U.S. patent application number 17/081452 was filed with the patent office on 2022-08-18 for method for producing a spirooxindole derivative.
The applicant listed for this patent is Daiichi Sankyo Company, Limited. Invention is credited to Keiji NAKAYAMA, Motoshi YAMAUCHI.
Application Number | 20220259216 17/081452 |
Document ID | / |
Family ID | 1000006504946 |
Filed Date | 2022-08-18 |
United States Patent
Application |
20220259216 |
Kind Code |
A9 |
YAMAUCHI; Motoshi ; et
al. |
August 18, 2022 |
METHOD FOR PRODUCING A SPIROOXINDOLE DERIVATIVE
Abstract
The present disclosure provides a method for efficiently
producing and providing compounds having a spirooxindole skeleton,
for example compounds having a spirooxindole skeleton and having
antitumor activity that inhibit the interaction between Mdm2
protein and p53 protein, or intermediates thereof, using an
asymmetric catalyst. Compounds having optically active tricyclic
dispiroindole skeletons are obtained through catalytic asymmetric
1,3-dipolar cycloaddition reaction using ketimine as a reaction
substrate and using a chiral ligand and a Lewis acid.
Inventors: |
YAMAUCHI; Motoshi;
(Kanagawa, JP) ; NAKAYAMA; Keiji; (Kanagawa,
JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Daiichi Sankyo Company, Limited |
Tokyo |
|
JP |
|
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20210323970 A1 |
October 21, 2021 |
|
|
Family ID: |
1000006504946 |
Appl. No.: |
17/081452 |
Filed: |
October 27, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
16031165 |
Jul 10, 2018 |
10851111 |
|
|
17081452 |
|
|
|
|
14916677 |
Mar 4, 2016 |
10030028 |
|
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PCT/JP2014/073233 |
Sep 3, 2014 |
|
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16031165 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
B01J 31/2409 20130101;
B01J 31/189 20130101; B01J 31/2457 20130101; B01J 31/22 20130101;
B01J 31/2295 20130101; B01J 31/2452 20130101; B01J 2231/32
20130101; B01J 31/2476 20130101; B01J 2531/0263 20130101; C07D
487/10 20130101; B01J 2540/10 20130101; B01J 31/143 20130101; B01J
31/226 20130101; B01J 2531/0272 20130101; B01J 31/04 20130101; B01J
2531/17 20130101; B01J 2531/0205 20130101; B01J 2540/40 20130101;
B01J 31/2414 20130101; B01J 2531/16 20130101; C07B 53/00 20130101;
C07D 491/20 20130101; B01J 2231/328 20130101; B01J 2531/842
20130101; B01J 31/02 20130101; B01J 2531/0266 20130101 |
International
Class: |
C07D 487/10 20060101
C07D487/10; B01J 31/02 20060101 B01J031/02; B01J 31/04 20060101
B01J031/04; B01J 31/22 20060101 B01J031/22; C07B 53/00 20060101
C07B053/00; C07D 491/20 20060101 C07D491/20; B01J 31/24 20060101
B01J031/24; B01J 31/18 20060101 B01J031/18; B01J 31/14 20060101
B01J031/14 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 4, 2013 |
JP |
2013-182928 |
Claims
1.-15. (canceled)
16. A method for hydrolyzing a compound or a salt thereof to
produce a compound of formula (XV) or a salt thereof provided by
condensing the compound of formula (XIV): ##STR00109## or a salt
thereof, with a compound represented by NHR.sup.22R.sup.23 to
produce formula (XV) or a salt thereof: ##STR00110## wherein
R.sup.1 represents a hydrogen atom, a C.sub.1-C.sub.6 alkylcarbonyl
group optionally having 1 to 3 substituents independently selected
from group A below, or a C.sub.1-C.sub.6 alkoxycarbonyl group
optionally having 1 to 3 substituents independently selected from
group A below, R.sup.2 represents a 5- or 6-membered heteroaryl
group having, in the ring, 1 to 3 heteroatoms independently
selected from the group consisting of a nitrogen atom, an oxygen
atom and a sulfur atom, a phenyl group, a C.sub.3-C.sub.6
cycloalkyl group, or a C.sub.3-C.sub.6 cycloalkenyl group, wherein
the 5- or 6-membered heteroaryl group, the phenyl group, the
C.sub.3-C.sub.6 cycloalkyl group, and the C.sub.3-C.sub.6
cycloalkenyl group each optionally have 1 to 3 substituents
independently selected from the group consisting of a halogen atom,
a vinyl group, an ethynyl group, a cyano group, a hydroxy group, an
amino group, a carboxy group, an aminocarbonyl group, a
C.sub.1-C.sub.6 alkyl group optionally having 1 to 3 substituents
independently selected from group A below, a C.sub.3-C.sub.4
cycloalkyl group optionally having 1 to 3 substituents
independently selected from group A below, a C.sub.1-C.sub.6 alkoxy
group optionally having 1 to 3 substituents independently selected
from group A below, a C.sub.3-C.sub.4 cycloalkoxy group optionally
having 1 to 3 substituents independently selected from group A
below, a C.sub.1-C.sub.6 alkylamino group optionally having 1 to 3
substituents independently selected from group A below, a
di-C.sub.1-C.sub.6 alkylamino group optionally having 1 to 3
substituents independently selected from group A below, a 4- to
7-membered saturated heterocyclic group containing one nitrogen
atom in the ring and optionally having 1 to 3 substituents
independently selected from group B below, a C.sub.1-C.sub.6
alkoxycarbonyl group optionally having 1 to 3 substituents
independently selected from group A below, a C.sub.3-C.sub.4
cycloalkoxycarbonyl group optionally having 1 to 3 substituents
independently selected from group A below, a C.sub.1-C.sub.6
alkylaminocarbonyl group optionally having 1 to 3 substituents
independently selected from group A below, and a C.sub.3-C.sub.4
cycloalkylaminocarbonyl group optionally having 1 to 3 substituents
independently selected from group A below, R.sup.3 and R.sup.4 each
independently represent a C.sub.1-C.sub.6 alkyl group optionally
having 1 to 3 substituents independently selected from group C
below, or R.sup.3 and R.sup.4 optionally together form a
C.sub.4-C.sub.6 cycloalkyl ring, a tetrahydrofuran ring, a
tetrahydropyran ring, or a piperidine ring, wherein the
C.sub.4-C.sub.6 cycloalkyl ring, the tetrahydrofuran ring, the
tetrahydropyran ring, and the piperidine ring each optionally have
1 to 8 substituents independently selected from a halogen atom and
a C.sub.1-C.sub.6 alkyl group optionally having 1 to 3 halogen
atoms; ring Z represents a benzene ring optionally having 1 to 4
substituents independently selected from a halogen atom, a hydroxy
group, a vinyl group, an ethynyl group, a cyano group, a
C.sub.1-C.sub.6 alkoxy group, an aminocarbonyl group, and a
C.sub.1-C.sub.6 alkyl group optionally having 1 to 3 halogen atoms;
a pyridine ring optionally having 1 to 3 substituents independently
selected from a halogen atom, a hydroxy group, a vinyl group, an
ethynyl group, a cyano group, a C.sub.1-C.sub.6 alkoxy group, an
aminocarbonyl group, and a C.sub.1-C.sub.6 alkyl group optionally
having 1 to 3 halogen atoms; or a pyrimidine ring optionally having
1 or 2 substituents independently selected from a halogen atom, a
hydroxy group, a vinyl group, an ethynyl group, a cyano group, a
C.sub.1-C.sub.6 alkoxy group, an aminocarbonyl group, and a
C.sub.1-C.sub.6 alkyl group optionally having 1 to 3 halogen atoms;
and R.sup.22 and R.sup.23 each independently represent a hydrogen
atom, a C.sub.1-C.sub.6 alkyl group optionally having 1 to 3
substituents independently selected from group I below, a
C.sub.1-C.sub.6 alkylsulfonyl group optionally having 1 to 3
substituents independently selected from group I below, a
C.sub.3-C.sub.6 cycloalkyl group optionally having 1 to 3
substituents independently selected from group I below, a 3- to
6-membered saturated heterocyclic group having, in the ring, one
heteroatom independently selected from the group consisting of a
nitrogen atom, an oxygen atom and a sulfur atom and optionally
having 1 to 3 substituents independently selected from group I
below, a phenyl group optionally having 1 to 3 substituents
independently selected from group I below, or a 5- or 6-membered
heteroaryl group having, in the ring, 1 to 3 heteroatoms
independently selected from the group consisting of a nitrogen
atom, an oxygen atom and a sulfur atom and optionally having 1 to 3
substituents independently selected from group I below, or R.sup.22
and R.sup.23 optionally together form a piperazine ring optionally
having 1 to 3 substituents independently selected from group I
below: group A: a halogen atom, a hydroxy group, a C.sub.1-C.sub.6
alkyl group, an amino group, and a phenyl group; group B: a
C.sub.1-C.sub.6 alkyl group and a hydroxy group; group I: a halogen
atom, a hydroxy group, an oxo group, a carboxy group, a formyl
group, an amino group, an aminocarbonyl group, a cyano group, a
C.sub.1-C.sub.6 alkylamino group, a C.sub.1-C.sub.6 alkylsulfonyl
group, a C.sub.1-C.sub.6 alkylsulfonylamide group, a
C.sub.1-C.sub.6 alkyl group optionally having 1 to 3 substituents
independently selected from group J below, a C.sub.1-C.sub.6 alkoxy
group optionally having 1 to 3 substituents independently selected
from group J below, a C.sub.1-C.sub.6 alkylcarbonyl group
optionally having 1 to 3 substituents independently selected from
group J below, a C.sub.3-C.sub.6 cycloalkylcarbonyl group
optionally having 1 to 3 substituents independently selected from
group J below, a C.sub.4-C.sub.6 cycloalkyl group optionally having
1 to 3 substituents independently selected from group J below, a
C.sub.1-C.sub.6 alkoxycarbonyl group optionally having 1 to 3
substituents independently selected from group J below, a
piperidinyl group optionally having 1 to 3 substituents
independently selected from group J below, a pyrrolidinyl group
optionally having 1 to 3 substituents independently selected from
group J below, a piperazinyl group optionally having 1 to 3
substituents independently selected from group J below, a phenyl
group optionally having 1 to 3 substituents independently selected
from group J below, a tetrazolyl group, an azetidinyl group
optionally having 1 to 3 substituents independently selected from
group J below, a morpholino group optionally having 1 to 3
substituents independently selected from group J below, a
dihydropyrazolyl group optionally having 1 to 3 substituents
independently selected from group J below, and an oxadiazolyl
group; and group J: a halogen atom, a hydroxy group, an amino
group, a carboxy group, an aminocarbonyl group, a phenyl group, a
C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.6 alkylamino group, a
di-C.sub.1-C.sub.6 alkylamino group, a C.sub.1-C.sub.6
alkylcarbonyl group, a C.sub.3-C.sub.6 cycloalkyl group, a
C.sub.1-C.sub.6 alkylsulfonyl group, and a C.sub.1-C.sub.6
alkylsulfonylamide group.
17. A method according to claim 16, wherein: R.sup.22 represents a
hydrogen atom, and R.sup.23 is ##STR00111##
18. A method for reacting a compound represented by formula (XVI):
##STR00112## a compound represented by formula (XVII): ##STR00113##
and a compound represented by formula (XVIII): ##STR00114## in a
solvent using an asymmetric catalyst prepared from a Lewis acid
selected from the group consisting of a Cu(I) Lewis acid and a
Cu(II) Lewis acid and a chiral ligand selected from the following
group: ##STR00115## ##STR00116## to stereoselectively produce a
compound of formula (XIX) or a salt thereof: ##STR00117## wherein M
is N or CH; L is a single bond, an oxygen atom, CH.sub.2, or
C(CH.sub.3).sub.2; and R.sup.53 represents a C.sub.1-C.sub.6 alkyl
group.
19. A method for reacting a compound represented by formula (XVI):
##STR00118## and a compound represented by formula (XX):
##STR00119## in a solvent using an asymmetric catalyst prepared
from a Lewis acid selected from the group consisting of a Cu(I)
Lewis acid and a Cu(II) Lewis acid and a chiral ligand selected
from the following group: ##STR00120## ##STR00121## to
stereoselectively produce a compound represented by formula (XIX)
or a salt thereof: ##STR00122## wherein M, L, and R.sup.53 are as
defined in claim 19.
20. A method for hydrolyzing a compound or a salt thereof produced
using a method according to claim 18 to produce a compound of
formula (XXI) or a salt thereof: ##STR00123## and condensing the
compound or the salt with a compound represented by the following
formula: ##STR00124## to produce a compound represented by the
following formula (XXII) or a salt thereof: ##STR00125##
21. A method for hydrolyzing a compound or a salt thereof produced
using a method according to claim 19 to produce a compound of
formula (XXI) or a salt thereof: ##STR00126## and condensing the
compound or the salt with a compound represented by the following
formula: ##STR00127## to produce a compound represented by the
following formula (XXII) or a salt thereof: ##STR00128##
Description
[0001] This application is a divisional application of U.S.
application Ser. No. 14/916,677, filed Mar. 4, 2016, entitled
"Method for Producing a Spirooxindole Derivative," which is a
national stage application under 35 U.S.C. .sctn. 371 of
International Application No. PCT/JP2014/073233, filed Sep. 3,
2014, entitled "Method for Producing Spirooxindole Derivative,"
which claims priority to Japanese Patent Application No.
2013-182928, filed Sep. 4, 2013.
TECHNICAL FIELD
[0002] The present invention relates to a method for producing a
pyrrolidine compound having a spirooxindole structure.
BACKGROUND ART
[0003] A method which involves using, as a reaction substrate,
aldimine synthesized from an aldehyde and an amine as starting
materials to synthesize a racemic compound through a 1,3-dipolar
cycloaddition reaction in the presence or absence of a catalyst
that promotes the reaction is known as a method for synthesizing a
pyrrolidine compound having a bicyclic spirooxindole structure (Non
Patent References 1 to 4). The obtained racemic compound can be
resolved using a chiral column based on a technique such as HPLC or
supercritical fluid chromatography (SFC) to separate a desired
optically active form.
[0004] An asymmetric synthesis method through a 1,3-dipolar
cycloaddition reaction using a chiral element has been reported as
a method for stereoselectively synthesizing the compound mentioned
above (Non Patent References 5 and 6). In addition, a method for
producing a pyrrolidine compound having a tricyclic dispirooxindole
structure through a 1,3-dipolar addition reaction using, as a
reaction substrate, ketimine synthesized with an amine and a ketone
as starting materials has also been reported (Patent Reference
1).
[0005] Meanwhile, as for catalytic asymmetric synthesis methods of
the compound mentioned above, a large number of studies have been
made on catalytic asymmetric 1,3-dipolar cycloaddition reactions
using aldimine as a reaction substrate (Non Patent References 7 to
18). Nonetheless, no report has been made on the synthesis of a
tricyclic dispiroindole using ketimine with a ketone and an amine
as reaction substrates.
CITATION LIST
Patent References
[0006] Patent Reference 1: WO2012/121361
Non Patent References
[0006] [0007] Non Patent Reference 1: Jorgensen, K. A. et al., Org.
Lett. 2005, 21, 4569 [0008] Non Patent Reference 2: Jorgensen, K.
A. et al., Chem. Rev. 1998, 98, 863 [0009] Non Patent Reference 3:
Grigg, R. et al., Tetrahedron, 1992, 48, 10431 [0010] Non Patent
Reference 4: Schreiber, S. L. et al., J. Am. Chem. Soc. 2003, 125,
10174 [0011] Non Patent Reference 5: Carretero, J. C. et al.,
Tetrahedron, 2007, 63, 6587 [0012] Non Patent Reference 6: Wang, S.
et al., J. Am. Chem. Soc., 2005, 127, 10130 [0013] Non Patent
Reference 7: Wang, S. et al., J. Med. Chem. 2006, 49, 3432 [0014]
Non Patent Reference 8: Williams, R. M. et al., J. Am. Chem. Soc.
2000, 122, 5666 [0015] Non Patent Reference 9: Gong, L.-Z. et al.,
J. Am. Chem. Soc., 2009, 131, 13819 [0016] Non Patent Reference 10:
Gong, L.-Z. et al., Org. Lett., 2011, 13, 2418 [0017] Non Patent
Reference 11: Gong, L.-Z. et al., Chem. Eur. J., 2012, 18, 6885
[0018] Non Patent Reference 12: Waldmann, H. et al., Nat. Chem.,
2010, 2, 735 [0019] Non Patent Reference 13: Waldmann, H. et al.,
Tetrahedron, 2011, 67, 10195 [0020] Non Patent Reference 14: Wang,
C.-J. et al., Org. Biomol. Chem., 2011, 9, 1980 [0021] Non Patent
Reference 15: Arai, T. et al., Chem. Eur. J., 2012, 18, 8287 [0022]
Non Patent Reference 16: Amedohkouh, M. et al., Tetrahedron
Asymmetry, 2005, 8, 1411 [0023] Non Patent Reference 17: Cordova,
A. et al., Chem. Comm. 2006, 460 [0024] Non Patent Reference 18:
Ma, J. A. et al., Org. Lett. 2007, 9, 923
SUMMARY OF INVENTION
Technical Problem
[0025] The present invention is intended to provide a method for
efficiently producing and providing a compound having a
spirooxindole skeleton, for example, a compound having a
spirooxindole skeleton and having antitumor activity that inhibits
the interaction between Mdm2 protein and p53 protein, or an
intermediate thereof using an asymmetric catalyst.
Solution to Problem
[0026] The present inventors have conducted diligent studies and
consequently established a method for efficiently synthesizing a
compound having an optically active tricyclic dispiroindole
skeleton by screening for a chiral ligand that promotes a catalytic
asymmetric 1,3-dipolar cycloaddition reaction using ketimine as a
reaction substrate, and a Lewis acid serving as a central metal
thereof, and the optimum reaction conditions.
[0027] Specifically the present invention relates to the following
(1) to (20):
[0028] (1) A Method for Reacting a Compound Represented by Formula
(I):
##STR00001##
a compound represented by formula (II):
##STR00002##
and a compound represented by formula (III):
##STR00003##
in a solvent using an asymmetric catalyst to stereoselectively
produce a compound represented by formula (IV) or a salt
thereof:
##STR00004##
wherein
[0029] R.sup.1 represents a hydrogen atom, a C.sub.1-C.sub.6
alkylcarbonyl group optionally having 1 to 3 substituents
independently selected from group A below, or a C.sub.1-C.sub.6
alkoxycarbonyl group optionally having 1 to 3 substituents
independently selected from group A below,
[0030] R.sup.2 represents a 5- or 6-membered heteroaryl group
having, in the ring, 1 to 3 heteroatoms independently selected from
the group consisting of a nitrogen atom, an oxygen atom and a
sulfur atom, a phenyl group, a C.sub.3-C.sub.6 cycloalkyl group, or
a C.sub.3-C.sub.6 cycloalkenyl group, wherein
[0031] the 5- or 6-membered heteroaryl group, the phenyl group, the
C.sub.3-C.sub.6 cycloalkyl group, and the C.sub.3-C.sub.6
cycloalkenyl group each optionally have 1 to 3 substituents
independently selected from the group consisting of a halogen atom,
a vinyl group, an ethynyl group, a cyano group, a hydroxy group, an
amino group, a carboxy group, an aminocarbonyl group, a
C.sub.1-C.sub.6 alkyl group optionally having 1 to 3 substituents
independently selected from group A below, a C.sub.3-C.sub.4
cycloalkyl group optionally having 1 to 3 substituents
independently selected from group A below, a C.sub.1-C.sub.6 alkoxy
group optionally having 1 to 3 substituents independently selected
from group A below, a C.sub.3-C.sub.4 cycloalkoxy group optionally
having 1 to 3 substituents independently selected from group A
below, a C.sub.1-C.sub.6 alkylamino group optionally having 1 to 3
substituents independently selected from group A below, a
di-C.sub.1-C.sub.6 alkylamino group optionally having 1 to 3
substituents independently selected from group A below, a 4- to
7-membered saturated heterocyclic group containing one nitrogen
atom in the ring and optionally having 1 to 3 substituents
independently selected from group B below, a C.sub.1-C.sub.6
alkoxycarbonyl group optionally having 1 to 3 substituents
independently selected from group A below, a C.sub.3-C.sub.4
cycloalkoxycarbonyl group optionally having 1 to 3 substituents
independently selected from group A below, a C.sub.1-C.sub.6
alkylaminocarbonyl group optionally having 1 to 3 substituents
independently selected from group A below, and a C.sub.3-C.sub.4
cycloalkylaminocarbonyl group optionally having 1 to 3 substituents
independently selected from group A below,
[0032] R.sup.3 and R.sup.4 each independently represent a
C.sub.1-C.sub.6 alkyl group optionally having 1 to 3 substituents
independently selected from group C below, or
[0033] R.sup.3 and R.sup.4 optionally together form a
C.sub.4-C.sub.6 cycloalkyl ring, a tetrahydrofuran ring, a
tetrahydropyran ring, or a piperidine ring, wherein
[0034] the C.sub.4-C.sub.6 cycloalkyl ring, the tetrahydrofuran
ring, the tetrahydropyran ring, and the piperidine ring each
optionally have 1 to 8 substituents independently selected from
group D below,
[0035] R.sup.5 represents a C.sub.1-C.sub.6 alkoxy group optionally
having 1 to 3 substituents independently selected from group E
below, a C.sub.3-C.sub.8 cycloalkoxy group optionally having 1 to 3
substituents independently selected from group E below, a
C.sub.2-C.sub.6 alkenyloxy group, or --NR.sup.51R.sup.52,
[0036] R.sup.51 and R.sup.52 each independently represent a
hydrogen atom, a C.sub.1-C.sub.6 alkyl group optionally having 1 to
3 substituents independently selected from group E below, a
C.sub.3-C.sub.8 cycloalkyl group optionally having 1 to 3
substituents independently selected from group E below, or a 3- to
6-membered saturated heterocyclic group having, in the ring, one
heteroatom independently selected from the group consisting of a
nitrogen atom, an oxygen atom and a sulfur atom and optionally
having 1 to 3 substituents independently selected from group E
below, and
ring Z represents a benzene ring optionally having 1 to 4
substituents independently selected from group E below, a pyridine
ring optionally having 1 to 3 substituents independently selected
from group E below, or a pyrimidine ring optionally having 1 or 2
substituents independently selected from group E below:
[0037] group A: a halogen atom, a hydroxy group, a C.sub.1-C.sub.6
alkyl group, an amino group, and a phenyl group,
[0038] group B: a C.sub.1-C.sub.6 alkyl group and a hydroxy
group
[0039] group C: a halogen atom, a hydroxy group, a phenyl group, a
pyridyl group, and an amino group
[0040] group D: a halogen atom and a C.sub.1-C.sub.6 alkyl group
optionally having 1 to 3 halogen atoms, and
[0041] group E: a halogen atom, a hydroxy group, a vinyl group, an
ethynyl group, a cyano group, a C.sub.1-C.sub.6 alkoxy group, an
aminocarbonyl group, and a C.sub.1-C.sub.6 alkyl group optionally
having 1 to 3 halogen atoms.
[0042] (2) A method for reacting a compound represented by formula
(I):
##STR00005##
and a compound represented by formula (V):
##STR00006##
in a solvent using an asymmetric catalyst to stereoselectively
produce a compound represented by formula (IV) or a salt
thereof:
##STR00007##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, and Z are as
defined in (1).
[0043] (3) A method according to (1) or (2), wherein the asymmetric
catalyst is a catalyst prepared from a Lewis acid and a chiral
ligand, wherein the Lewis acid is a Lewis acid selected from the
group consisting of a Zn(II) Lewis acid, a Ag(I) Lewis acid, a
Ni(II) Lewis acid, a Co(II) Lewis acid, a Ru(I) Lewis acid, a Cu(I)
Lewis acid, and a Cu(II) Lewis acid, and the chiral ligand is a
chiral ligand selected from the group consisting of a compound
represented by the following formula (VI):
##STR00008##
a compound represented by the following formula (VII):
##STR00009##
a compound represented by the following formula (VIII):
##STR00010##
a compound represented by the following formula (IX):
##STR00011##
a compound represented by the following formula (X):
##STR00012##
a compound represented by the following formula (XI):
##STR00013##
and a compound represented by the following formula (XII):
##STR00014##
wherein
[0044] R.sup.6 represents a phenyl group optionally having 1 to 3
substituents independently selected from group F below,
[0045] ring Y represents a benzene ring, a cyclohexane ring, or a
dioxolane ring optionally having 1 to 4 halogen atoms,
[0046] R.sup.7 represents a phenyl group optionally having 1 to 3
substituents independently selected from group G below, or a
furanyl group optionally having 1 to 3 substituents independently
selected from group G below,
[0047] R.sup.8 represents a hydrogen atom or a C.sub.1-C.sub.6
alkoxy group,
[0048] R.sup.9 represents a C.sub.1-C.sub.6 alkoxy group, or
[0049] two R.sup.9 moieties optionally together form a 7- to
12-membered heterocyclic ring containing two oxygen atoms in the
ring,
[0050] X represents CH, CR.sup.10, or a nitrogen atom, wherein
[0051] R.sup.10 represents a C.sub.1-C.sub.6 alkoxy group,
[0052] V represents a phenyl group having one P(R.sup.11).sub.2 or
PH(O)R.sup.12, wherein
[0053] R.sup.11 represents a C.sub.1-C.sub.6 alkyl group, a
cyclohexyl group, or a phenyl group optionally having two
trifluoromethyl groups, and
[0054] R.sup.12 represents a C.sub.1-C.sub.6 alkyl group or a
phenyl group, W represents a C.sub.1-C.sub.6 alkylthio group, a
dihydrooxazolyl group optionally having one C.sub.1-C.sub.6 alkyl
group, CH(CH.sub.3)P(R.sup.13).sub.2, or CHR.sup.14R.sup.15,
wherein
[0055] R.sup.13 represents a cyclohexyl group, a C.sub.1-C.sub.6
alkyl group, or a phenyl group optionally having 1 or 2
substituents independently selected from group H below,
[0056] R.sup.14 represents a phenyl group optionally substituted by
one P(R.sup.16).sub.2,
[0057] R.sup.15 represents a C.sub.1-C.sub.6 alkyl group or a
di-C.sub.1-C.sub.6 alkylamino group, and
[0058] R.sup.16 represents a phenyl group or a cyclohexyl
group,
U represents any one of the following U.sup.a to U.sup.d:
##STR00015##
[0059] R.sup.17 represents a phenyl group optionally having 1 to 3
substituents independently selected from group F below,
[0060] R.sup.18 represents a C.sub.1-C.sub.6 alkyl group or a
phenyl group,
[0061] R.sup.19 represents a hydrogen atom or a C.sub.1-C.sub.6
alkyl group, and
[0062] R.sup.20 and R.sup.21 each independently represent a
C.sub.1-C.sub.6 alkyl group:
[0063] group F: a C.sub.1-C.sub.6 alkyl group and a C.sub.1-C.sub.6
alkoxy group,
[0064] group G: a C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.6
alkoxy group, and a di-C.sub.1-C.sub.6 alkylamino group, and
[0065] group H: a C.sub.1-C.sub.6 alkyl group and a C.sub.1-C.sub.6
alkyl group optionally having three halogen atoms.
[0066] (4) A method according to any one of (1) to (3), wherein the
Lewis acid used in the preparation of the asymmetric catalyst is a
Cu(I) Lewis acid or a Cu(II) Lewis acid.
[0067] (5) A method according to any one of (1) to (4), wherein the
Lewis acid used in the preparation of the asymmetric catalyst is a
Lewis acid selected from the group consisting of CuOAc, CuCl, CuBr,
CuI, CuOTf, CuPF.sub.6, CuBF.sub.4, Cu(OAc).sub.2, Cu(OTf).sub.2,
and CuSO.sub.4.
[0068] (6) A method according to any one of (1) to (5), wherein the
chiral ligand used in the preparation of the asymmetric catalyst is
a chiral ligand selected from the group consisting of a compound
represented by formula (V), a compound represented by formula (VI),
a compound represented by formula (VII), a compound represented by
formula (VIII), a compound represented by formula (IX), a compound
represented by formula (X), and a compound represented by formula
(XI),
[0069] wherein
[0070] R.sup.6 represents a phenyl group optionally having 1 to 3
substituents independently selected from the group consisting of a
methyl group, a t-butyl group, and a methoxy group,
[0071] ring Y represents a benzene ring, a cyclohexane ring, or a
dioxolane ring,
[0072] R.sup.7 represents a phenyl group or a furanyl group,
wherein
[0073] the phenyl group and the furanyl group each optionally have
1 to 3 substituents independently selected from the group
consisting of a methyl group, a t-butyl group, and a methoxy
group,
[0074] R.sup.8 represents a hydrogen atom or a methoxy group,
[0075] R.sup.9 represents a methoxy group, or,
[0076] two R.sup.9 moieties optionally together form a 9-membered
heterocyclic ring containing two oxygen atoms in the ring,
[0077] X represents CH, CR.sup.10, or a nitrogen atom,
[0078] R.sup.10 represents a methoxy group,
[0079] V represents P(R.sup.11).sub.2, wherein
[0080] R.sup.11 represents a phenyl group optionally having two
trifluoromethyl groups,
[0081] W represents a t-butylthio group, a dihydrooxazolyl group
optionally substituted by one isopropyl group, or
CH(CH.sub.3)P(R.sup.13).sub.2, wherein
[0082] R.sup.13 represents a phenyl group optionally having 1 or 2
methyl groups,
[0083] U represents U.sup.a or U.sup.d mentioned above,
[0084] R.sup.17 represents a phenyl group,
[0085] R.sup.18 represents an isopropyl group, a t-butyl group, or
a phenyl group,
[0086] R.sup.19 represents a hydrogen atom, and
[0087] R.sup.20 and R.sup.21 each independently represent a methyl
group or a t-butyl group.
[0088] (7) A method according to any one of (1) to (6), wherein the
chiral ligand used in the preparation of the asymmetric catalyst is
a chiral ligand selected from the following group:
##STR00016## ##STR00017##
[0089] (8) A method according to any one of (1) to (7), wherein the
solvent used in the reaction is one or more solvents selected from
the group consisting of N,N-dimethylacetamide, tetrahydrofuran,
dimethoxyethane, 2-propanol, toluene, and ethyl acetate.
[0090] (9) A method according to any one of (1) to (8), wherein the
compound produced or salt thereof has the following
configuration:
##STR00018##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, and Z are as
defined in (1).
[0091] (10) A method according to any one of (1) to (9), wherein
R.sub.1 is a hydrogen atom.
[0092] (11) A method according to any one of (1) to (10), wherein
in formula (I),
ring Z is a benzene ring optionally having 1 to 4 halogen
atoms.
[0093] (12) A method according to any one of (1) to (11), wherein
in formula (I) or formula (IV),
R.sup.2 is a pyridyl group optionally having 1 to 3 halogen atoms,
or a phenyl group optionally having 1 to 3 halogen atoms.
[0094] (13) A method according to any one of (1) to (12), wherein
in formula (II) or formula (V),
R.sup.3 and R.sup.4 each represent a methyl group, or R.sup.3 and
R.sup.4 together form a cyclopentane ring, a cyclohexane ring, or a
tetrahydropyran ring, wherein
[0095] the cyclopentane ring, the cyclohexane ring, and the
tetrahydropyran ring each optionally have 1 to 4 C.sub.1-C.sub.6
alkyl groups on the ring.
[0096] (14) A method according to any one of (1) to (13), wherein
in formula (III) or formula (V),
[0097] R.sup.5 is a substituent represented by the following:
##STR00019##
[0098] (15) A method according to any one of (1) to (13), wherein
in formula (III) or formula (V),
[0099] R.sup.5 is a C.sub.1-C.sub.6 alkoxy group.
[0100] (16) A method for hydrolyzing a compound or a salt thereof
produced using a method according to (15) to produce a compound
represented by the following formula (XIV) or a salt thereof:
##STR00020##
and condensing the compound or the salt with a compound represented
by NHR.sup.22R.sup.23 to produce a compound represented by the
following formula (XV) or a salt thereof:
##STR00021##
wherein
[0101] R.sup.1, R.sup.2, R.sup.3, R.sup.4, and Z are as defined in
any one of (1) to (13), and
[0102] R.sup.22 and R.sup.23 each independently represent a
hydrogen atom, a C.sub.1-C.sub.6 alkyl group optionally having 1 to
3 substituents independently selected from group I below, a
C.sub.1-C.sub.6 alkylsulfonyl group optionally having 1 to 3
substituents independently selected from group I below, a
C.sub.3-C.sub.6 cycloalkyl group optionally having 1 to 3
substituents independently selected from group I below, a 3- to
6-membered saturated heterocyclic group having, in the ring, one
heteroatom independently selected from the group consisting of a
nitrogen atom, an oxygen atom and a sulfur atom and optionally
having 1 to 3 substituents independently selected from group I
below, a phenyl group optionally having 1 to 3 substituents
independently selected from group I below, or a 5- or 6-membered
heteroaryl group having, in the ring, 1 to 3 heteroatoms
independently selected from the group consisting of a nitrogen
atom, an oxygen atom and a sulfur atom and optionally having 1 to 3
substituents independently selected from group I below, or
[0103] R.sup.22 and R.sup.23 optionally together form a piperazine
ring optionally having 1 to 3 substituents independently selected
from group I below:
[0104] group I: a halogen atom, a hydroxy group, an oxo group, a
carboxy group, a formyl group, an amino group, an aminocarbonyl
group, a cyano group, a C.sub.1-C.sub.6 alkylamino group, a
C.sub.1-C.sub.6 alkylsulfonyl group, a C.sub.1-C.sub.6
alkylsulfonylamide group, a C.sub.1-C.sub.6 alkyl group optionally
having 1 to 3 substituents independently selected from group J
below, a C.sub.1-C.sub.6 alkoxy group optionally having 1 to 3
substituents independently selected from group J below, a
C.sub.1-C.sub.6 alkylcarbonyl group optionally having 1 to 3
substituents independently selected from group J below, a
C.sub.3-C.sub.6 cycloalkylcarbonyl group optionally having 1 to 3
substituents independently selected from group J below, a
C.sub.4-C.sub.6 cycloalkyl group optionally having 1 to 3
substituents independently selected from group J below, a
C.sub.1-C.sub.6 alkoxycarbonyl group optionally having 1 to 3
substituents independently selected from group J below, a
piperidinyl group optionally having 1 to 3 substituents
independently selected from group J below, a pyrrolidinyl group
optionally having 1 to 3 substituents independently selected from
group J below, a piperazinyl group optionally having 1 to 3
substituents independently selected from group J below, a phenyl
group optionally having 1 to 3 substituents independently selected
from group J below, a tetrazolyl group, an azetidinyl group
optionally having 1 to 3 substituents independently selected from
group J below, a morpholino group optionally having 1 to 3
substituents independently selected from group J below, a
dihydropyrazolyl group optionally having 1 to 3 substituents
independently selected from group J below, and an oxadiazolyl
group, and
[0105] group J: a halogen atom, a hydroxy group, an amino group, a
carboxy group, an aminocarbonyl group, a phenyl group, a
C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.6 alkylamino group, a
di-C.sub.1-C.sub.6 alkylamino group, a C.sub.1-C.sub.6
alkylcarbonyl group, a C.sub.3-C.sub.6 cycloalkyl group, a
C.sub.1-C.sub.6 alkylsulfonyl group, and a C.sub.1-C.sub.6
alkylsulfonylamide group.
[0106] (17) A method according to (16), wherein
[0107] R.sup.22 represents a hydrogen atom, and
[0108] R.sup.23 is a substituent represented by the following:
##STR00022##
[0109] (18) A method for reacting
[0110] a compound represented by formula (XVI):
##STR00023##
a compound represented by formula (XVII):
##STR00024##
and a compound represented by formula (XVIII):
##STR00025##
in a solvent using an asymmetric catalyst prepared from a Lewis
acid selected from the group consisting of a Cu(I) Lewis acid and a
Cu(II) Lewis acid and a chiral ligand selected from the following
group:
##STR00026## ##STR00027##
to stereoselectively produce a compound represented by formula
(XIX) or a salt thereof:
##STR00028##
wherein
[0111] M represents a nitrogen atom or CH,
[0112] L represents a single bond, an oxygen atom, CH.sub.2, or
C(CH.sub.3).sub.2, and
[0113] R.sup.53 represents a C.sub.1-C.sub.6 alkyl group.
[0114] (19) A method for reacting a compound represented by formula
(XVI):
##STR00029##
and a compound represented by formula (XX):
##STR00030##
in a solvent using an asymmetric catalyst prepared from a Lewis
acid selected from the group consisting of a Cu(I) Lewis acid and a
Cu(II) Lewis acid and a chiral ligand selected from the following
group:
##STR00031## ##STR00032##
to stereoselectively produce a compound represented by formula
(XIX) or a salt thereof:
##STR00033##
wherein
[0115] M, L, and R.sup.53 are as defined in 18.
[0116] (20) A method for hydrolyzing a compound or a salt thereof
produced using a method according to (18) or (19) to produce a
compound represented by the following formula (XXI) or a salt
thereof:
##STR00034##
and condensing the compound or the salt with a compound represented
by the following formula:
##STR00035##
to produce a compound represented by the following formula (XXII)
or a salt thereof:
##STR00036##
wherein M and L are as defined in (18) or (19).
Advantageous Effects of Invention
[0117] According to the present invention, a compound having a
spirooxindole skeleton, for example, a compound having a
spirooxindole skeleton and having antitumor activity that inhibits
the interaction between Mdm2 protein and p53 protein can be
stereoselectively synthesized in an efficient and inexpensive
manner.
DESCRIPTION OF EMBODIMENTS
[0118] In the present invention, a "halogen atom" is a fluorine
atom, a chlorine atom, a bromine atom, or an iodine atom.
[0119] In the present invention, a "C.sub.1-C.sub.6 alkyl group"
refers to a linear or branched alkyl group having 1 to 6 carbon
atoms and is a methyl group, an ethyl group, a propyl group, an
isopropyl group, a butyl group, an isobutyl group, a s-butyl group,
a t-butyl group, a pentyl group, an isopentyl group, a
2-methylbutyl group, a neopentyl group, a 1-ethylpropyl group, a
hexyl group, an isohexyl group, or a 4-methylpentyl group.
[0120] In the present invention, a "C.sub.3-C.sub.6 cycloalkyl
group" is a cyclopropyl group, a cyclobutyl group, a cyclopentyl
group, or a cyclohexyl group.
[0121] In the present invention, a "C.sub.3-C.sub.4 cycloalkyl
group" is a cyclopropyl group or a cyclobutyl group.
[0122] In the present invention, a "C.sub.1-C.sub.6 alkoxy group"
refers to a group in which a C.sub.1-C.sub.6 alkyl group mentioned
above is substituted by an oxy group, and is a methoxy group, an
ethoxy group, a propoxy group, an isopropoxy group, a butoxy group,
an isobutoxy group, a s-butoxy group, a t-butoxy group, a pentoxy
group, an isopentoxy group, a 2-methylbutoxy group, a hexyloxy
group, or an isohexyloxy group.
[0123] In the present invention, a "C.sub.3-C.sub.6 cycloalkoxy
group" refers to a group in which a C.sub.3-C.sub.6 cycloalkyl
group mentioned above is substituted by an oxy group, and is a
cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group, or
a cyclohexyloxy group.
[0124] In the present invention, a "C.sub.3-C.sub.4 cycloalkoxy
group" is a cyclopropoxy group or a cyclobutoxy group.
[0125] In the present invention, a "C.sub.3-C.sub.8 cycloalkoxy
group" is a cyclopropoxy group, a cyclobutoxy group, a
cyclopentyloxy group, a cyclohexyloxy group, a cycloheptyloxy
group, or a cyclooctyloxy group.
[0126] In the present invention, a "C.sub.1-C.sub.6 alkylthio
group" refers to a group in which a C.sub.1-C.sub.6 alkyl group
mentioned above is substituted by a thio group. Examples thereof
include a methylthio group, an ethylthio group, a propylthio group,
and an isopropylthio group.
[0127] In the present invention, a "C.sub.1-C.sub.6 alkylsulfonyl
group" refers to a group in which a C.sub.1-C.sub.6 alkyl group
mentioned above is substituted by a sulfonyl group. Examples
thereof include a methylsulfonyl group, an ethylsulfonyl group, a
propylsulfonyl group, and an isopropylsulfonyl group.
[0128] In the present invention, a "C.sub.1-C.sub.6
alkylsulfonylamide group" refers to a group in which a
C.sub.1-C.sub.6 alkylsulfonyl group mentioned above is substituted
by an amino group. Examples thereof include a methylsulfonylamide
group, an ethylsulfonylamide group, a propylsulfonylamide group,
and an isopropylsulfonylamide group.
[0129] In the present invention, a "C.sub.1-C.sub.6 alkylcarbonyl
group" refers to a group in which a C.sub.1-C.sub.6 alkyl group
mentioned above is substituted by a carbonyl group. Examples
thereof include an acetyl group, an ethylcarbonyl group, a
propylcarbonyl group, and an isopropylcarbonyl group.
[0130] In the present invention, a "C.sub.1-C.sub.6 alkoxycarbonyl
group" refers to a group in which a C.sub.1-C.sub.6 alkoxy group
mentioned above is substituted by a carbonyl group. Examples
thereof include a methoxycarbonyl group, an ethoxycarbonyl group, a
propoxycarbonyl group, and an isopropoxycarbonyl group.
[0131] In the present invention, a "C.sub.3-C.sub.6
cycloalkylcarbonyl group" refers to a group in which a
C.sub.3-C.sub.6 cycloalkyl group mentioned above is substituted by
a carbonyl group, and is a cyclopropylcarbonyl group, a
cyclobutylcarbonyl group, a cyclopentylcarbonyl group, or a
cyclohexylcarbonyl group.
[0132] In the present invention, a "C.sub.3-C.sub.6
cycloalkoxycarbonyl group" refers to a group in which a
C.sub.3-C.sub.6 cycloalkoxy group mentioned above is substituted by
a carbonyl group, and is a cyclopropoxycarbonyl group, a
cyclobutoxycarbonyl group, a cyclopentyloxycarbonyl group, or a
cyclohexyloxycarbonyl group.
[0133] In the present invention, a "C.sub.1-C.sub.6 alkylamino
group" refers to a group in which a C.sub.1-C.sub.6 alkyl group
mentioned above is substituted by an amino group. Examples thereof
include a methylamino group, an ethylamino group, a propylamino
group, and an isopropylamino group.
[0134] In the present invention, a "di-C.sub.1-C.sub.6 alkylamino
group" refers to a group in which two identical or different
C.sub.1-C.sub.6 alkyl groups mentioned above are substituted by an
amino group. Examples thereof include a dimethylamino group, a
diethylamino group, a dipropylamino group, and a diisopropylamino
group.
[0135] In the present invention, a "C.sub.1-C.sub.6
alkylaminocarbonyl group" refers to a group in which a
C.sub.1-C.sub.6 alkylamino group mentioned above is substituted by
a carbonyl group. Examples thereof include a methylaminocarbonyl
group, an ethylaminocarbonyl group, a propylaminocarbonyl group,
and an isopropylaminocarbonyl group.
[0136] In the present invention, a "C.sub.3-C.sub.6
cycloalkylaminocarbonyl group" refers to a group in which a
C.sub.3-C.sub.6 cycloalkyl group mentioned above is bonded to the
amino group side of a (--NH--C(.dbd.O)--) group, and is a
cyclopropylaminocarbonyl group, a cyclobutylaminocarbonyl group, a
cyclopentylaminocarbonyl group, or a cyclohexylaminocarbonyl
group.
[0137] In the present invention, a "C.sub.3-C.sub.8 cycloalkylamino
group" refers to a group in which a C.sub.3-C.sub.8 cycloalkyl
group mentioned above is bonded to an amino group, and is a
cyclopropylamino group, a cyclobutylamino group, or a
cyclopentylamino group.
[0138] In the present invention, a "C.sub.2-C.sub.6 alkenyloxy
group" refers to a group in which a linear or branched
C.sub.2-C.sub.6 alkenyl group having 2 to 6 carbon atoms is bonded
to an oxy group. Examples thereof include a vinyloxy group, an
allyloxy group, and an isopropenyloxy group.
[0139] In the present invention, a "C.sub.3-C.sub.6 cycloalkenyl
group" is a cyclopropenyl group, a cyclobutenyl group, a
cyclopentenyl group, or a cyclohexenyl group.
[0140] In the present invention, a "5- or 6-membered heteroaryl
group" refers to a group derived from a 5- or 6-membered monocyclic
aromatic compound containing 1 to 3 atoms each independently
selected from the group consisting of a nitrogen atom, an oxygen
atom and a sulfur atom in addition to carbon as atoms constituting
the ring. Examples thereof include a furyl group, a thienyl group,
a pyrrolyl group, an oxazolyl group, an isoxazolyl group, a
thiazolyl group, an isothiazolyl group, an imidazolyl group, a
pyrazolyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl
group, and a pyridazinyl group.
[0141] In the present invention, a "3- to 6-membered saturated
heterocyclic group" refers to a group derived from a 3- to
6-membered monocyclic saturated heterocyclic compound containing
one atom selected from the group consisting of a nitrogen atom, an
oxygen atom and a sulfur atom in addition to carbon as atoms
constituting the ring. Examples thereof include an aziridinyl
group, an oxiranyl group, a thiiranyl group, an azetidinyl group,
an oxetanyl group, a thietanyl group, a pyrrolidinyl group, a
tetrahydrofuranyl group, a tetrahydrothienyl group, a piperidinyl
group, a tetrahydropyranyl group, and a tetrahydrothiopyranyl
group.
[0142] In the present invention, an "asymmetric catalyst" refers to
a catalyst for use in asymmetric synthesis. Examples thereof
include catalysts having a metal atom therein.
[0143] In the present invention, a "Lewis acid" refers to a
substance capable of accepting an electron pair. Examples thereof
include Zn(OTf).sub.2, AgOAc, Cu(OTf).sub.2, CuOAc, Ni(OAc).sub.2,
Co(OAc).sub.2, CuCl, CuBr, CuI, CuPF.sub.6, CuBF.sub.4,
Cu(OAc).sub.2, Cu(OTf).sub.2, and CuSO.sub.4.
[0144] In the present invention, a "chiral ligand" refers to a
substance having asymmetry and capable of forming a coordinate bond
with a metal and includes not only unidentate ligands but
multidentate ligands. Examples thereof include BINAP derivatives,
MeBIPHEP derivatives, TunePHOS derivatives, P-Phos derivatives,
JOSIPHOS derivatives, Walphos derivatives, FESULPHOS derivatives,
Taniaphos derivatives, Jospophos derivatives, FOXAP derivatives,
Mandyphos derivatives, Ferrocelane derivatives, PHOX derivatives,
and QuinoxP derivatives.
[0145] In the present invention, the phrase "having asymmetry"
means having an asymmetric center, axial chirality, or planar
chirality.
[0146] In the present invention, the symbol "*" means an asymmetric
center or axial chirality.
[0147] In the present invention, the symbol "Cy" is an abbreviation
of a cyclopentyl group.
[0148] In the present invention, a "ketimine" refers to an imine
formed from a ketone and an amine and is a compound having a
structure in which the carbonyl group of the ketone is substituted
by the nitrogen atom of the amine.
[0149] A compound represented by formula (I), a compound
represented by formula (II), a compound represented by formula
(III), a compound represented by formula (IV) or a salt thereof, a
compound represented by formula (V), a compound represented by
formula (VI), a compound represented by formula (VII), a compound
represented by formula (VIII), a compound represented by formula
(IX), a compound represented by formula (X), a compound represented
by formula (XI), a compound represented by formula (XII), a
compound represented by formula (XIII) or a salt thereof, a
compound represented by formula (XIV) or a salt thereof, a compound
represented by formula (XV) or a salt thereof, a compound
represented by formula (XVI), a compound represented by formula
(XVII), a compound represented by formula (XVIII), a compound
represented by formula (XIX) or a salt thereof, a compound
represented by formula (XX), a compound represented by formula
(XXI) or a salt thereof, and a compound represented by formula
(XXII) or a salt thereof according to the present invention
encompass all isomers (diastereomers, optical isomers, geometric
isomers, rotational isomers, etc.)
[0150] In the compound represented by formula (I), the compound
represented by formula (II), the compound represented by formula
(III), the compound represented by formula (IV) or a salt thereof,
the compound represented by formula (V), the compound represented
by formula (VI), the compound represented by formula (VII), the
compound represented by formula (VIII), the compound represented by
formula (IX), the compound represented by formula (X), the compound
represented by formula (XI), the compound represented by formula
(XII), the compound represented by formula (XIII) or a salt
thereof, the compound represented by formula (XIV) or a salt
thereof, the compound represented by formula (XV) or a salt
thereof, the compound represented by formula (XVI), the compound
represented by formula (XVII), the compound represented by formula
(XVIII), the compound represented by formula (XIX) or a salt
thereof, the compound represented by formula (XX), the compound
represented by general formula (XXI) or a salt thereof, and the
compound represented by formula (XXII) or a salt thereof, their
isomers and mixtures of these isomers are all represented by single
formulae. Thus, the present invention includes all of these isomers
and mixtures of these isomers in arbitrary ratios.
[0151] A compound represented by formula (IV), a compound
represented by formula (XIII), a compound represented by formula
(XIV), a compound represented by formula (XV), a compound
represented by formula (XIX), a compound represented by formula
(XXI), and a compound represented by formula (XXII) according to
the present invention may each be converted into a salt through its
reaction with an acid when having a basic group or through its
reaction with a base when having an acidic group.
[0152] Examples of a salt based on a basic group can include:
hydrohalides such as hydrofluoride, hydrochloride, hydrobromide,
and hydroiodide; inorganic acid salts such as nitrate, perchlorate,
sulfate, and phosphate; C.sub.1-C.sub.6 alkylsulfonates such as
methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate;
arylsulfonates such as benzenesulfonate and p-toluenesulfonate; and
carboxylates such as acetate, oxalate, tartrate, and maleate.
[0153] On the other hand, examples of a salt based on an acidic
group can include: alkali metal salts such as sodium salt,
potassium salt, and lithium salt; alkaline earth metal salts such
as calcium salt and magnesium salt; metal salts such as aluminum
salt and iron salt; inorganic salts such as ammonium salt; amine
salts of organic salts, etc., such as t-octylamine salt,
dibenzylamine salt, morpholine salt, glucosamine salt,
phenylglycine alkyl ester salt, ethylenediamine salt,
N-methylglucamine salt, guanidine salt, diethylamine salt,
triethylamine salt, dicyclohexylamine salt,
N,N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine
salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine
salt, tetramethylammonium salt, and tris(hydroxymethyl)aminomethane
salt; and amino acid salts such as glycine salt, lysine salt,
arginine salt, ornithine salt, glutamate, and aspartate.
[0154] A compound represented by formula (IV) or a salt thereof, a
compound represented by formula (XIII) or a salt thereof, a
compound represented by formula (XIV) or a salt thereof, a compound
represented by formula (XV) or a salt thereof, a compound
represented by formula (XIX) or a salt thereof, a compound
represented by formula (XXI) or a salt thereof, and a compound
represented by formula (XXII) or a salt thereof according to the
present invention, when left in air or recrystallized, may each
incorporate a water molecule to form a hydrate. Such a hydrate is
also included in a salt of the present invention.
[0155] A compound represented by formula (IV) or a salt thereof, a
compound represented by formula (XIII) or a salt thereof, a
compound represented by formula (XIV) or a salt thereof, a compound
represented by formula (XV) or a salt thereof, a compound
represented by formula (XIX) or a salt thereof, a compound
represented by formula (XXI) or a salt thereof, and a compound
represented by formula (XXII) or a salt thereof according to the
present invention, when left in a solvent or recrystallized, may
each absorb a certain kind of solvent to form a solvate. Such a
solvate is also included in a salt of the present invention.
[0156] Examples of a solvent include: ether solvents such as
tetrahydrofuran and 1,2-dimethoxyethane; alcohol solvents such as
methanol, ethanol, and 2-propanol; hydrocarbon solvents such as
toluene; nitrile solvents such as acetonitrile; aliphatic ester
solvents such as ethyl acetate; and amide solvents such as
N,N-dimethylacetamide and N,N-dimethylformamide.
[0157] Next, preferred embodiments of the present invention will be
described.
[0158] Preferred forms of each substituent in a compound
represented by formula (I), a compound represented by formula (II),
a compound represented by formula (III), a compound represented by
formula (IV), a compound represented by formula (V), a compound
represented by formula (XIII), a compound represented by formula
(XIV), and a compound represented by formula (XV) are given
below.
[0159] R.sup.1 represents a hydrogen atom, a C.sub.1-C.sub.6
alkylcarbonyl group, or a C.sub.1-C.sub.6 alkoxycarbonyl group
optionally having one phenyl group. R.sup.1 is more preferably a
hydrogen atom, an acetyl group, a t-butoxycarbonyl group, or a
benzyloxycarbonyl group, further preferably a hydrogen atom.
[0160] R.sup.2 represents a 5- or 6-membered heteroaryl group
having, in the ring, 1 to 3 heteroatoms independently selected from
the group consisting of a nitrogen atom, an oxygen atom and a
sulfur atom, or a phenyl group, wherein the 5- or 6-membered
heteroaryl group and the phenyl group each optionally have 1 to 3
substituents independently selected from the group consisting of a
halogen atom, a hydroxy group, an amino group, an aminocarbonyl
group, and a C.sub.1-C.sub.6 alkyl group.
[0161] R.sup.2 is more preferably a phenyl group optionally having
1 to 3 halogen atoms, or a pyridyl group optionally having 1 to 3
halogen atoms, even more preferably a phenyl group having one
fluorine atom and one chlorine atom, or a pyridyl group having one
fluorine atom and one chlorine atom.
[0162] Ring Z is a benzene ring optionally having 1 to 4 halogen
atoms and is more preferably a benzene ring having one chlorine
atom.
[0163] R.sup.3 and R.sup.4 each independently represent a
C.sub.1-C.sub.6 alkyl group optionally having 1 to 3 substituents
independently selected from the group consisting of a halogen atom,
a hydroxy group, and an amino group. Both R.sup.3 and R.sup.4 are
more preferably the same C.sub.1-C.sub.6 alkyl groups, even more
preferably methyl groups.
[0164] In another form of R.sup.3 and R.sup.4, preferably, R.sup.3
and R.sup.4 together form a C.sub.4-C.sub.6 cycloalkyl ring
optionally having 1 to 3 C.sub.1-C.sub.6 alkyl groups on the ring,
a piperidine ring optionally having 1 to 3 C.sub.1-C.sub.6 alkyl
groups on the ring, or a tetrahydropyran ring optionally having 1
to 3 C.sub.1-C.sub.6 alkyl groups on the ring. The ring formed is
more preferably a cyclopentane ring optionally having 1 to 3
C.sub.1-C.sub.6 alkyl groups on the ring, a cyclohexane ring
optionally having 1 to 3 C.sub.1-C.sub.6 alkyl groups on the ring,
or a tetrahydropyran ring optionally having 1 to 3 C.sub.1-C.sub.6
alkyl groups on the ring, even more preferably a
4,4-dimethylcyclohexane ring.
[0165] R.sup.5 represents a C.sub.1-C.sub.6 alkoxy group, a
C.sub.3-C.sub.8 cycloalkoxy group, a C.sub.2-C.sub.6 alkenyloxy
group, a C.sub.1-C.sub.6 alkylamino group, a C.sub.3-C.sub.8
cycloalkylamino group, or a tetrahydropyranylamino group. R.sup.5
is more preferably a C.sub.1-C.sub.6 alkoxy group or a
tetrahydropyranylamino group, even more preferably a
C.sub.1-C.sub.6 alkoxy group.
[0166] R.sup.22 and R.sup.23 each independently represent a
hydrogen atom, a C.sub.1-C.sub.6 alkyl group optionally having 1 to
3 substituents independently selected from group I below, a
C.sub.1-C.sub.6 alkylsulfonyl group optionally having 1 to 3
substituents independently selected from group I below, a
C.sub.3-C.sub.6 cycloalkyl group optionally having 1 to 3
substituents independently selected from group I below, an
azetidinyl group optionally having 1 to 3 substituents
independently selected from group I below, a pyrrolidinyl group
optionally having 1 to 3 substituents independently selected from
group I below, a piperidinyl group optionally having 1 to 3
substituents independently selected from group I below, a
piperazinyl group optionally having 1 to 3 substituents
independently selected from group I below, a morpholino group
optionally having 1 to 3 substituents independently selected from
group I below, a phenyl group optionally having 1 to 3 substituents
independently selected from group I below, a pyridyl group
optionally having 1 to 3 substituents independently selected from
group I below, a pyrimidinyl group optionally having 1 to 3
substituents independently selected from group I below, a
pyridazinyl group optionally having 1 to 3 substituents
independently selected from group I below, a pyrrolyl group
optionally having 1 to 3 substituents independently selected from
group I below, a pyrazolyl group optionally having 1 to 3
substituents independently selected from group I below, an
imidazolyl group optionally having 1 to 3 substituents
independently selected from group I below, an oxazolyl group
optionally having 1 to 3 substituents independently selected from
group I below, an oxadiazolyl group optionally having 1 to 3
substituents independently selected from group I below, or a
triazolyl group optionally having 1 to 3 substituents independently
selected from group I below:
group I: a halogen atom, a hydroxy group, an oxo group, a carboxy
group, a formyl group, an amino group, an aminocarbonyl group, a
cyano group, a C.sub.1-C.sub.6 alkylamino group, a C.sub.1-C.sub.6
alkylsulfonyl group, a C.sub.1-C.sub.6 alkylsulfonylamide group, a
C.sub.1-C.sub.6 alkyl group optionally having 1 to 3 substituents
independently selected from group J below, a C.sub.1-C.sub.6 alkoxy
group optionally having 1 to 3 substituents independently selected
from group J below, a C.sub.1-C.sub.6 alkylcarbonyl group
optionally having 1 to 3 substituents independently selected from
group J below, a C.sub.3-C.sub.6 cycloalkylcarbonyl group
optionally having 1 to 3 substituents independently selected from
group J below, a C.sub.4-C.sub.6 cycloalkyl group optionally having
1 to 3 substituents independently selected from group J below, a
C.sub.1-C.sub.6 alkoxycarbonyl group optionally having 1 to 3
substituents independently selected from group J below, a
piperidinyl group optionally having 1 to 3 substituents
independently selected from group J below, a pyrrolidinyl group
optionally having 1 to 3 substituents independently selected from
group J below, a piperazinyl group optionally having 1 to 3
substituents independently selected from group J below, a phenyl
group optionally having 1 to 3 substituents independently selected
from group J below, a tetrazolyl group, an azetidinyl group
optionally having 1 to 3 substituents independently selected from
group J below, a morpholinyl group optionally having 1 to 3
substituents independently selected from group J below, a
dihydropyrazolyl group optionally having 1 to 3 substituents
independently selected from group J below, and an oxadiazolyl
group: group J: a halogen atom, a hydroxy group, an amino group, a
carboxy group, an aminocarbonyl group, a phenyl group, a
C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.6 alkylamino group, a
di-C.sub.1-C.sub.6 alkylamino group, a C.sub.1-C.sub.6
alkylcarbonyl group, a C.sub.3-C.sub.6 cycloalkyl group, a
C.sub.1-C.sub.6 alkylsulfonyl group, and a C.sub.1-C.sub.6
alkylsulfonylamide group.
[0167] R.sup.22 and R.sup.23 are, more preferably, each
independently a hydrogen atom, a methyl group, a methylsulfonyl
group, or any of the following T.sup.1 to T.sup.35:
##STR00037## ##STR00038## ##STR00039## ##STR00040## ##STR00041##
##STR00042## ##STR00043##
[0168] M is a nitrogen atom or CH and is more preferably a nitrogen
atom.
[0169] L is CH.sub.2 or C(CH.sub.3).sub.2 and is more preferably
C(CH.sub.3).sub.2.
[0170] R.sup.53 is a C.sub.1-C.sub.6 alkyl group.
[0171] In a preferred combination of the substituents in the
compound represented by the formula (I), R.sup.1 is a hydrogen
atom, R.sup.2 is a phenyl group having one fluorine atom and one
chlorine atom, and ring Z is a benzene ring having one chlorine
atom.
[0172] In a preferred combination of the substituents in the
compound represented by formula (V), R.sup.3 and R.sup.4 together
form a 4,4-dimethylcyclohexane ring, and R.sup.5 is a
C.sub.1-C.sub.6 alkoxy group.
[0173] In a preferred combination of the substituents in the
compound represented by formula (IV) or the compound represented by
formula (XIII) in the present invention, R.sup.1 is a hydrogen
atom, R.sup.2 is a phenyl group having one fluorine atom and one
chlorine atom, ring Z is a benzene ring having one chlorine atom,
R.sup.3 and R.sup.4 together form a 4,4-dimethylcyclohexane ring,
and R.sup.5 is a C.sub.1-C.sub.6 alkoxy group.
[0174] In a preferred combination of the substituents in the
compound represented by formula (XIV), R.sup.1 is a hydrogen atom,
R.sup.2 is a phenyl group having one fluorine atom and one chlorine
atom, ring Z is a benzene ring having one chlorine atom, and
R.sup.3 and R.sup.4 together form a 4,4-dimethylcyclohexane
ring.
[0175] In a preferred combination of the substituents in the
compound represented by formula (XV), R.sup.1 is a hydrogen atom,
R.sup.2 is a phenyl group having one fluorine atom and one chlorine
atom, ring Z is a benzene ring having one chlorine atom, R.sup.3
and R.sup.4 together form a 4,4-dimethylcyclohexane ring, and each
of R.sup.22 and R.sup.23 is T.sup.24 mentioned above.
[0176] In a preferred combination of the substituents in the
compound represented by formula (XIX), M is a nitrogen atom, L is
C(CH.sub.3).sub.2, and R.sup.53 is a C.sub.1-C.sub.6 alkyl
group.
[0177] In a preferred combination of the substituents in the
compound represented by formula (XX), L is C(CH.sub.3).sub.2, and
R.sup.53 is a C.sub.1-C.sub.6 alkyl group.
[0178] In a preferred combination of the substituents in the
compound represented by formula (XXI) or the compound represented
by formula (XXII), M is a nitrogen atom, and L is
C(CH.sub.3).sub.2.
[0179] Next, preferred compounds of the compound represented by
formula (VI), the compound represented by formula (VII), the
compound represented by formula (VIII), the compound represented by
formula (IX), the compound represented by formula (X), the compound
represented by formula (XI), and the compound represented by
formula (XII) will be described.
[0180] The compound represented by formula (VI) is a BINAP
derivative and is preferably a compound represented by any of the
following formulae:
##STR00044##
more preferably a compound represented by any of the following
formulae:
##STR00045##
[0181] The compound represented by formula (VII) is a MeBIOPHEP
derivative, a P-Phos derivative, or a TunePHOS derivative and is
preferably a compound represented by any of the following
formulae:
##STR00046## ##STR00047## ##STR00048##
more preferably a compound represented by any of the following
formulae:
##STR00049##
[0182] The compound represented by formula (VIII) is a JOSIPHOS
derivative, a Walphos derivative, a FESULPHOS derivative, a
Taniaphos derivative, a Jospophos derivative, or a FOXAP derivative
and is preferably a compound represented by any of the following
formulas:
##STR00050## ##STR00051## ##STR00052##
more preferably a compound represented by any of the following
formulae:
##STR00053##
[0183] The compound represented by formula (IX) is a Mandyphos
derivative and is preferably a compound represented by any of the
following formulae:
##STR00054##
[0184] The compound represented by formula (X) is a Ferrocelane
derivative and is preferably a compound represented by any of the
following formula:
##STR00055## ##STR00056##
[0185] The compound represented by formula (XI) is a PHOX
derivative and is preferably a compound represented by any of the
following formulae:
##STR00057##
[0186] The compound represented by formula (XII) is a QuinoxP
derivative and is preferably a compound represented by the
following formula:
##STR00058##
[0187] In the present invention, the Lewis acid is CuOAc, CuCl,
CuBr, CuI, CuOTf, CuPF.sub.6, CuBF.sub.4, Cu(OAc).sub.2,
Cu(OTf).sub.2, or CuSO.sub.4 and is more preferably CuOAc or
Cu(OAc).sub.2.
[0188] In the present invention, a preferred combination of the
Lewis acid and the chiral ligand is CuOAc or Cu(OAc).sub.2 as the
Lewis acid and a compound represented by any of the following
formulae as the chiral ligand:
##STR00059## ##STR00060##
[0189] In the present invention, the solvent is preferably one or
two selected from the group consisting of N,N-dimethylacetamide,
tetrahydrofuran, dimethoxyethane, 2-propanol, toluene, and ethyl
acetate, more preferably one or two selected from the group
consisting of N,N-dimethylacetamide and ethyl acetate.
Alternatively, a mixture of the solvents in an arbitrary ratio may
be used.
[0190] Next, the present invention will be described. It should be
understood that the reaction conditions of the present invention
are not limited to those described herein. In the present
invention, a functional group in a compound may be protected with
an appropriate protective group. Examples of such a functional
group can include a hydroxy group, a carboxy group, and an amino
group. For the type of protective group and conditions for the
introduction and removal of the protective group, see those
described in, for example, Protective Groups in Organic Synthesis
(T. W. Greene and P. G. M. Wuts, John Wiley & Sons, Inc., New
York, 2006).
[Production Method]
[0191] 1) Method for producing a compound represented by formula
(IV)
##STR00061##
[0192] A compound represented by formula (IV) is obtained by
reacting a compound represented by formula (I), a compound
represented by formula (II), and a compound represented by formula
(III) in the presence of an asymmetric catalyst prepared from a
Lewis acid and a chiral ligand, and a solvent. Also, the compound
represented by formula (IV) can be obtained by forming in advance a
compound represented by formula (V) (ketimine) from a compound
represented by formula (II) and a compound represented by formula
(III) and then reacting the ketimine with a compound represented by
formula (I).
[0193] The reaction is preferably carried out in the presence of a
base.
[0194] A compound represented by the formula (I) can be produced
according to various references (e.g., WO2006/091646 and
WO2012/121361).
[0195] The amount of the compound represented by formula (II) used
is in the range of 0.5 equivalents to 10 equivalents with respect
to the compound represented by formula (I) and is preferably in the
range of 1.0 equivalent to 3.0 equivalents with respect to the
compound represented by formula (I).
[0196] The amount of the compound represented by formula (III) used
is in the range of 0.5 equivalents to 10 equivalents with respect
to the compound represented by formula (I) and is preferably in the
range of 1.0 equivalent to 3.0 equivalents with respect to the
compound represented by formula (I).
[0197] Examples of the Lewis acid that can be used include a Zn(II)
Lewis acid, a Ag(I) Lewis acid, a Ni(II) Lewis acid, a Co(II) Lewis
acid, a Ru(I) Lewis acid, a Cu(I) Lewis acid, and a Cu(II) Lewis
acid. The Lewis acid is preferably CuOAc, CuCl, CuBr, CuI, CuOTf,
CuPF.sub.6, CuBF.sub.4, Cu(OAc).sub.2, Cu(OTf).sub.2, or
CuSO.sub.4.
[0198] As for the amounts of the Lewis acid and the chiral ligand
used, the ligand is preferably added in the range of 0.8 to 3.0
equivalents with respect to the Lewis acid and in the range of 0.01
to 100 mol % of the Lewis acid with respect to the compound
represented by formula (I). More preferably, the ligand is added in
the range of 1.01 to 2.4 equivalents with respect to the Lewis acid
and in the range of 0.5 to 20 mol % of the Lewis acid with respect
to the compound (I).
[0199] Examples of the chiral ligand that can be used include BINAP
derivatives, MeBIPHEP derivatives, TunePHOS derivatives, P-Phos
derivatives, JOSIPHOS derivatives, Walphos derivatives, FESULPHOS
derivatives, Taniaphos derivatives, Jospophos derivatives, FOXAP
derivatives, Mandyphos derivatives, Ferrocelane derivatives, PHOX
derivatives, and QuinoxP derivatives. The chiral ligand is
preferably a BINAP derivative, a Tunephos derivative, a MeBIPHEP
derivative, a P-Phos derivative, a JOSIPHOS derivative, a FOXAP
derivative, a FESULPHOS derivative, or the like.
[0200] The chiral ligand can be purchased from, for example,
Sigma-Aldrich Inc., Tokyo Chemical Industry Co., Ltd., Wako Pure
Chemical Industries, Ltd., or Strem Chemicals Inc.
[0201] Examples of the base that can be used include: tertiary
amines such as triethylamine and N,N-diisopropylethylamine; organic
bases such as sodium ethoxide and t-butoxy potassium; and inorganic
bases such as sodium hydroxide, sodium carbonate, sodium
bicarbonate, sodium acetate, potassium hydroxide, potassium
carbonate, potassium bicarbonate, and potassium acetate. The base
is preferably a tertiary amine such as triethylamine or
N,N-diisopropylethylamine, more preferably triethylamine.
[0202] The amount of the base used is in the range of 0.01
equivalents to 10 equivalents with respect to the compound
represented by formula (I) and is preferably in the range of 0.01
equivalents to 0.2 equivalents with respect to the compound
represented by formula (I).
[0203] Examples of the solvent include: ether solvents such as
tetrahydrofuran and 1,2-dimethoxyethane; alcohol solvents such as
methanol, ethanol, and 2-propanol; hydrocarbon solvents such as
toluene; nitrile solvents such as acetonitrile; aliphatic ester
solvents such as ethyl acetate; and amide solvents such as
N,N-dimethylacetamide and N,N-dimethylformamide. These solvents can
be used alone or as a mixture in an arbitrary ratio. Preferably,
ether solvents such as tetrahydrofuran, amide solvents such as
N,N-dimethylacetamide, and aliphatic ester solvents such as ethyl
acetate are preferably used alone or as a mixture in an arbitrary
ratio.
[0204] The amount of the solvent used is in the range of 1 to 100
times the amount of the compound (I) and is preferably in the range
of 5 to 50 times the amount of the compound represented by formula
(I), more preferably in the range of 8 to 25 times the amount of
the compound represented by formula (I).
[0205] The reaction temperature is in the range of -88.degree. C.
to the boiling point of the solvent used and is preferably in the
range of -20.degree. C. to 60.degree. C.
[0206] The reaction time is in the range of 30 minutes to 96 hours
and is preferably in the range of 30 minutes to 64 hours, more
preferably in the range of 30 minutes to 48 hours.
[0207] 2) Method for Producing a Compound Represented by Formula
(XIV)
##STR00062##
[0208] A compound represented by formula (XIV) is obtained by
hydrolyzing a compound represented by formula (IV) (provided that
R.sup.5 is not --NR.sup.51R.sup.52).
[0209] The hydrolysis can be carried out by the addition of a base
or an acid in a solvent.
[0210] Examples of the base that can be used include: organic bases
such as sodium ethoxide and t-butoxy potassium; and inorganic bases
such as sodium hydroxide, lithium hydroxide, sodium carbonate,
potassium hydroxide, and potassium carbonate. The base is
preferably an inorganic base such as sodium hydroxide, lithium
hydroxide, or potassium hydroxide, more preferably sodium
hydroxide.
[0211] The amount of the base used is in the range of 1 equivalent
to 10 equivalents with respect to the compound represented by
formula (IV) and is preferably in the range of 1 equivalent to 5
equivalents with respect to the compound represented by formula
(IV), more preferably in the range of 1 equivalent to 3 equivalents
with respect to the compound represented by formula (IV).
[0212] Examples of the acid include: hydrohalic acids such as
hydrofluoric acid, hydrochloric acid, hydrobromic acid, and
hydroiodic acid; inorganic acids such as nitric acid, perchloric
acid, sulfuric acid, and phosphoric acid; C.sub.1-C.sub.6
alkylsulfonic acids such as methanesulfonic acid,
trifluoromethanesulfonic acid, and ethanesulfonic acid;
arylsulfonic acids such as benzenesulfonic acid and
p-toluenesulfonic acid; and carboxylic acids such as acetic acid,
trifluoroacetic acid, oxalic acid, tartaric acid, and maleic acid.
The acid is preferably trifluoroacetic acid or hydrochloric
acid.
[0213] The amount of the acid used is in the range of 1 equivalent
to 100 equivalents with respect to the compound represented by
formula (IV) and is preferably in the range of 1 equivalent to 10
equivalents with respect to the compound represented by formula
(IV).
[0214] Examples of the solvent include: ether solvents such as
tetrahydrofuran and 1,2-dimethoxyethane; alcohol solvents such as
methanol, ethanol, and 2-propanol; hydrocarbon solvents such as
toluene; nitrile solvents such as acetonitrile; aliphatic ester
solvents such as ethyl acetate; amide solvents such as
N,N-dimethylacetamide and N,N-dimethylformamide; and halogen
solvents such as dichloromethane and chloroform. These solvents can
be used alone or as a mixture at an arbitrary ratio. The solvent is
preferably a halogen solvent such as dichloromethane, an alcohol
solvent such as methanol, or a mixed solvent of an ether solvent
such as tetrahydrofuran and an alcohol solvent such as
methanol.
[0215] The amount of the solvent used is in the range of 1 to 100
times the amount of the compound represented by formula (IV) and is
preferably in the range of 5 to 50 times the amount of the compound
represented by formula (IV), more preferably in the range of 8 to
25 times the amount of the compound represented by formula
(IV).
[0216] The reaction temperature is in the range of -88.degree. C.
to the boiling point of the solvent used and is preferably in the
range of -20.degree. C. to 60.degree. C.
[0217] The reaction time is in the range of 30 minutes to 96 hours
and is preferably in the range of 30 minutes to 64 hours, more
preferably in the range of 30 minutes to 48 hours.
3) Method for Producing a Compound Represented by Formula (XV)
##STR00063##
[0219] A compound represented by formula (XV) is obtained by
condensing a compound represented by formula (XIV) with an amine
NHR.sup.22R.sup.23 using a condensing agent in a solvent. The amine
can be produced according to various references (e.g.,
WO2006/091646 and WO2012/121361).
[0220] The amount of the amine used is in the range of 0.5
equivalents to 10 equivalents with respect to the compound
represented by formula (XIV) and is preferably in the range of 1.0
equivalent to 2.0 equivalents with respect to the compound
represented by formula (XIV).
[0221] Examples of the condensing agent include: azodicarboxylic
acid di-lower alkyl ester-triphenylphosphines such as
azodicarboxylic acid diethyl ester-triphenylphosphine; carbodiimide
derivatives such as N,N'-dicyclohexylcarbodiimide (DCC) and
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI);
2-halo-1-lower alkylpyridinium halides such as
2-chloro-1-methylpyridinium iodide; diarylphosphorylazides such as
diphenylphosphorylazide (DPPA); phosphoryl chlorides such as
diethylphosphoryl chloride; imidazole derivatives such as
N,N'-carbodiimidazole (CDI); benzotriazole derivatives such as
benzotriazol-1-yloxy-tris(dimethylamino)phosphonium
hexafluorophosphate (BOP),
0-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HBTU),
0-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU), and
(1H-benzotriazol-1-yloxy)tripyrrolidinophosphonium
hexafluorophosphate (PyBOP); and triazine derivatives such as
4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride
(DM-TMM). The condensing agent is preferably
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI),
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HBTU),
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU),
(1H-benzotriazol-1-yloxy)tripyrrolidinophosphonium
hexafluorophosphate (PyBOP), diphenylphosphorylazide (DPPA), or
4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride
(DM-TMM).
[0222] The amount of the condensing agent used is in the range of 1
equivalent to 10 equivalents with respect to the compound
represented by formula (XIV) and is preferably in the range of 1
equivalent to 5 equivalents with respect to the compound
represented by formula (XIV), more preferably in the range of 1
equivalent to 2 equivalents with respect to the compound
represented by formula (XIV).
[0223] Examples of the solvent that can be used include: ether
solvents such as tetrahydrofuran and 1,2-dimethoxyethane; alcohol
solvents such as methanol, ethanol, and 2-propanol; hydrocarbon
solvents such as toluene; nitrile solvents such as acetonitrile;
aliphatic ester solvents such as ethyl acetate; and amide solvents
such as N,N-dimethylacetamide and N,N-dimethylformamide. The
solvent is preferably an amide solvent such as
N,N-dimethylacetamide.
[0224] The amount of the solvent used is in the range of 1 to 100
times the amount of the compound represented by formula (XIV) and
is preferably in the range of 3 to 50 times the amount of the
compound represented by formula (XIV), more preferably in the range
of 5 to 25 times the amount of the compound represented by formula
(XIV).
[0225] The reaction temperature is in the range of -88.degree. C.
to the boiling point of the solvent used and is preferably in the
range of -20.degree. C. to 60.degree. C.
[0226] The reaction time is in the range of 30 minutes to 96 hours
and is preferably in the range of 30 minutes to 64 hours, more
preferably in the range of 30 minutes to 48 hours.
EXAMPLES
[0227] Hereinafter, the present invention will be described in more
detail with reference to Examples. However, the scope of the
present invention is not intended to be limited by them.
[0228] Abbreviations used in the Examples are as defined below. mg:
milligram, g: gram, ml: milliliter, L: liter, MHz: megahertz.
[0229] In the Examples below, nuclear magnetic resonance
(hereinafter, referred to as 1H NMR; 500 MHz) spectra were
indicated by the 8 value (ppm) of chemical shift with
tetramethylsilane as a standard. As for split patterns, s: singlet,
d: doublet, t: triplet, q: quartet, m: multiplet, and br: broad. In
the present Examples, "UHPLC" or "ultrahigh-performance liquid
chromatography" was performed using Prominence UFLC (Shimadzu
Corp.).
Example 1
Ethyl
(3'R,4'S,5'R)-6''-chloro-4'-(3-chloro-2-fluorophenyl)-2''-oxo-1'',2'-
'-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indole]-5'-carboxylat-
e
##STR00064##
[0231] To a mixture of
(3E/Z)-6-chloro-3-(3-chloro-2-fluorobenzylidene)-1,3-dihydro-2H-indol-2-o-
ne (WO2006/091646) (99.9 mg, 0.32 mmol), (R)-BINAP (12.1 mg, 0.019
mmol), and CuOAc (2.0 mg, 0.016 mmol), a solution of cyclohexanone
(50.4 .mu.L, 0.49 mmol), glycine ethyl ester (39.6 LL, 0.39 mmol)
and triethylamine (6.8 .mu.L, 0.049 mmol) in N,N-dimethylacetamide
(2.0 mL) was added under a nitrogen atmosphere, and the resulting
mixture was stirred at room temperature for 40 hours. To the
reaction mixture, ethyl acetate (2 mL), water (1 mL), and a 20%
aqueous ammonium chloride solution (1 mL) were added, and the
mixture was vigorously stirred to separate an organic layer. The
aqueous layer was subjected to extraction with ethyl acetate twice
(2 mL each), and the organic layers were all combined and then
washed with water three times (5 mL each). The organic layer
obtained was concentrated under reduced pressure. To the residue,
ethyl acetate (6 mL) and silica gel (500 mg) were added, and the
silica gel was filtered off. The filtrate was concentrated under
reduced pressure. To the residue, ethanol (1.25 mL) was added, then
water (1 mL) was added dropwise, and the mixture was stirred
overnight at room temperature. The deposited solid was filtered and
dried under reduced pressure at 40.degree. C. to obtain the title
compound (102.9 mg, yield: 65%, 91% ee) as a solid.
[0232] .sup.1H NMR (500 MHz, CDCl.sub.3): .delta.=0.91-1.60 (m,
2H), 1.17 (t, J=7.3 Hz, 3H), 1.38-1.74 (m, 6H), 1.87-2.0 (m, 1H),
2.12-2.20 (m, 1H), 3.19 (s, 1H), 4.07-4.20 (m, 2H), 4.54 (d, J=9.0
Hz, 1H), 4.84 (d, J=9.0 Hz, 1H), 6.73 (d, J=2.0 Hz, 1H), 6.83-6.89
(m, 1H), 7.05 (dd, J=8.3, 1.8 Hz, 1H), 7.10-7.16 (m, 1H), 7.36 (dd,
J=8.0, 2.0 Hz, 1H), 7.49-7.55 (m, 1H), 7.65 (s, 1H).
[0233] (Conditions for High-Performance Liquid Chromatography
(HPLC) for Optical Purity Measurement)
[0234] Column: CHIRALPAK IC 4.6.times.250 mm, 5 .mu.m
[0235] Mobile phase: 10 mM AcOH buffer:MeCN=40:60
[0236] Flow rate: 1.0 min/min
[0237] Column temperature: 40.degree. C.
[0238] Detection wavelength: 254 nm
[0239] Injection quantity: 5 .mu.L
[0240] Retention time: title compound=14.1 min, enantiomer=11.4
min
Example 2
Ethyl
(3'R,4'S,5'R)-6''-chloro-4'-(3-chloro-2-fluorophenyl)-4,4-dimethyl-2-
''-oxo-1'',2''-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indole]--
5'-carboxylate
##STR00065##
[0242] To a mixture of
(3E/Z)-6-chloro-3-(3-chloro-2-fluorobenzylidene)-1,3-dihydro-2H-indol-2-o-
ne (WO2006/091646) (98.7 mg), (R)-BINAP (12.1 mg, 0.019 mmol), and
CuOAc (2.0 mg, 0.016 mmol), a solution of 4,4-dimethlcyclohexanone
(61.4 mg, 0.48 mmol), glycine ethyl ester (39.5 LL, 0.39 mmol) and
triethylamine (6.8 .mu.L, 0.049 mmol) in N,N-dimethylacetamide (2.0
mL) was added under a nitrogen atmosphere, and the resulting
mixture was stirred at room temperature for 22 hours. To the
reaction mixture, ethyl acetate (2 mL), water (1 mL), and a 20%
aqueous ammonium chloride solution (1 mL) were added, and the
mixture was vigorously stirred to separate an organic layer. The
aqueous layer was subjected to extraction with ethyl acetate twice
(2 mL each), and the organic layers were all combined and then
washed with water three times (5 mL each). The organic layer
obtained was concentrated under reduced pressure. To the residue,
ethyl acetate (6 mL) and silica gel (500 mg) were added, and the
silica gel was filtered off. The filtrate was concentrated under
reduced pressure. To the residue, ethanol (1.0 mL) was added, then
water (1 mL) was added dropwise, and the mixture was stirred
overnight at room temperature. The deposited solid was filtered and
dried under reduced pressure at 40.degree. C. to obtain the title
compound (137 mg, yield: 82%, 94% ee) as a solid.
[0243] .sup.1H NMR (500 MHz, CDCl.sub.3): .delta.=0.67 (s, 3H),
0.91 (s, 3H), 1.10-1.19 (m, 2H), 1.17 (t, J=7.3 Hz, 3H), 1.25-1.33
(m, 1H), 1.44-1.72 (m, 3H), 1.87-2.01 (m, 1H), 3.16 (s, 1H),
4.07-4.21 (m, 2H), 4.52 (d, J=8.5 Hz, 1H), 4.83 (d, J=8.5 Hz, 1H),
6.74 (d, J=1.5 Hz, 1H), 6.81-6.86 (m, 1H), 7.06 (dd, J=8.3, 2.8 Hz,
1H), 7.10-7.16 (m, 1H), 7.37 (dd, J=8.3, 1.8 Hz, 1H), 7.48-7.54 (m,
1H), 7.81 (s, 1H).
[0244] (Conditions for HPLC for Optical Purity Measurement)
[0245] Column: CHIRALPAK OD-3R 4.6.times.150 mm, 3 .mu.m
[0246] Mobile phase: 10 mM phosphate buffer:MeCN=40:60
[0247] Flow rate: 1.0 min/min
[0248] Column temperature: 40.degree. C.
[0249] Detection wavelength: 254 nm
[0250] Injection quantity: 5 .mu.L
[0251] Retention time: title compound=13.8 min, enantiomer=12.9
min
Example 3
Ethyl
(3'R,4'S,5'R)-6''-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-2''-oxo--
1'',2''-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indole]-5'-carb-
oxylate
##STR00066##
[0253] To a mixture of
(3E/Z)-6-chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methylene]-1,3-dihydro--
2H-indol-2-one (WO2012/121361) (99.2 mg), (R)-BINAP (12.1 mg, 0.019
mmol), and CuOAc (2.0 mg, 0.016 mmol), a solution of cyclohexanone
(50.4 .mu.L, 0.49 mmol), glycine ethyl ester (39.6 .mu.L, 0.39
mmol), and triethylamine (6.8 .mu.L, 0.049 mmol) in
N,N-dimethylacetamide (2.0 mL) was added under a nitrogen
atmosphere, and the resulting mixture was stirred at 0.degree. C.
for 18 hours. To the reaction mixture, ethyl acetate (2 mL), water
(1 mL), and a 20% aqueous ammonium chloride solution (1 mL) were
added, and the mixture was vigorously stirred to separate an
organic layer. The aqueous layer was subjected to extraction with
ethyl acetate twice (2 mL each), and the organic layers were all
combined and then washed with water three times (5 mL each). The
organic layer obtained was concentrated under reduced pressure, and
the residue was purified by silica gel chromatography
[heptane:ethyl acetate=1:1 (v/v)]. To the residue obtained, ethanol
(1.0 mL) was added, then water (1 mL) was added dropwise, and the
mixture was stirred overnight at room temperature. The deposited
solid was filtered and dried under reduced pressure at 40.degree.
C. to obtain the title compound (101.2 mg, yield: 64%, 99% ee) as a
solid.
[0254] .sup.1H NMR (500 MHz, CDCl.sub.3): .delta.=0.9-1.1 (m, 2H),
1.19 (t, J=7.3 Hz, 3H), 1.44 (td, J=12.9, 3.2 Hz, 1H) m, 1.48-1.70
(m, 1H), 3.2 (s, 1H), 4.12-4.20 (m, 2H), 4.53 (d, J=9.0 Hz, 1H),
4.82 (d, J=10.0 Hz, 1H), 6.77 (d, J=2.0 Hz, 1H), 7.07 (dd, J=8.0,
1.5 Hz, 1H), 7.34 (dd, J=8.3, 1.8 Hz, 1H), 7.5-7.56 (m, 1H), 7.59
(s, 1H), 8.06 (d, J=5.0 Hz, 1H).
[0255] (Conditions for HPLC for Optical Purity Measurement)
[0256] Column: CHIRALPAK OD-3R 4.6.times.150 mm, 3 .mu.m
[0257] Mobile phase: 10 mM phosphate buffer:MeCN=40:60
[0258] Flow rate: 1.0 min/min
[0259] Column temperature: 40.degree. C.
[0260] Detection wavelength: 254 nm
[0261] Injection quantity: 5 .mu.L
[0262] Retention time: title compound=7.7 min, enantiomer=8.7
min
Example 4
Ethyl
(3'R,4'S,5'R)-6''-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dime-
thyl-2''-oxo-1'',2''-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-in-
dole]-5'-carboxylate
##STR00067##
[0264] To a mixture of
(3E/Z)-6-chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methylene]-1,3-dihydro--
2H-indol-2-one (WO2012/121361) (100.7 mg), (R)-BINAP (12.1 mg,
0.019 mmol), and CuOAc (2.0 mg, 0.016 mmol), a solution of
4,4-dimethylcyclohexanone (61.4 mg, 0.48 mmol), glycine ethyl ester
(39.5 .mu.L, 0.39 mmol), and triethylamine (6.8 .mu.L, 0.049 mmol)
in N,N-dimethylacetamide (2.0 mL) was added under a nitrogen
atmosphere, and the resulting mixture was stirred at 0.degree. C.
for 14 hours. To the reaction mixture, ethyl acetate (2 mL), water
(1 mL), and a 20% aqueous ammonium chloride solution (1 mL) were
added, and the mixture was vigorously stirred to separate an
organic layer. The aqueous layer was subjected to extraction with
ethyl acetate twice (2 mL each), and the organic layers were all
combined and then washed with water three times (5 mL each). The
organic layer obtained was concentrated under reduced pressure. To
the residue, ethyl acetate (6 mL) and silica gel (500 mg) were
added, and the silica gel was filtered off. The filtrate was
concentrated under reduced pressure. To the residue, ethanol (1.0
mL) was added, then water (1 mL) was added dropwise, and the
mixture was stirred overnight at room temperature. The deposited
solid was filtered and dried under reduced pressure at 40.degree.
C. to obtain the title compound (134.9 mg, yield: 80%, 99% ee) as a
solid.
[0265] 1H NMR (500 MHz, CDCl.sub.3): .delta.=0.67 (s, 3H), 0.91 (s,
3H), 1.11-1.21 (m, 2H), 1.19 (t, J=7.0 Hz, 3H), 1.24-1.34 (m, 1H),
1.43-1.58 (m, 2H), 1.60-1.72 (m, 1H), 1.85-1.95 (m, 1H), 3.19 (s,
1H), 4.10-4.21 (m, 2H), 4.51 (d, J=9.0 Hz, 1H), 4.82 (d, J=9.5 Hz,
1H), 6.77 (d, J=2.0 Hz, 1H), 7.07 (dd, J=8.5, 1.5 Hz, 1H), 7.36
(dd, J=8.3, 1.8 Hz, 1H), 7.5-7.55 (m, 1H), 7.68 (bs, 1H), 8.05 (d,
J=5.5 Hz, 1H).
[0266] (Conditions for HPLC for Optical Purity Measurement)
[0267] Column: CHIRALPAK OD-3R 4.6.times.150 mm, 3 .mu.m
[0268] Mobile phase: 10 mM phosphate buffer:MeCN=40:60
[0269] Flow rate: 1.0 min/min
[0270] Column temperature: 40.degree. C.
[0271] Detection wavelength: 254 nm
[0272] Injection quantity: 5 .mu.L
[0273] Retention time: title compound=9.4 min, enantiomer=10.5
min
Example 5
Ethyl
(3'R,4'S,5'R)-6-chloro-4'-(3-chloro-2-fluorophenyl)-3',3'-dimethyl-2-
-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-carboxylate
##STR00068##
[0275] To a mixture of
(3E/Z)-6-chloro-3-(3-chloro-2-fluorobenzylidene)-1,3-dihydro-2H-indol-2-o-
ne (WO2006/091646) (50.8 mg, 0.16 mmol), (R)-BINAP (6.1 mg, 0.01
mmol), and CuOAc (1.0 mg, 0.008 mmol), a solution of acetone (23.8
.mu.L, 0.32 mmol), glycine ethyl ester (26.4 LL, 0.26 mmol), and
triethylamine (3.4 LL, 0.024 mmol) in N,N-dimethylacetamide (1.0
mL) was added under a nitrogen atmosphere, and the resulting
mixture was stirred at 0.degree. C. for 42 hours. To the reaction
mixture, ethyl acetate (1 mL), water (0.5 mL), and a 20% aqueous
ammonium chloride solution (0.5 mL) were added, and the mixture was
vigorously stirred to separate an organic layer. The aqueous layer
was subjected to extraction with ethyl acetate twice (1 mL each),
and the organic layers were all combined and then washed with water
three times (2.5 mL each). The organic layer obtained was
concentrated under reduced pressure, and the residue was purified
by silica gel chromatography [heptane:ethyl
acetate:triethylamine=50:50:1 (v/v)] and dried under reduced
pressure at 40.degree. C. to obtain a mixture of the title compound
and diastereomers (66.8 mg, yield: 90%, diastereomer ratio: 84
(title compound):13:3, optical purity of the title compound: 92%
ee) as an oil compound.
[0276] .sup.1H NMR (500 MHz, CDCl.sub.3): .delta.=1.07 (s, 3H),
1.17 (t, J=7.0 Hz, 3H), 1.48 (s, 3H), 3.40-3.62 (m, 1H), 4.07-4.23
(m, 2H), 4.55 (d, J=9.0 Hz, 1H), 4.91 (d, J=9.5 Hz, 1H), 6.75-6.80
(m, 1H), 6.80 (d, J=1.5 Hz, 1H), 7.06 (dd, J=8.0, 2.0 Hz, 1H),
7.09-7.15 (m, 1H), 7.38 (dd, J=8.3, 2.3 Hz, 1H), 7.45-7.50 (m, 1H),
8.62 (s, 1H).
[0277] (Conditions for HPLC for Optical Purity Measurement)
[0278] Column: CHIRALPAK IC 4.6.times.250 mm, 5 .mu.m
[0279] Mobile phase: 0.1% HCOOH aq.:MeCN=70:30
[0280] Flow rate: 1.0 min/min
[0281] Column temperature: 27.degree. C.
[0282] Detection wavelength: 254 nm
[0283] Injection quantity: 5 .mu.L
[0284] Retention time: title compound=10.3 min, enantiomer=11.1
min
Example 6
Ethyl
(3'R,4'S,5'R)-6-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-2-oxo-1,2--
dihydrodispiro[indole-3,3'-pyrrolidine-2',4''-pyran]-5'-carboxylate
##STR00069##
[0286] To a mixture of
(3E/Z)-6-chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methylene]-1,3-dihydro--
2H-indol-2-one (WO2012/121361) (48.7 mg, 0.16 mmol), (R)-BINAP (6.1
mg, 0.01 mmol), and CuOAc (1.0 mg, 0.008 mmol), a solution of
tetrahydro-4H-pyran-4-one (22.4 .mu.L, 0.24 mmol), glycine ethyl
ester (20 .mu.L, 0.20 mmol), and triethylamine (3.4 LL, 0.024 mmol)
in N,N-dimethylacetamide (1.0 mL) was added under a nitrogen
atmosphere, and the resulting mixture was stirred at 0.degree. C.
for 42 hours. To the reaction mixture, ethyl acetate (1 mL), water
(0.5 mL), and a 20% aqueous ammonium chloride solution (0.5 mL)
were added, and the mixture was vigorously stirred to separate an
organic layer. The aqueous layer was subjected to extraction with
ethyl acetate twice (1 mL each), and the organic layers were all
combined and then washed with water three times (2.5 mL each). The
organic layer obtained was concentrated under reduced pressure, and
the residue was purified by silica gel chromatography
[heptane:ethyl acetate:triethylamine=50:50:1 (v/v)] and dried under
reduced pressure at 40.degree. C. to obtain a mixture of the title
compound and diastereomers (74.9 mg, yield: 96%, diastereomer
ratio: 75 (title compound):20:5, optical purity of the title
compound: 98% ee) as an oil compound.
[0287] .sup.1H NMR (500 MHz, CDCl.sub.3): .delta.=1.19 (t, J=7.3
Hz, 3H), 1.31-1.41 (m, 1H), 1.42-1.50 (m, 1H), 1.85-1.98 (m, 2H),
3.18-3.38 (m, 1H), 3.67-3.77 (m, 2H), 3.84-3.92 (m, 1H), 3.88-4.06
(m, 1H), 4.08-4.20 (m, 2H), 4.56 (d, J=9.5 Hz, 1H), 4.78 (d, J=9.5
Hz, 1H), 6.79 (d, J=2.5 Hz, 1H), 7.08 (dd, J=8.3, 1.8 Hz, 1H), 7.34
(dd, J=8.3, 2.3 Hz, 1H), 7.49-7.54 (m, 1H), 8.06 (d, J=5.0 Hz, 1H),
8.43 (s, 1H).
[0288] (Conditions for HPLC for optical purity measurement)
[0289] Column: CHIRALPAK IC 4.6.times.250 mm, 5 .mu.m
[0290] Mobile phase: 10 mM AcOH buffer:MeCN=40:60
[0291] Flow rate: 1.0 min/min
[0292] Column temperature: 27.degree. C.
[0293] Detection wavelength: 220 nm
[0294] Injection quantity: 5 .mu.L
[0295] Retention time: title compound=26.2 min, enantiomer=22.8
min
Example 7
Ethyl
(3'R,4'S,5'R)-6-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-3',3'-dime-
thyl-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-carboxylate
##STR00070##
[0297] To a mixture of
(3E/Z)-6-chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methylene]-1,3-dihydro--
2H-indol-2-one (WO2012/121361) (51 mg, 0.16 mmol), (R)-BINAP (6.1
mg, 0.01 mmol), and CuOAc (1.0 mg, 0.008 mmol), a solution of
acetone (17.8 .mu.L, 0.24 mmol), glycine ethyl ester (20 .mu.L,
0.20 mmol), and triethylamine (3.4 .mu.L, 0.024 mmol) in
N,N-dimethylacetamide (1.0 mL) was added under a nitrogen
atmosphere, and the resulting mixture was stirred at 0.degree. C.
for 42 hours. To the reaction mixture, ethyl acetate (1 mL), water
(0.5 mL), and a 20% aqueous ammonium chloride solution (0.5 mL)
were added, and the mixture was vigorously stirred to separate an
organic layer. The aqueous layer was subjected to extraction with
ethyl acetate twice (1 mL each), and the organic layers were all
combined and then washed with water three times (2.5 mL each). The
organic layer obtained was concentrated under reduced pressure, and
the residue was purified by silica gel chromatography
[heptane:ethyl acetate:triethylamine=50:50:1 (v/v)] and dried under
reduced pressure at 40.degree. C. to obtain a mixture of the title
compound and diastereomers (68.9 mg, yield: 92%, diastereomer
ratio: 87 (title compound):13, optical purity of the title
compound: 98% ee) as an oil compound.
[0298] 1H NMR (500 MHz, CDCl.sub.3): .delta.=1.08 (s, 3H), 1.20 (t,
J=7.0 Hz, 3H), 1.46 (s, 3H), 3.40-3.65 (m, 1H), 4.09-4.26 (m, 2H),
4.54 (d, J=9.5 Hz, 1H), 4.89 (d, J=9.0 Hz, 1H), 6.79 (d, J=1.5 Hz,
1H), 7.07 (dd, J=8.5, 2.0 Hz, 1H), 7.36 (dd, J=8.0, 1.5 Hz, 1H),
7.49-7.55 (m, 1H), 7.86 (s, 1H), 8.07 (d, J=5.0 Hz, 1H).
[0299] (Conditions for HPLC for Optical Purity Measurement)
[0300] Column: CHIRALPAK AS-RH 4.6.times.150 mm, 5 .mu.m
[0301] Mobile phase: 10 mM AcOH buffer:MeCN=60:40
[0302] Flow rate: 1.0 min/min
[0303] Column temperature: 40.degree. C.
[0304] Detection wavelength: 254 nm
[0305] Injection quantity: 5 .mu.L
[0306] Retention time: title compound=8.4 min, enantiomer=7.1
min
Example 8
Ethyl
(3'R,4'S,5'R)-6''-chloro-4'-(3-chloro-2-fluorophenyl)-2''-oxo-1'',2'-
'-dihydrodispiro[cyclopentane-1,2'-pyrrolidine-3',3''-indole]-5'-carboxyla-
te
##STR00071##
[0308] To a mixture of
(3E/Z)-6-chloro-3-(3-chloro-2-fluorobenzylidene)-1,3-dihydro-2H-indol-2-o-
ne (WO2006/091646) (52.1 mg, 0.17 mmol), (R)-BINAP (6.1 mg, 0.01
mmol), and CuOAc (1.0 mg, 0.008 mmol), a solution of cyclopentanone
(28.7 .mu.L, 0.32 mmol), glycine ethyl ester (26.4 LL, 0.26 mmol),
and triethylamine (3.4 .mu.L, 0.024 mmol) in N,N-dimethylacetamide
(1.0 mL) was added under a nitrogen atmosphere, and the resulting
mixture was stirred at 0.degree. C. for 42 hours. To the reaction
mixture, ethyl acetate (1 mL), water (0.5 mL), and a 20% aqueous
ammonium chloride solution (0.5 mL) were added, and the mixture was
vigorously stirred to separate an organic layer. The aqueous layer
was subjected to extraction with ethyl acetate twice (1 mL each),
and the organic layers were all combined and then washed with water
three times (2.5 mL each). The organic layer obtained was
concentrated under reduced pressure, and the residue was purified
by silica gel chromatography [heptane:ethyl
acetate:triethylamine=100:50:1.5 (v/v)] and dried under reduced
pressure at 40.degree. C. to obtain a mixture of the title compound
and diastereomers (69 mg, yield: 86%, diastereomer ratio: 84 (title
compound):14:2, optical purity of the title compound: 99% ee) as an
oil compound.
[0309] 1H NMR (500 MHz, CDCl.sub.3): .delta.=1.17 (t, J=7.3 Hz,
3H), 1.22-1.30 (m, 1H), 1.32-1.42 (m, 1H), 1.50-1.60 (m, 2H),
1.66-1.83 (m, 2H), 1.86-1.97 (m, 1H), 2.07-2.15 (m, 1H), 3.25-3.64
(m, 1H), 4.07-4.23 (m, 2H), 4.53 (d, J=9.5 Hz, 1H), 4.76 (d, J=9.0
Hz, 1H), 6.72-6.77 (m, 1H), 6.80 (d, J=2.0 Hz, 1H), 7.06 (dd,
J=8.0, 1.5 Hz, 1H), 7.08-7.13 (m, 1H), 7.38 (dd, J=8.0, 2.0 Hz,
1H), 7.43-7.50 (m, 1H), 8.68 (s, 1H).
[0310] (Conditions for HPLC for Optical Purity Measurement)
[0311] Column: CHIRALPAK IC 4.6.times.250 mm, 5 .mu.m
[0312] Mobile phase: 0.1% HCOOH aq.:MeCN=50:50
[0313] Flow rate: 1.0 min/min
[0314] Column temperature: 27.degree. C.
[0315] Detection wavelength: 220 nm
[0316] Injection quantity: 5 .mu.L
[0317] Retention time: title compound=6.0 min, enantiomer=5.6
min
Example 9
Ethyl
(3'R,4'S,5'R)-6''-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-2''-oxo--
1'',2''-dihydrodispiro[cyclopentane-1,2'-pyrrolidine-3',3''-indole]-5'-car-
boxylate
##STR00072##
[0319] To a mixture of
(3E/Z)-6-chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methylene]-1,3-dihydro--
2H-indol-2-one (WO2012/121361) (50.9 mg, 0.16 mmol), (R)-BINAP (6.1
mg, 0.01 mmol), and CuOAc (1.0 mg, 0.008 mmol), a solution of
cyclopentanone (21.6 .mu.L, 0.24 mmol), glycine ethyl ester (20
.mu.L, 0.20 mmol), and triethylamine (3.4 LL, 0.024 mmol) in
N,N-dimethylacetamide (1.0 mL) was added under a nitrogen
atmosphere, and the resulting mixture was stirred at 0.degree. C.
for 42 hours. To the reaction mixture, ethyl acetate (1 mL), water
(0.5 mL), and a 20% aqueous ammonium chloride solution (0.5 mL)
were added, and the mixture was vigorously stirred to separate an
organic layer. The aqueous layer was subjected to extraction with
ethyl acetate twice (1 mL each), and the organic layers were all
combined and then washed with water three times (2.5 mL each). The
organic layer obtained was concentrated under reduced pressure, and
the residue was purified by silica gel chromatography
[heptane:ethyl acetate:triethylamine=50:50:1 (v/v)] and dried under
reduced pressure at 40.degree. C. to obtain a mixture of the title
compound and diastereomers (69.1 mg, yield: 88%, diastereomer
ratio: 87 (title compound):13, optical purity of the title
compound: 98% ee) as an oil compound.
[0320] 1H NMR (500 MHz, CDCl.sub.3): .delta.=1.19 (t, J=7.3 Hz,
3H), 1.22-1.30 (m, 1H), 1.32-1.43 (m, 1H), 1.48-1.60 (m, 2H),
1.66-1.82 (m, 2H), 1.86-1.96 (m, 1H), 2.02-2.09 (m, 1H), 3.40-3.62
(m, 1H), 4.08-4.24 (m, 2H), 4.53 (d, J=9.0 Hz, 1H), 4.73 (d, J=9.0
Hz, 1H), 6.82 (d, J=1.5 Hz, 1H), 7.07 (dd, J=8.3, 1.8 Hz, 1H), 7.36
(dd, J=8.3, 2.3 Hz, 1H), 7.50-7.54 (m, 1H), 8.04 (d, J=5.5 Hz, 1H),
8.60 (s, 1H).
[0321] (Conditions for HPLC for Optical Purity Measurement)
[0322] Column: CHIRALPAK IC 4.6.times.250 mm, 5 .mu.m
[0323] Mobile phase: 0.1% HCOOH aq.:MeCN=50:50
[0324] Flow rate: 1.0 min/min
[0325] Column temperature: 27.degree. C.
[0326] Detection wavelength: 220 nm
[0327] Injection quantity: 5 .mu.L
[0328] Retention time: title compound=6.7 min, enantiomer=13.3
min
Example 10
(3'R,4'S,5'R)--N-[(3R,6S)-6-Carbamoyltetrahydro-2H-pyran-3-yl]-6''-chloro--
4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2''-oxo-1'',2''-dihydrodis-
piro[cyclohexane-1,2'-pyrrolidine-3',3''-indole]-5'-carboxamide
##STR00073##
[0329] Step 1
(4'S,5'R)-6''-Chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2''-o-
xo-1'',2''-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indole]-5'-c-
arboxylic Acid
[0330] To a solution of the compound (5.00 g, 9.61 mmol) obtained
in Example 4 in methanol (25 mL) and tetrahydrofuran (25 mL), a 1 N
aqueous sodium hydroxide solution (18.3 mL, 18.3 mmol) was added
under ice cooling, and the mixture was stirred at 0.degree. C. for
41.5 hours. The reaction mixture was neutralized to pH 3 by the
addition of concentrated hydrochloric acid under ice cooling. Water
(75 mL) was added dropwise thereto, and the mixture was then
stirred at room temperature for 4 hours. The deposited solid was
filtered at 0.degree. C. and dried under reduced pressure at
40.degree. C. to obtain the title compound (4.52 g, yield: 96%) as
a solid.
Step 2
(3'R,4'S,5'R)--N-[(3R,6S)-6-Carbamoyltetrahydro-2H-pyran-3-yl]-6''-chloro--
4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2''-oxo-1'',2''-dihydrodis-
piro[cyclohexane-1,2'-pyrrolidine-3',3''-indole]-5'-carboxamide
[0331] To a solution of the compound (2.00 g, 4.06 mmol) obtained
in the preceding step 1 in N,N-dimethylacetamide (20 mL),
1-hydroxybenzotriazole monohydrate (310 mg, 2.02 mmol),
(2S,5R)-5-aminotetrahydro-2H-pyran-2-carboxamide (WO2012/121361)
(707 mg, 4.90 mmol), diisopropylethylamine (850 LL, 4.88 mmol), and
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (934
mg, 4.87 mmol) were added, and the mixture was stirred at 0.degree.
C. for 47.5 hours. To the reaction mixture, ethyl acetate (20 mL)
and water (10 mL) were added, and the mixture was stirred to
separate an organic layer. The aqueous layer was subjected to
extraction with ethyl acetate twice (20 mL each), and the organic
layers were all combined and then washed with water three times (20
mL each). The solvent was distilled off under reduced pressure. To
the residue, acetonitrile (30 mL) was then added, and the mixture
was stirred at 60.degree. C. for 2 hours. The reaction mixture was
allowed to cool, and the deposited solid was then filtered and
dried under reduced pressure at 40.degree. C. to obtain the title
compound (2.13 g, yield: 80%) as a solid.
Example 11
11-1) Influence of Various Asymmetric Catalysts
##STR00074##
[0333] To a solution of
(3E/Z)-6-chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methylene]-1,3-dihydro--
2H-indol-2-one (WO2012/121361), 4,4-dimethylcyclohexanone (1.5
eq.), glycine ethyl ester (1.2 eq.), and triethylamine (15 mol %)
in THF (10-fold amount), a catalyst solution separately prepared by
stirring a Lewis acid (5 mol %), a chiral ligand (6 mol %), and THF
(10-fold amount) for 1 hour under a nitrogen atmosphere was added
under a nitrogen atmosphere, and the mixture was stirred at room
temperature for 12 to 16 hours. Then, the optical purity and HPLC
yield of the obtained trans-1 compound ((ethyl
(3'S,4'R,5'S)-6''-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl--
2''-oxo-1'',2''-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indole]-
-5'-carboxylate) were measured by HPLC.
[0334] (Conditions for HPLC for Optical Purity Measurement)
[0335] Column: CHIRALPAK OD-3R 4.6.times.150 mm, 3 .mu.m
[0336] Mobile phase: 10 mM phosphate buffer:MeCN=40:60
[0337] Flow rate: 1.0 min/min
[0338] Column temperature: 40.degree. C.
[0339] Detection wavelength: 254 nm
[0340] Injection quantity: 5 .mu.L
[0341] Retention time: title compound=13.8 min, enantiomer=12.9
min
[0342] Main results are shown in Table 1
TABLE-US-00001 TABLE 1 Lewis acid AgOAc Cu(OTf).sub.2 CuOAc ee %
No. Ligand (ee %) (ee %) (yield %) 1 ##STR00075## 31.9 34.1 88.0
(76.8) 2 ##STR00076## 34.9 36.6 88.8 (76.3) 3 ##STR00077## 32.1
18.7 76.2 4 ##STR00078## 19.1 45.8 72.6 5 ##STR00079## 51.6 29.4
89.0 (74.2) 6 ##STR00080## 26.0 27.9 72.5 7 ##STR00081## 48.9 --
86.9 (76.3) 8 ##STR00082## 32.9 -- 43.9
11-2) Influence of Various Solvents
##STR00083##
[0344] To
(3E/Z)-6-chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methylene]-1,3-
-dihydro-2H-indol-2-one (WO2012/121361), 4,4-dimethylcyclohexanone
(1.5 eq.), glycine ethyl ester (1.2 eq.), triethylamine (15 mol %),
and a solvent (10-fold amount), a catalyst solution separately
prepared by stirring CuOAc (5 mol %), (S)-BINAP (6 mol %), and a
solvent (10-fold amount) for 1 hour under a nitrogen atmosphere was
added under a nitrogen atmosphere, and the mixture was stirred at
room temperature for 21.5 hours. Then, the HPLC yield and optical
purity of the obtained trans-2 compound (ethyl
(3'S,4'R,5'S)-6''-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl--
2''-oxo-1'',2''-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indole]-
-5'-carboxylate) were measured by HPLC.
[0345] Main results are shown in Table 2.
TABLE-US-00002 TABLE 2 No. Solvent HPLC yield (%) ee (%) trans/cis
1 THF 78.7 91.3 92/8 2 MeOH -- 66.2 84/16 3 EtOH -- 72.8 86/14 4
IPA -- 83.8 85/15 5 toluene -- 87.5 9/1 6 MeCN -- 56.4 86/14 7 DMAc
85.2 97.1 94/6 8 DME 85.5 93.4 93/7 9 AcOEt -- 88.7 92/8
11-3) Study on Cu(I) Lewis Acid
##STR00084##
[0347] To
(3E/Z)-6-chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methylene]-1,3-
-dihydro-2H-indol-2-one (WO2012/121361), 4,4-dimethylcyclohexanone
(1.5 eq.), glycine ethyl ester (1.2 eq.), triethylamine (15 mol %),
and N,N-dimethylacetamide (10-fold amount), a catalyst solution
separately prepared by stirring Cu(I) Lewis acid (5 mol %),
(S)-BINAP (6 mol %), and N,N-dimethylacetamide (10-fold amount) for
1 hour under a nitrogen atmosphere was added under a nitrogen
atmosphere, and the mixture was stirred at room temperature for 17
to 21.5 hours. Then, the HPLC yield and optical purity of the
obtained trans-2 compound (ethyl
(3'S,4'R,5'S)-6''-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl--
2''-oxo-1'',2''-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indole]-
-5'-carboxylate) were measured by HPLC.
[0348] Main results are shown in Table 3.
TABLE-US-00003 TABLE 3 No. Lewis Acid HPLC yield (%) ee (%)
trans/cis 1 CuOAc 85.2 97.1 94/6 2 CuCl 38.2 52.8 87/13 3 CuBr 55.9
76.4 92/8 4 CuI 72.9 89 94/6 5 Cu.sub.2O 25.4 23.5 83/17 6
(CuOTf).sub.2 toluene 84.1 95 93/7 7 Cu(CH.sub.3CN).sub.4PF.sub.6
88.6 95.9 95/5 8 Cu(CH.sub.3CN).sub.4BF.sub.4 89.1 95.8 94/6
11-4) Study on Cu(II) Lewis Acid
##STR00085##
[0350]
(3E/Z)-6-Chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methylene]-1,3-di-
hydro-2H-indol-2-one (WO2012/121361), 4,4-dimethylcyclohexanone
(1.5 eq.), glycine ethyl ester (1.2 eq.), Cu(II) Lewis acid (5 mol
%), (R)-BINAP (6 mol %), and N,N-dimethylacetamide (20-fold amount)
were stirred at room temperature for 15 hours under a nitrogen
atmosphere. Then, the UPLC yield and optical purity of the obtained
trans-2 compound (ethyl
(3'R,4'S,5'R)-6''-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl--
2''-oxo-1'',2''-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indole]-
-5'-carboxylate) were measured by UPLC and HPLC, respectively.
[0351] Main results are shown in Table 4.
TABLE-US-00004 TABLE 4 No. Lewis Acid HPLC yield (%) ee (%)
trans/cis 1 Cu(OAc).sub.2.cndot.H.sub.2O 79.4 97.1 95/5 2
Cu(OTf).sub.2 58.5 88.5 92/8 3 CuSO.sub.4.cndot.5H.sub.2O 53.4 83.1
92/8 4 CuO 14.3 -13.3 49/51 5 CuCl.sub.2 17.8 -6.7 72/28 6
CuBr.sub.2 19.0 -3.3 74/26 7
CuCO.sub.3.cndot.Cu(OH).sub.2.cndot.H.sub.2O 13.8 -15.8 74/26 *
Sign "-" in the column "ee" indicates that the trans-2 compound
(ethyl
(3'S,4'R,5'S)-6''-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl--
2''-oxo-1'',2''-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indole]-
-5'-carboxylate) was a main product.
11-5) Study Using CuOAc and Various Chiral Ligands
##STR00086##
[0353] To a solution of
(3E/Z)-6-chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methylene]-1,3-dihydro--
2H-indol-2-one (WO2012/121361), 4,4-dimethylcyclohexanone (1.5
eq.), glycine ethyl ester (1.2 eq.), and triethylamine (15 mol %)
in THF (10-fold amount), a catalyst solution separately prepared by
stirring CuOAc (5 mol %), a chiral ligand (6 mol %), and THF
(10-fold amount) for 1 hour under a nitrogen atmosphere was added
under a nitrogen atmosphere, and the mixture was stirred at room
temperature for 12 to 16 hours. Then, the yield and optical purity
of the obtained trans-1 compound (ethyl
(3'S,4'R,5'S)-6''-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl--
2''-oxo-1'',2''-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indole]-
-5'-carboxylate) were measured by HPLC.
[0354] Main results are shown in Table 5.
TABLE-US-00005 TABLE 5 No. Ligand ee % Yield % 1 ##STR00087## 88.0
76.8 2 ##STR00088## 88.8 76.3 3 ##STR00089## 76.2 -- 4 ##STR00090##
72.6 -- 5 ##STR00091## 89.0 74.2 6 ##STR00092## 72.5 -- 7
##STR00093## 91.4 79.2 8 ##STR00094## 90.2 76.9 9 ##STR00095## 76.1
-- 10 ##STR00096## 59.9 -- 11 ##STR00097## 51.4 -- 12 ##STR00098##
91.9 78.0 13 ##STR00099## -54.1 -- 14 ##STR00100## 53.0 -- 15
##STR00101## 86.9 76.3 16 ##STR00102## -85.9 71.0 17 ##STR00103##
-94.6 73.7 18 ##STR00104## -86.2 75.5 *: Sign "--" in the column
"ee" indicates that the trans-2 compound (ethyl
(3'S,4'R,5'S)-6''-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl--
2''-oxo-1'',2''-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indole]-
-5'-carboxylate) was a main product.
Example 12
tert-Butyl
(3'R,4'S,5'R)-6''-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-
-dimethyl-2''-oxo-1'',2''-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3-
''-indole]-5'-carboxylate
##STR00105##
[0356] To a mixture of
(3E/Z)-6-chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methylene]-1,3-dihydro--
2H-indol-2-one (WO2012/121361) (50.0 mg, 0.16 mmol), (R)-BINAP (6.0
mg, 0.009 mmol), and CuOAc (1.0 mg, 0.008 mmol), a solution of
4,4-dimethylcyclohexanone (31.0 mg, 0.25 mmol), glycine tert-butyl
ester (27.8 mg, 0.21 mmol), and triethylamine (3.4 .mu.l, 0.024
mmol) in N,N-dimethylacetamide (1.0 ml) was added under a nitrogen
atmosphere, and the resulting mixture was stirred at 0.degree. C.
for 19.5 hours. To the reaction mixture, ethyl acetate (2.0 ml),
water (0.5 ml), and a 20% aqueous ammonium chloride solution (0.5
ml) were added, and the mixture was vigorously stirred to separate
an organic layer. The aqueous layer was subjected to extraction
with ethyl acetate twice (2.0 ml each), and the organic layers were
all combined and then washed with water three times (2.0 ml each).
The organic layer obtained was concentrated under reduced pressure,
and the residue was purified by silica gel chromatography
[heptane:ethyl acetate:triethylamine=50:50:1 (v/v)] and dried under
reduced pressure at 40.degree. C. to obtain a mixture of the title
compound and a diastereomer (61.0 mg, yield: 69%, diastereomer
ratio: 90 (title compound):10, optical purity of the title
compound: 97% ee) as an oil compound.
[0357] 1H NMR (500 MHz, CDCl.sub.3): .delta.=0.67 (s, 3H), 0.92 (s,
3H), 1.10-1.25 (m, 3H), 1.33 (s, 9H), 1.45-1.75 (m, 3H), 1.80-2.00
(m, 2H), 3.15-3.20 (m, 1H), 4.42 (d, J=9.0 Hz, 1H), 4.68 (d, J=9.5
Hz, 1H), 6.77 (d, J=2.0 Hz, 1H), 7.06 (dd, J=8.3, 1.8 Hz, 1H), 7.34
(dd, J=8.5, 2.0 Hz, 1H), 7.53-7.63 (m, 2H), 8.06 (d, J=5.0 Hz,
1H)
[0358] (Conditions for HPLC for Optical Purity Measurement)
[0359] Column: CHIRALPAK OD-3R 4.6.times.150 mm, 3 .mu.m
[0360] Mobile phase: 0.1% (v/v) HCOOH aq.:MeCN=50:50
[0361] Flow rate: 1.0 ml/min
[0362] Column temperature: 40.degree. C.
[0363] Detection wavelength: 254 nm
[0364] Injection quantity: 5 .mu.l
[0365] Retention time: title compound=9.4 min, enantiomer=11.4
min
Reference Example 1
(2S,5R)-5-[(2-Aminoacetyl)amino]tetrahydro-2H-pyran-2-carboxamide
##STR00106##
[0366] Step 1
tert-Butyl
N-(2-{[(3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl]amino}-2-oxo-
ethyl)carbamate
[0367] To a slurry of N-(tert-butoxycarbonyl)glycine (1.01 g, 5.77
mmol), (2S,5R)-5-aminotetrahydro-2H-pyran-2-carboxamide
(WO2012/121361) (0.85 g, 5.90 mmol), and diisopropylethylamine (994
.mu.l, 5.71 mmol) in tetrahydrofuran (40 ml),
0-(7-azabenzotriazol-1-yl)-N,N,N',N',-tetramethyluronium
hexafluorophosphate (2.21 g, 5.83 mmol) was added, and the mixture
was stirred at room temperature for 18 hours. The reaction mixture
was concentrated under reduced pressure, and the residue was
purified by silica gel chromatography [ethyl
acetate:methanol=98:2.fwdarw.80:20 (v/v)]. To the solid obtained,
ethyl acetate (20 ml) was added, and the mixture was stirred at
room temperature for 4 hours. The slurry obtained was filtered and
dried under reduced pressure at 40.degree. C. to obtain the title
compound (1.47 g, yield: 83%) as a white solid.
[0368] .sup.1H NMR (500 MHz, CDCl.sub.3): .delta.=1.40-1.50 (m,
1H), 1.46 (s, 9H), 1.57-1.66 (m, 1H), 2.08-2.16 (m, 1H), 2.22-2.28
(m, 1H), 3.09 (t, J=10.5 Hz, 1H), 3.70-3.82 (m, 3H), 3.90-4.02 (m,
1H), 4.16 (ddd, J=10.9, 4.9, 1.9 Hz, 1H), 5.08-5.15 (m, 1H),
5.38-5.46 (m, 1H), 5.95-6.05 (m, 1H), 6.43-6.53 (m, 1H)
Step 2
(2S,5R)-5-[(2-Aminoacetyl)amino]tetrahydro-2H-pyran-2-carboxamide
[0369] To the compound (500 mg, 1.66 mmol) obtained in the
preceding step 1, a solution of 4 N hydrogen chloride in
cyclopentyl methyl ether (5 ml, 20 mmol) was added, and the mixture
was stirred at room temperature for 15 hours. The reaction mixture
was filtered and washed with cyclopentyl methyl ether (5 ml). To a
solution of the solid obtained in methanol (5 ml), a solution of
28% sodium methoxide in methanol (810 .mu.l, 3.32 mmol) was added,
and the mixture was stirred at room temperature for 2 hours. To the
reaction mixture obtained, neutral silica gel (500 mg) was added,
and the mixture was concentrated under reduced pressure. To the
residue, ethyl acetate (50 ml) and methanol (5 ml) were added, and
the silica gel was filtered off. The filtrate was concentrated
under reduced pressure. To the residue, tetrahydrofuran (2.0 ml)
was added, and the mixture was stirred at room temperature for 17
hours. The slurry obtained was filtered and dried under reduced
pressure at 40.degree. C. to obtain the title compound (111 mg,
yield: 33%) as a white solid.
[0370] .sup.1H NMR (500 MHz, CD.sub.3OD): .delta.=1.50-1.61 (m,
2H), 2.00-2.18 (m, 2H), 3.16 (t, J=10.8 Hz, 1H), 3.21 (d, J=16.5
Hz, 1H), 3.25 (d, J=17.0 Hz, 1H), 3.72-3.78 (m, 1H), 3.80-3.90 (m,
1H), 4.07 (ddd, J=10.9, 4.9, 1.9 Hz, 1H)
Example 13
(3'R,4'S,5'R)--N-[(3R,6S)-6-Carbamoyltetrahydro-2H-pyran-3-yl]-6''-chloro--
4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2''-oxo-1'',2''-dihydrodis-
piro[cyclohexane-1,2'-pyrrolidine-3',3''-indole]-5'-carboxamide
##STR00107##
[0372] To a mixture of the compound (39.1 mg, 0.19 mmol) obtained
in Reference Example 1,
(3E/Z)-6-chloro-3-(3-chloro-2-fluorobenzylidene)-1,3-dihydro-2H-indol-2-o-
ne (WO2006/091646) (48.6 mg, 0.16 mmol), (R)-BINAP (6.6 mg, 0.011
mmol), and CuOAc (1.2 mg, 0.010 mmol), a solution of
4,4-dimethylcyclohexanone (30.6 mg, 0.24 mmol) in
N,N-dimethylacetamide (1.0 ml) was added under a nitrogen
atmosphere, and the resulting mixture was stirred at room
temperature for 17 hours. The whole amount of the reaction mixture
was diluted with methanol (100 ml) to obtain the title compound
(ultrahigh-performance liquid chromatography (UHPLC) yield: 65%,
96% de) as a solution in methanol.
[0373] (Conditions for UHPLC Measurement for UHPLC Yield
Calculation)
[0374] Column: CAPCELL CORE ADME 2.1.times.100 mm, 2.7 m
[0375] Mobile phase: 0.1% (v/v) HCOOH aq.:MeCN
[0376] Gradient: MeCN 20%.fwdarw.92%
[0377] Gradient conditions: 0-2.5 min MeCN 20%, 2.5-7.3 min MeCN
20.fwdarw.92%, 7.3-14 min MeCN 92%, 14.01-17 min MeCN 20%
[0378] Flow rate: 0.6 ml/min
[0379] Column temperature: 40.degree. C.
[0380] Detection wavelength: 254 nm
[0381] Injection quantity: 5 .mu.l
[0382] Retention time: title compound=6.6 min
[0383] (Conditions for HPLC for De Measurement)
[0384] Column: CHIRALPAK OD-3R 4.6.times.150 mm, 3 .mu.m
[0385] Mobile phase: 0.1% (v/v) HCOOH aq.:MeCN=60:40
[0386] Flow rate: 1.0 ml/min
[0387] Column temperature: 40.degree. C.
[0388] Detection wavelength: 254 nm
[0389] Injection quantity: 10 .mu.l
[0390] Retention time: title compound=17.7 min, diastereomer=8.5
min
Example 14
(3'R,4'S,5'R)-6''-Chloro-4'-(3-chloro-2-fluorophenyl)-N-(trans-4-hydroxycy-
clohexyl)-2''-oxo-1'',2''-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3-
''-indole]-5'-carboxamide
##STR00108##
[0391] Step 1
(4'S,5'R)-6''-Chloro-4'-(3-chloro-2-fluorophenyl)-N-(trans-4-hydroxycycloh-
exyl)-2''-oxo-1'',2''-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-i-
ndole]-5''-carboxylic Acid
[0392] To a slurry of the compound (1.00 g, 2.04 mmol) obtained in
Example 1 and methanol (10 ml), a 25% (w/v) aqueous sodium
hydroxide solution (1.0 ml, 6.25 mmol) was added under ice cooling,
and the mixture was stirred at 0.degree. C. for 27.5 hours. The
reaction mixture was neutralized by the addition of 35% (w/w)
concentrated hydrochloric acid (651 mg, 6.25 mmol) under ice
cooling. Water (15 ml) was added dropwise thereto, and the mixture
was then stirred at 0.degree. C. for 18 hours. The deposited
crystals were filtered at 0.degree. C. and dried under reduced
pressure at 40.degree. C. to obtain the title compound (0.90 g,
yield: 95%, >99.5% ee) as a pale yellow solid.
[0393] .sup.1H NMR (500 MHz, CD.sub.3OD): 8=1.10-1.30 (m, 2H),
1.50-1.68 (m, 1H), 1.70-2.13 (m, 5H), 2.18-2.28 (m, 1H), 2.50-2.62
(m, 1H), 4.81 (d, J=10.0 Hz, 1H), 5.01 (d, J=10.0 Hz, 1H), 6.76 (d,
J=2.0 Hz, 1H), 7.07-7.15 (m, 2H), 7.28-7.35 (m, 1H), 7.54 (dd,
J=8.0, 2.5 Hz, 1H), 7.60-7.68 (m, 1H)
[0394] (Conditions for HPLC for Optical Purity Measurement)
[0395] Column: CHIRALPAK QN-AX 4.6.times.150 mm, 3 .mu.m
[0396] Mobile phase: 0.1% (v/v) HCOOH aq.:MeCN=60:40
[0397] Flow rate: 1.0 ml/min
[0398] Column temperature: 40.degree. C.
[0399] Detection wavelength: 254 nm
[0400] Injection quantity: 5 .mu.l
[0401] Retention time: title compound=7.5 min, enantiomer=4.0
min
Step 2
(3'R,4'S,5'R)-6''-Chloro-4'-(3-chloro-2-fluorophenyl)-N-(trans-4-hydroxycy-
clohexyl)-2''-oxo-1'',2''-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3-
''-indole]-5'-carboxamide
[0402] To a solution of the compound (501 mg, 1.08 mmol, 99% ee)
obtained in the preceding step 1 and trans-4-aminocyclohexanol (157
mg, 1.36 mmol) in N,N-dimethylacetamide (5 ml),
4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride
(392 mg, 1.42 mmol) was added under ice cooling, and the mixture
was stirred at 0.degree. C. for 1 hour. To the reaction mixture,
ethyl acetate (10 ml) and water (5 ml) were added, and the mixture
was stirred to separate an organic layer. The aqueous layer was
subjected to extraction with ethyl acetate (10 ml), and the organic
layers were all combined and then washed with water three times (10
ml each). The solvent was distilled off under reduced pressure. To
the residue, acetonitrile (15 ml) was then added, and the mixture
was stirred at room temperature for 18 hours. The deposited
crystals were filtered and dried under reduced pressure at
40.degree. C. to obtain the title compound (426 g, yield: 70%,
>99.5% ee) as a white solid.
[0403] .sup.1H NMR (500 MHz, CD.sub.3OD): 8=0.93 (td, J=13.5, 4.2
Hz, 1H), 1.0-1.15 (m, 1H), 1.25-1.45 (m, 4H), 1.5-2.05 (m, 12H),
3.5-3.65 (m, 2H), 4.49 (d, J=9.5 Hz, 1H), 4.65 (d, J=9.0 Hz, 1H),
6.71 (d, J=2.0 Hz, 1H), 7.02 (td, J=8.5, 2.0 Hz, 1H), 7.20 (td,
J=15.0, 1.5 Hz, 1H), 7.39 (dd, J=8.5, 2.5 Hz, 1H), 7.61 (td,
J=14.8, 1.3 Hz, 1H)
[0404] (Conditions for HPLC for Optical Purity Measurement)
[0405] Column: CHIRALPAK OD-3R 4.6.times.150 mm, 3 .mu.m
[0406] Mobile phase: 0.1% (v/v) HCOOH aq.:MeCN=60:40
[0407] Flow rate: 1.0 ml/min
[0408] Column temperature: 40.degree. C.
[0409] Detection wavelength: 254 nm
[0410] Injection quantity: 5 .mu.l
[0411] Retention time: title compound=4.9 min, enantiomer=4.2
min
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