dddd,J=46.2,15.8,9.9,2.0 Hz),
6.42(1H,br s), 7.31(2H,d,J=8.6 Hz), 7.63(2H,d,J=8.6 Hz).
[0372] (B) An amount (61 mg) of
1-fluoro-2-fluoromethyl-3-butyn-2-yl 4-trifluoromethylphenyl ether
was dissolved in t-butyl methyl ether (2 ml); to the solution, 1.69
M n-butyllithium (0.148 ml) was added at -70.degree. C. under a
nitrogen atmosphere and the mixture was stirred for 10 minutes. To
the reaction mixture, 2-cyanoethyl isocyanate (28 mg) was added and
the resulting mixture was stirred at -70.degree. C. for 10 minutes.
To the reaction mixture, a saturated aqueous solution of ammonium
chloride was added, followed by extraction with hexane/ethyl
acetate (1/1); the resulting organic layers were washed with a 1 N
aqueous solution of sodium hydroxide and a saturated aqueous
solution of sodium chloride, dried with anhydrous sulfate and
concentrated under reduced pressure; the resulting residue was
subjected to silica gel column chromatography (eluent; hexane/ethyl
acetate=3/2) to give the titled compound (45 mg) as a colorless
oil.
Example B6
[0373] Preparation of
2,2-bis(fluoromethyl)-N-(2-cyanoethyl)-6-trifluorome-
thyl-2H-1-benzopyran-4-carboxamide
[0374] To undecane (0.8 ml) being heated under reflux,
N-(2-cyanoethyl)-5-fluoro-4-fluoromethyl-4-(4-trifluoromethylphenoxy)-2-p-
entynamide (60 mg) was added and the mixture was heated under
reflux for 1 hour. After concentrating under reduced pressure, the
resulting residue was subjected to silica gel column chromatography
(eluent, dichloromethane/ethyl acetate=10/1) to give the titled
compound (54 mg), which was identical to the authentic sample.
Comparative Example
[0375] Preparation of
N-(2-cyanoethyl)-2-(1-(fluoromethyl)ethenyl)-5-trifl-
uoromethylbenzofuran-3-carboxamide
[0376] Reaction was performed as in Example B6, except that the
reaction solvent undecane was replaced by diethylaniline. Only the
titled compound was obtained quantitatively.
[0377] 1H-NMR (CDCl.sub.3) .delta.:2.78(2H,t,J=6.3 Hz),
3.75(2H,dt,J=6.3, 6.3 Hz), 5.33(2H,d,J=46.5 Hz), 5.91(1H,d,J=3.6
Hz), 6.20(1H,s), 6.53(1H,br s), 7.57(1H,d,J=8.6 Hz),
7.64(1H,dd,J=8.6, 1.6 Hz), 8.13(1H,br s)
Example B7
[0378] Reaction was performed as in Example B6 using various
reaction solvents. The solvents used, their boiling points and the
resulting yield ratios are listed in the following table, in which
A stands for
2,2-bis(fluoromethyl)-N-(2-cyanoethyl)-6-trifluoromethyl-2H-1-benzopyran--
4-carboxamide and B stands for
N-(2-cyanoethyl)-2-(1-fluoromethylethenyl)--
5-trifluoromethylbenzofuran-3-carboxamide.
1 TABLE 1 Solvent Boiling point Yield ratio (A:B) Tetraglyme
275.degree. 6:1 Diphenyl ether 260.degree. 7:1 N-methylpyrrolidone
209.degree. 1:20 Tetralin 207.degree. 7:1 No solvent 200.degree. B
alone Dodecane 216.degree. 14:1 Undecane 196.degree. 14:1 Decane
174.degree. 6:1 Perfluorofluorene 210.degree. 2.5:1
Perfluorofluorene + 196.degree. 4:1 undecane Note: The numeral
(200.degree.) in the column of "Boiling Points" given for "No
solvent" represents the heating temperature.
Example B8
[0379] Preparation of
5-fluoro-4-fluoromethyl-4-(4-trifluoromethylphenoxy)-
-N-propyl-2-pentynamide
[0380] An amount (264 mg) of 1-fluoro-2-fluoromethyl-3-butyn-2-yl
4-trfluoromethyl phenyl ether was dissolved in diethyl ether (2
ml); to the solution, 1.68 M n-butyllithium (0.71 ml) was added at
0.degree. C. under a nitrogen atmosphere and the mixture was
stirred for 1 hour. To the reaction mixture, propyl isocyanate (85
mg) was added at 0.degree. C. and the mixture was stirred at room
temperature for 5 hours. The reaction mixture was diluted with
diethyl ether, washed with a saturated aqueous solution of sodium
chloride, dried with anhydrous sodium sulfate and concentrated
under reduced pressure; the resulting residue was subjected to
silica gel column chromatography (eluent;
dichloromethane/methanol=100- /3) to give the titled compound (320
mg) as a colorless oil.
[0381] 1H-NMR (CDCl.sub.3) .delta.:0.93(3H,t,J=7.3 Hz),
1.47-1.61(2H,m), 3.25(2H,dt J=7.3, 6.6 Hz), 4.54-4.81(4H,m),
5.79(1H,br s), 7.31(2H,d,J=8.6 Hz), 7.61(2H,d,J=8.6 Hz).
Example B9
[0382] Preparation of
2,2-bis(fluoromethyl)-6-trifluoromethyl-N-propyl-2H--
1-benzopyran-4-carboxamide
[0383] An amount (50 mg) of
5-fluoro-4-fluoromethyl-4-(4-trifluoromethylph-
enoxy)-N-propyl-2-pentynamide was dissolved in o-dichlorobenzene (5
ml) and the solution was heated under reflux for 3.5 hours. The
reaction mixture was concentrated under reduced pressure and the
resulting residue was subjected to silica gel column chromatography
(eluent; hexane/ethyl acetate=3/1) to give the titled compound (31
mg).
[0384] 1H-NMR (CDCl.sub.3) .delta.:0.99(3H,t,J=7.3 Hz),
1.56-1.70(2H,m), 3.37(2H,dt J=6.9, 6.6 Hz), 4.44-4.73(4H,m),
5.98(2H,br s), 6.99(1H,d,J=8.6 Hz), 7.48(1H,dd,J=8.6, 2.0 Hz),
7.83(1H,d,J=2.0 Hz).
[0385] C. Examples for Schemes (5) and (6):
Example C1
[0386] 1-Fluoro-2-fluoromethyl-3-butyn-2-yl p-toluenesulfonate
[0387] An amount (6.6 g) of 1-fluoro-2-fluoromethyl-3-butyn-2-ol
and p-toluenesulfonyl chloride (9.5 g) were dissolved in
tetrahydrofuran (100 ml); to the solution under cooling with ice,
60% oily sodium hydride (2.4 g) was added under a nitrogen
atmosphere. After the end of the addition, the mixture was stirred
for 5 hours while its temperature was raised to room temperature.
Water was added to the reaction mixture, followed by extraction
with ether. The extract was washed with water and a saturated
aqueous solution of sodium chloride, dried with anhydrous sodium
sulfate and concentrated under reduced pressure. The resulting
residue was subjected to silica gel column chromatography (eluent;
hexane/methylene chloride=1/1) to give the titled compound (11.1
g).
[0388] 1H-NMR (CDCl.sub.3) .delta.:2.45(3H,s), 2.74(1H,s),
4.53-4.87(4H,m), 7.34(2H,d,J=8.3 Hz), 7.83(2H,d,J=8.3 Hz).
Example C2
[0389] 1-Fluoro-2-fluoromethyl-3-butyn-2-yl methanesulfonate
[0390] An amount (1.2 g) of 1-fluoro-2-fluoromethyl-3-butyn-2-ol
and methanesulfonyl chloride (0.85 ml) were dissolved in tert-butyl
methyl ether (15 ml); to the solution under cooling with ice,
triethylamine (1.5 ml) was added dropwise in a nitrogen atmosphere.
After stirring for 1.5 hours under cooling with ice, tert-butyl
methyl ether was added to the reaction mixture, which was then
washed with water and a saturated aqueous solution of sodium
chloride. The mixture was dried with anhydrous sodium sulfate and
concentrated under reduced pressure to give the titled compound
(1.9 g).
[0391] 1H-NMR (CDCl.sub.3) .delta.:2.98(1H,s), 3.22(3H,s),
4.57-4.89(4H,m).
Example C3
[0392] 1-Fluoro-2-fluoromethyl-3-butyn-2-yl propanesulfonate
[0393] An amount (2.4 g) of 1-fluoro-2-fluoromethyl-3-butyn-2-ol
was dissolved in tetrahydrofuran (20 ml); to the solution under
cooling with ice, 60% oily sodium hydride (0.96 g) was added under
a nitrogen atmosphere. After stirring for 30 minutes under cooling
with ice, propanesulfonyl chloride (2.2 ml) was added dropwise. The
mixture was stirred for 5 hours while its temperature was raised to
room temperature. Water was added to the reaction mixture, followed
by extraction with ether. The extract was washed with water and a
saturated aqueous solution of sodium chloride, dried with anhydrous
sodium sulfate and concentrated under reduced pressure. The
resulting residue was subjected to silica gel column chromatography
(eluent; 30% ethyl acetate/hexane) to give the titled compound (4.1
g).
[0394] 1H-NMR (CDCl.sub.3) .delta.:1.09(3H,t,J=7.3 Hz),
1.87-2.02(2H,m), 3.25-3.31(2H,m), 4.56-4.88(4H,m).
Example C4
[0395] 1-Fluoro-2-fluoromethyl-3-butyn-2-yl
p-chlorobenzenesulfonate
[0396] An amount (1.2 g) of 1-fluoro-2-fluoromethyl-3-butyn-2-ol
and p-chlorobenzenesulfonyl chloride (2.1 g) were dissolved in
tetrahydrofuran (10 ml); to the solution under cooling with ice,
60% oily sodium hydride (0.48 g) was added under a nitrogen
atmosphere. After the end of the addition, the mixture was stirred
for 4 hours while its temperature was raised to room temperature. A
hexane/ethane mixed solvent (1/1) was added to the reaction
mixture, which was then washed with water and a saturated aqueous
solution of sodium chloride, dried with anhydrous sodium sulfate
and concentrated under reduced pressure. The resulting residue was
subjected to silica gel column chromatography (eluent;
hexane/methylene chloride=1/1) and then recrystallized from
methylene chloride/hexane to give the titled compound (2.2 g).
[0397] 1H-NMR (CDCl.sub.3) .delta.:2.77(1H,s), 4.54-4.88(4H,m),
7.53(2H,d,J=8.6 Hz), 7.89(2H,d,J=8.6 Hz).
Example C5
[0398] 1-Fluoro-2-fluoromethyl-3-butyn-2-yl benzenesulfonate
[0399] An amount (1.2 g) of 1-fluoro-2-fluoromethyl-3-butyn-2-ol
and benzenesulfonyl chloride (1.8 g) were dissolved in
tetrahydrofuran (10 ml); to the solution under cooling with ice,
60% oily sodium hydride (0.48 g) was added in a nitrogen
atmosphere. After the end of the addition, the mixture was stirred
for 4 hours while its temperature was raised to room temperature. A
hexane/ether mixed solvent (1/1) was added to the reaction mixture,
which was then washed with water and a saturated aqueous solution
of sodium chloride, dried with anhydrous sodium sulfate and
concentrated under reduced pressure. The resulting residue was
subjected to silica gel column chromatography (eluent;
hexane/methylene chloride 1/1) to give the titled compound (2.2
g).
[0400] 1H-NMR (CDCl.sub.3) .delta.:2.74(1H,s), 4.55-4.88(4H,m),
7.52-7.69(3H,m), 7.96 (2H, d, J=7.3 Hz)
Example C6
[0401] 1-Fluoro-2-fluoromethyl-3-butyn-2-yl 4-trifluoromethylphenyl
ether
[0402] (A) An amount (18.6 g) of
1-fluoro-2-fluoromethyl-3-butyn-2-yl methanesulfonate and
4-hydroxybenzotrifluoride (19.8 g) were dissolved in acetonitrile
(200 ml). To the solution under cooling with ice, cupric chloride
dihydrate (3 mg) was added under a nitrogen atmosphere; then,
diisopropylethylamine (12.3 g) as dissolved in acetonitrile (100
ml) was added dropwise. After the end of the dropwise addition, the
mixture was stirred overnight while its temperature was raised to
room temperature. The acetonitrile was distilled off under reduced
pressure and hexane was added to the residue, which was washed with
water, an aqueous solution of sodium hydroxide, dilute hydrochloric
acid, aqueous sodium bicarbonate and a saturated aqueous solution
of sodium chloride. The residue was dried with anhydrous sodium
sulfate and concentrated under reduced pressure; the resulting
residue was distilled under reduced pressure to give the titled
compound (13.9 g).
[0403] 1H-NMR (CDCl.sub.3) .delta.:2.77(1H,s), 4.52-4.79(4H,m),
7.32(2H,d,J=8.6 Hz), 7.59(2H,d,J=8.6 Hz).
[0404] (B) An amount (24.8 g) of
1-fluoro-2-fluoromethyl-3-butyn-2-yl p-toluenesulfonate and 16.2 g
of 4-hydroxybenzotrifluoride were dissolved in acetonitrile (400
ml). To the solution under cooling with ice, cupric chloride
dihydrate (5 mg) was added under a nitrogen atmosphere; then,
diisopropylethylamine (11.7 g) as dissolved in acetonitrile (100
ml) was added dropwise. After the end of the dropwise addition, the
mixture was stirred for 6 hours while its temperature was raised to
room temperature. The acetonitrile was distilled off under reduced
pressure and hexane was added to the residue, which was washed with
water, an aqueous solution of sodium hydroxide, dilute hydrochloric
acid, aqueous sodium bicarbonate and a saturated aqueous solution
of sodium chloride. The residue was dried with anhydrous sodium
sulfate and concentrated under reduced pressure; the resulting
residue was distilled under reduced pressure to give the titled
compound (11.9 g).
Example C7
[0405] 4-Bromo-1-fluoro-2-fluoromethyl-3-butyn-2-yl
4-trifluoromethylphenyl ether
[0406] An amount (13.9 g) of 1-fluoro-2-fluoromethyl-3-butyn-2-yl
4-trifluoromethylphenyl ether was dissolved in a solvent consisting
of a mixture of tert-butyl methyl ether (100 ml) and tert-butyl
alcohol (150 ml). To the solution under cooling with ice, potassium
tert-butoxide (7.1 g) was added under a nitrogen atmosphere; after
stirring for a while, bromine (3 ml) was added dropwise. After the
end of the dropwise addition, the mixture was stirred for 30
minutes under stirring with ice. Hexane was added to the reaction
mixture, which was then washed with water and a saturated aqueous
solution of sodium chloride. The mixture was dried with anhydrous
sodium sulfate and concentrated under reduced pressure to give the
titled compound (18.1 g).
[0407] 1H-NMR (CDCl.sub.3) .delta.:4.50-4.77(4H,m), 7.29(2H,d,J=8.6
Hz), 7.60 (2H, d, J=8.6 Hz)
Example C8
[0408]
4-Bromo-2,2-bis(fluoromethyl)-6-trifluoromethyl-2H-1-benzopyran
[0409] An amount (18.1 g) of
4-bromo-1-fluoro-2-fluoromethyl-3-butyn-2-yl
4-trifluoromethylphenyl ether was dissolved in solvent naphtha (100
ml) and the solution was refluxed for 4 hours under a nitrogen
atmosphere. The solvent was distilled off under reduced pressure
and the resulting residue was distilled under reduced pressure to
give the titled compound (14.5 g).
[0410] 1H-NMR (CDCl.sub.3) .delta.:4.41-4.71(4H,m), 6.14(1H,s),
6.95(1H,d,J=8.6 Hz), 7.50(1H,dd,J=8.6, 2.0 Hz), 7.71 (1H, d, J=2.0
Hz)
Example C9
[0411]
N-(2-cyanoethyl)-2,2-bis(fluoromethyl)-6-trifluoromethyl-2H-1-benzo-
pyran-4-carbothioamide
[0412] An amount (103 mg) of
4-bromo-2,2-bis(fluoromethyl)-6-trifluorometh- yl-2H-1-benzopyran
was dissolved in diethyl ether (0.5 ml); to the solution, 1.68 M
n-butyllithium (0.18 ml) was added at -10.degree. C. under a
nitrogen atmosphere. After stirring the reaction mixture for 10
minutes, copper(I) cyanide (27 mg) and tetrahydrofuran (0.6 ml)
were added and the resulting mixture was stirred for 30 minutes at
0.degree. C. Subsequently, a tetrahydrofuran solution (0.3 ml) of
2-cyanoethyl isothiocyanate (34 mg) was added and the mixture was
stirred for 4 hours at 0.degree. C. To the reaction mixture, a
saturated aqueous solution of ammonium chloride was added, followed
by extraction with diethyl ether; the resulting organic layer was
washed with 2 N HCl, a saturated aqueous solution of sodium
hydrogencarbonate and a saturated aqueous solution of sodium
chloride, dried with anhydrous sodium sulfate and concentrated
under reduced pressure; the resulting residue was subjected to
silica gel column chromatography (eluent; dichloromethane/diethyl
ether=10/1) to give the titled compound (8 mg), which was identical
to the authentic sample.
Example C10
[0413]
N-ethyl-2,2-bis(fluoromethyl)-6-trifluoromethyl-2H-1-benzopyran-4-c-
arbothioamide
[0414] An amount (103 mg) of
4-bromo-2,2-bis(fluoromethyl)-6-trifluorometh- yl-2H-1-benzopyran
was dissolved in diethyl ether (0.3 ml); to the solution, 1.68 M
n-butyllithium (0.18 ml) was added at 0.degree. C. under a nitrogen
atmosphere. After stirring the reaction mixture for 2 minutes, a
diethyl ether solution (0.3 ml) of ethyl isothiocyanate (34 mg) was
added and the mixture was stirred for 2.5 hours at 0.degree. C. The
reaction mixture was diluted with diethyl ether, washed with a
saturated aqueous solution of sodium hydrogencarbonate and a
saturated aqueous solution of sodium chloride, dried with anhydrous
sodium sulfate and concentrated under reduced pressure; the
resulting residue was subjected to silica gel column chromatography
(eluent; hexane/ethyl acetate=4/1) to give the titled compound (60
mg) as a pale yellow crystal.
[0415] mp 65-67.degree. C.
[0416] 1H-NMR (CDCl.sub.3) .delta.:1.36(3 h,t,J=7.2 Hz),
3.82(2H,m), 4.35-4.80(4H,m), 5.84(1H,s), 7.00(1H,d,J=8.6 Hz),
7.40(1H,br s), 7.48(1H,d,J=8.6 Hz), 7.69(1H,s).
Example C11
[0417] O-methyl
2,2-bis(fluoromethyl)-6-trifluoromethyl-2H-1-benzopyran-4--
carbothioate
[0418] An amount (65 mg) of
4-bromo-2,2-bis(fluoromethyl)-6-trifluoromethy- l-2H-1-benzopyran
was dissolved in t-butyl methyl ether (2 ml); to the solution, 1.69
M n-butyllithium (0.11 ml) was added at -70.degree. C. under a
nitrogen atmosphere and the mixture was stirred for 10 minutes.
Then, dimethoxycarbon sulfide (39 mg) was slowly added dropwise to
the reaction mixture, which was stirred for 30 minutes at
-70.degree. C. To the reaction mixture, a saturated aqueous
solution of ammonium chloride was added, followed by extraction
with hexane/ethyl acetate (3/1). The resulting organic layers were
washed with a saturated aqueous solution of sodium chloride, dried
with anhydrous sodium sulfate and concentrated under reduced
pressure; the resulting residue was subjected to silica gel column
chromatography (eluent; hexane/ethyl acetate=2/1) to give the
titled compound (36 mg) as a colorless oil.
[0419] 1H-NMR (CDCl.sub.3) .delta.:4.26(3H,s),
4.51(2H,ddd,J=46.5,9.9,2.0 Hz), 4.68(2H,ddd,J=46.8,9.9,1.6 Hz),
6.39(1H,s), 7.03(1H,d,J=8.6 Hz), 7.48(1H,d,J=8.6 Hz),
7.74(1H,s).
Example C12
[0420] O-ethyl
2,2-bis(fluoromethyl)-6-trifluoromethyl-2H-1-benzopyran-4-c-
arbothioate
[0421] An amount (58 mg) of
4-bromo-2,2-bis(fluoromethyl)-6-trifluoromethy- l-2H-1-benzopyran
was dissolved in t-butyl methyl ether (2 ml); to the solution, 1.69
M n-butyllithium (0.108 ml) was added at -70.degree. C. under a
nitrogen atmosphere and the mixture was stirred for 15 minutes.
Then, diethyl thiocarbonate (67 mg) was added dropwise to the
reaction mixture, which was stirred for 30 minutes at -70.degree.
C. To the reaction mixture, a saturated aqueous solution of
ammonium chloride was added, followed by extraction with
hexane/ethyl acetate (3/1). The resulting organic layers were
washed with a saturated aqueous solution of sodium chloride, dried
with anhydrous sodium sulfate and concentrated under reduced
pressure; the resulting residue was subjected to silica gel column
chromatography (eluent; hexane/ethyl acetate=2/1) to give the
titled compound (31 mg) as a colorless oil.
[0422] 1H-NMR (CDCl.sub.3) .delta.:1.50(3H,t,J=7.4 Hz),
4.43-4.76(6H,m), 6.42(1H,s), 7.03(1H,d,J=8.6 Hz), 7.48(1H,d,J=8.6
Hz), 7.77(1H,s)
Example C13
[0423]
N-(2-cyanoethyl)-2,2-bis(fluoromethyl)-6-trifluoromethyl-2H-1-benzo-
pyran-4-carbothioamide
[0424] O-methyl
2,2-bis(fluoromethyl)-6-trifluoromethyl-2H-1-benzopyran-4--
carbothioate (0.34 g) and DBU (10 mg) were dissolved in
tetrahydrofuran (5 ml); to the solution, 3-aminopropionitrile (0.2
ml) was added at room temperature in a nitrogen atmosphere and the
resulting mixture was stirred for 7 hours at room temperature.
Ethyl acetate was added to the reaction mixture, which was washed
with water, dilute HCl, aqueous sodium bicarbonate and a saturated
aqueous solution of sodium chloride. The mixture was dried with
anhydrous sodium sulfate and concentrated under reduced pressure;
the resulting residue was subjected to silica gel column
chromatography (eluent; methylene chloride) to give the titled
compound (0.33 g), which was identical to the authentic sample.
Example C14
[0425] Methyl
5-fluoro-4-fluoromethyl-4-(4-trifluoromethylphenoxy)-2-penty-
noate
[0426] An amount (0.53 g) of 1-fluoro-2-fluoromethyl-3-butyn-2-yl
4-trifluoromethylphenyl ether was dissolved in diethyl ether (3
ml); to the solution under cooling with ice, a hexane solution (1.4
ml) of 1.69 M n-butyllithium was added dropwise under a nitrogen
atmosphere. After the end of the dropwise addition, the mixture was
stirred for 1 hour under cooling with ice. The resulting mixture
was added dropwise to a solution of methyl chloroformate (0.38 g)
in diethyl ether (3 ml) under a nitrogen atmosphere under cooling
with ice. After stirring the mixture for 1 hour under cooling with
ice, hexane was added, followed by washing with water and a
saturated aqueous solution of sodium chloride. The mixture was
dried with anhydrous sodium sulfate and concentrated under reduced
pressure; the resulting residue was subjected to silica gel column
chromatography (eluent; hexane/methylene chloride=1/1) to give the
titled compound (0.51 g).
[0427] 1H-NMR (CDCl.sub.3) .delta.:3.80(3H,s), 4.55-4.82(4H,m),
7.31(2H,d,J=8.6 Hz), 7.62(2H,d,J=8.6 Hz).
Example C15
[0428] Methyl
2,2-bis(fluoromethyl)-6-trifluoromethyl-2H-1-benzopyran-4-ca-
rboxylate
[0429] An amount (0.28 g) of methyl
5-fluoro-4-fluoromethyl-4-(4-trifluoro- methylphenoxy)-2-pentynoate
was added dropwise to o-dichlorobenzene (10 ml) during refluxing
under a nitrogen atmosphere. After the end of the dropwise
addition, the reaction mixture was refluxed for 3 hours. The
solvent was distilled off under reduced pressure and the resulting
residue was subjected to silica gel column chromatography (eluent;
10% tetrahydrofuran/hexane) to give the titled compound (0.25
g).
[0430] 1H-NMR (CDCl.sub.3) .delta.:3.90(3H,s), 4.45-4.74(4H,m),
6.70(1H,s), 7.00(1H,d,J=8.6 Hz), 7.49(1H,br.d,J=8.6 Hz),
8.32(1H,br.s).
Example C16
[0431] 0-Methyl
2,2-bis(fluoromethyl)-6-trifluoromethyl-2H-1-benzopyran-4--
carbothioate
[0432] Methyl
2,2-bis(fluoromethyl)-6-trifluoromethyl-2H-1-benzopyran-4-ca-
rboxylate (1.0 g) was dissolved in xylene (2.5 ml); to the
solution,
2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphoethane-2,4-disulfide
(1.6 g) was added under a nitrogen atmosphere and the mixture was
refluxed for 6 hours. The insoluble matter was filtered off by
addition of a hexane and toluene (2/1) mixed solvent. The filtrate
was concentrated under reduced pressure and the resulting residue
was subjected to silica gel column chromatography (eluent;
hexane/methylene chloride=2/1) to give the titled compound (0.75
g).
[0433] 1H-NMR (CDCl.sub.3) .delta.:4.26(3H,s), 4.45-4.75(4H,m),
6.39(1H,s), 7.03(1H,d,J=8.6 Hz), 7.48(1H,br.d,J=8.6 Hz),
7.74(1H,br.s).
Example C17
[0434] Preparation of
N-(2-cyanoethyl)-2,2-bis(fluoromethyl)-6-trifluorome-
thyl-2H-1-benzopyran-4-carboxamide
[0435] A mixture of
4-bromo-2,2-bis(fluoromethyl)-6-trifluoromethyl-2H-1-b- enzopyran
(1.73 g), 2-cyanoethylamine (1.44 g), potassium iodide (0.86 g),
triphenylphosphine (26 mg), palladium acetate (11 mg) and
N,N-dimethylacetamide (10 ml) was stirred under a CO atmosphere at
100.degree. C. for 3 hours. To the reaction mixture, 2 N HCl was
added and the precipitating crystals were recovered by filtration.
To the recovered crystals, ethyl acetate was added and the
insoluble matter was filtered off; the filtrate was washed with a
saturated aqueous solution of sodium thiosulfate and a saturated
aqueous solution of sodium chloride, dried with anhydrous sodium
sulfate and concentrated under reduced pressure; the resulting
residue was recrystallized with an ethanol and water mixed solvent
to give N-(2-cyanoethyl)-2,2-bis(fluorome-
thyl)-6-trifluoromethyl-2H-1-benzopyran-4-carboxamide (1.46 g)
represented by the formula (C1-1) and having a melting point of
129-131.degree. C.
[0436] 1H-NMR (DMSO-d.sub.6) .delta.:2.77(2H,t,J=6.3 Hz),
3.47(2H,q,J=6.3 Hz), 4.53-4.82(4H,m), 6.14(1H,s), 7.11(1H,d,J=8.6
Hz), 7.59(1H,dd,J=8.6, 2.0 Hz), 7.83(1H,d,J=2.0 Hz),
8.85-9.00(1H,m) MSm/z: 360 (M.sup.+)
Example C18
[0437] Preparation of
N-(2-cyanoethyl)-2,2-bis(fluoromethyl)-6-trifluorome-
thyl-2H-1-benzopyran-4-carboxamide via
2,2-bis(fluoromethyl)-6-trifluorome-
thyl-2H-1-benzopyran-4-carboxylic acid (Alternative Method for
Preparing the End Compound of Example C17)
[0438] 1)
2,2-Bis(fluoromethyl)-6-trifluoromethyl-2H-1-benzopyran-4-carbox-
ylic acid
[0439] A mixture of
4-bromo-2,2-bis(fluoromethyl)-6-trifluoromethyl-2H-1-b- enzopyran
(1.72 g), potassium acetate (2.00 g), potassium iodide (0.85 g),
triphenylphosphine (27 mg), palladium acetate (11 mg) and
N,N-dimethylacetamide (10 ml) was stirred under a CO atmosphere at
120.degree. C. for 9 hours. To the reaction mixture, 2 N HCl was
added and the precipitating crystals were recovered by filtration.
To the recovered crystals, ethyl acetate was added and the
insoluble matter was filtered off; the filtrate was washed with a
saturated aqueous solution of sodium thiosulfate and a saturated
aqueous solution of sodium chloride, dried with anhydrous sodium
sulfate and concentrated under reduced pressure; the resulting
residue was dissolved in/a saturated aqueous solution of sodium
hydrogencarbonate washed with dichloromethane; concentrated HCl was
added to the resulting aqueous layer to make it acidic and the
precipitating crystals were recovered by filtration. The recovered
crystals were dissolved in ethyl acetate, dried with anhydrous
magnesium sulfate and concentrated under reduced pressure; the
resulting residue was recrystallized with a solvent consisting of a
mixture of ethyl acetate and hexane, thereby giving
2,2-bis(fluoromethyl)-6-trifluor-
omethyl-2H-1-benzopyran-4-carboxylic acid (1.25 g) represented by
the formula (C2-1) and having a melting point of 162-163.degree.
C.
[0440] 1H-NMR (DMSO-d.sub.6) .delta.:4.56-4.85(4H,m), 6.81(1H,s),
7.08(1H,d,J=8.6 Hz), 7.60(1H,dd,J=8.6, 2.0 Hz), 7.83(1H,d,J=2.0
Hz), 8.86(1H,d,J=2.0 Hz), 13.45-13.70(1H,m). MSm/z:308(M.sup.+)
[0441] 2)
N-(2-cyanoethyl)-2,2-bis(fluoromethyl)-6-trifluoromethyl-2H-1-be-
nzopyran-4-carboxamide
[0442] A mixture of
2,2-bis(fluoromethyl)-6-trifluoromethyl-2H-1-benzopyra-
n-4-carboxylic acid (1.55 g), thionyl chloride (0.51 ml) and
toluene (5 ml) was heated at 80.degree. C. for 5 hours. The
reaction mixture was concentrated under reduced pressure; to the
resulting residue, a mixture of 2-cyanoethylamine (0.42 g) and
acetonitrile (5 ml) was added on an ice bath; following the
addition of a mixture of triethylamine (2.52 g) and acetonitrile (5
ml), the resulting mixture was stirred first on an ice bath for 10
minutes, then at room temperature for 1 hour. To the reaction
mixture, 2 N HCl was added and the precipitating crystals were
recovered by filtration. The recovered crystals were dissolved in
ethyl acetate, washed with a saturated aqueous solution of sodium
chloride, dried with anhydrous sodium sulfate and concentrated
under reduced pressure; the resulting residue was recrystallized
with an ethanol and water mixed solvent to give
N-(2-cyanoethyl)-2,2-bis(fluoromethyl)-6-trifluoromethyl--
2H-1-benzopyran-4-carboxamide (1.61 g) represented by the formula
(C2-2) and having a melting point of 129-131.degree. C.
[0443] 1H-NMR (DMSO-d.sub.6) .delta.:2.77(2H,t,J=6.3 Hz),
3.47(2H,q,J=6.3 Hz), 4.53-4.82(4H,m), 6.14(1H,s), 7.11(1H,d,J=8.6
Hz), 7.59(1H,dd,J=8.6, 2.0 Hz), 7.83(1H,d,J=2.0 Hz),
8.85-9.00(1H,m). MSm/z:360 (M.sup.+)
Example C19
[0444]
N-(2-cyanoethyl)-2,2-bis(fluoromethyl)-6-trifluoromethyl-2H-1-benzo-
pyran-4-carboxamide
[0445] To an ice-cooled mixture of
2,2-bis(fluoromethyl)-6-trifluoromethyl-
-2H-1-benzopyran-4-carboxylic acid (0.20 g) and tetrahydrofuran (3
ml), N,N'-carbonyldiimidazole (0.12 g) was added with stirring and
the mixture was stirred for 1 hour. Thereafter, 2-cyanoethylamine
(0.06 g) was added and the mixture was stirred first under cooling
with ice for 1 hour, then at room temperature for 12 hours. To the
reaction mixture, an aqueous solution of potassium carbonate was
added, followed by extraction with methylene chloride; the organic
layer was washed with water and dried; the solvent was distilled
off and the resulting residue was recrystallized with a solvent
consisting of a mixture of ethyl acetate and hexane, thereby giving
the titled compound (0.20 g) having a melting point of
135-136.degree. C.
[0446] 1H-NMR (DMSO-d.sub.6) .delta.:2.77(2H,t,J=6.3 Hz),
3.47(2H,q,J=6.3 Hz), 4.53-4.82(4H,m), 6.14(1H,s), 7.11(1H,d,J=8.6
Hz), 7.59(1H,dd,J=8.6, 2.0 Hz), 7.83(1H,d,J=2.0 Hz),
8.85-9.00(1H,m). MSm/z:360(M.sup.+)
Example C20
[0447]
N-(2-cyanoethyl)-6-pentafluoroethyl-2,2-bis(fluoromethyl)-2H-1-benz-
opyran-4-carboxamide
[0448] To an ice-cooled mixture of
2,2-bis(fluoromethyl)-6-trifluoromethyl-
-2H-1-benzopyran-4-carboxylic acid (0.20 g) and tetrahydrofuran (3
ml), N,N'-carbonyldiimidazole (0.10 g) was added with stirring and
the mixture was stirred for 1 hour. Thereafter, 2-cyanoethylamine
(0.05 g) was added and the mixture was stirred first under cooling
with ice for 1 hour, then at room temperature for 12 hours. To the
reaction mixture, an aqueous solution of potassium carbonate was
added, followed by extraction with methylene chloride; the organic
layer was washed with water and dried; the solvent was distilled
off and the resulting residue was recrystallized with a solvent
consisting of a mixture of ethyl acetate and hexane, thereby giving
the titled compound (0.19 g) having a melting point of
144-145.degree. C.
[0449] 1H-NMR (CDCl.sub.3) .delta.:2.73(2H,t,J=6.3 Hz),
3.67(2H,q,J=6.3 Hz), 4.44-4.73(4H,m), 6.08(1H,s), 6.40-6.60(1H,m),
7.03(1H,d,J=8.6 Hz), 7.47(1H,dd,J=8.6, 2.0 Hz), 7.81(1H,d,J=2.0
Hz). MSm/z: 410 (M.sup.+)
INDUSTRIAL APPLICABILITY
[0450] The processes of the present invention for producing
4-substituted benzopyran derivatives involve fewer steps and
feature greater convenience and safety than the prior art
processes; therefore, these processes have outstanding practical
utility as methods of synthesizing intermediates for the
manufacture of medicines, agrichemicals, cosmetics, etc.
[0451] A List of Chemical Formulae (Part 1) Compounds Described in
Prior Art Documents (1) 1
[0452] A List of Chemical Formulae (Part 2)
[0453] Compounds Described in Prior Art Documents (2) 2
[0454] A List of Chemical Formulae (Part 3)
[0455] Compounds Described in Prior Art Documents (3) 3
[0456] A List of Chemical Formulae (Part 4)
[0457] Compounds Relted to the Invention (1) 4
[0458] A List of Chemical Formulae (Part 5)
[0459] Compounds Relted to the Invention (2) 5
[0460] A List of Chemical Formulae (Part 6)
[0461] Compounds Relted to the Invention (3) 6
[0462] A List of Chemical Formulae (Part 7)
[0463] Compounds Relted to the Invention (4) 7
[0464] A List of Chemical Formulae (Part 8)
[0465] Compounds Relted to the Invention (5) 8
[0466] A List of Chemical Formulae (Part 9)
[0467] Compounds Relted to the Invention (6) 9
[0468] A List of Chemical Formulae (Part 10)
[0469] Compounds Relted to the Invention (7) 10
[0470] A List of Chemical Formulae (Part 11)
[0471] Compounds Relted to the Invention (8) 11
[0472] A List of Chemical Formulae (Part 12)
[0473] Compounds Relted to the Invention (9) 12
[0474] A List of Chemical Formulae (Part 13)
[0475] Compounds Relted to the Invention (10) 13
[0476] A List of Chemical Formulae (Part 14)
[0477] Compounds Relted to the Invention (11) 14
[0478] A List of Chemical Formulae (Part 15)
[0479] Synthesis Procedures for Process Schemes (1) and (2) 15
[0480] A List of Chemical Formulae (Part 16)
[0481] Synthesis Procedures for Process Schemes (3) and (4) 16
[0482] A List of Chemical Formulae (Part 17)
[0483] Synthesis Procedures for Process Schemes (5) and (6) 17
* * * * *