U.S. patent application number 11/294626 was filed with the patent office on 2006-05-04 for process for preparation of benzylpiperidine compounds.
Invention is credited to Shokyo Miki, Koji Nakamoto, Mitsuhiro Takeda.
Application Number | 20060094877 11/294626 |
Document ID | / |
Family ID | 18877680 |
Filed Date | 2006-05-04 |
United States Patent
Application |
20060094877 |
Kind Code |
A1 |
Miki; Shokyo ; et
al. |
May 4, 2006 |
Process for preparation of benzylpiperidine compounds
Abstract
According to the process as shown in the following scheme having
a step for reacting Compound (I) with Compound (II) to produce
Compound (III), benzylpiperidine compounds useful as synthesis
starting materials of pharmaceutical agents, agricultural chemicals
and the like can be produced conveniently by a short step: ##STR1##
wherein R.sup.1 is a hydrogen atom or an amino-protecting group,
R.sup.2 is a hydrogen atom, a hydrocarbon group optionally having
substituents, an alkoxy group optionally having substituents or a
heterocyclic group optionally having substituents, and R.sup.3 is a
lower alkyl group.
Inventors: |
Miki; Shokyo; (Osaka,
JP) ; Takeda; Mitsuhiro; (Osaka, JP) ;
Nakamoto; Koji; (Osaka, JP) |
Correspondence
Address: |
TAKEDA PHARMACEUTICALS NORTH AMERICA, INC;INTELLECTUAL PROPERTY DEPARTMENT
475 HALF DAY ROAD
SUITE 500
LINCOLNSHIRE
IL
60069
US
|
Family ID: |
18877680 |
Appl. No.: |
11/294626 |
Filed: |
December 5, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10939293 |
Sep 10, 2004 |
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11294626 |
Dec 5, 2005 |
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10466494 |
Jul 17, 2003 |
6833457 |
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PCT/JP02/00304 |
Jan 18, 2002 |
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10939293 |
Sep 10, 2004 |
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Current U.S.
Class: |
546/22 ; 546/207;
558/190 |
Current CPC
Class: |
C07D 211/34 20130101;
Y02P 20/55 20151101; C07D 211/96 20130101; C07F 9/4056 20130101;
C07D 211/62 20130101; C07D 401/12 20130101; C07D 211/70 20130101;
C07F 9/094 20130101 |
Class at
Publication: |
546/022 ;
546/207; 558/190 |
International
Class: |
C07F 9/02 20060101
C07F009/02; C07D 401/02 20060101 C07D401/02 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 18, 2001 |
JP |
10354/2001 |
Claims
1. A process for the preparation of a compound represented by the
formula: ##STR78## wherein R.sup.2 is a hydrogen atom, a
hydrocarbon group optionally having substituents, an alkoxy group
optionally having substituents or a heterocyclic group optionally
having substituents, and R.sup.3 is a lower alkyl group, or a salt
thereof, which comprises reacting a compound represented by the
formula: ##STR79## wherein X.sup.1 is a halogen atom and R.sup.2 is
as defined above, or a salt thereof, with a trialkyl phosphite
represented by the formula: ##STR80## wherein R.sup.3 is as defined
above.
2. The process of claim 1, wherein the compound represented by the
formula (IV) or a salt thereof is reacted with the compound
represented by the formula (V) in the presence of alkali metal
iodide.
3. The process of claim 2, wherein the alkali metal iodide is
potassium iodide.
4. A process for the preparation of a compound represented by the
formula: ##STR81## wherein G.sup.1 is a bond, CO or SO.sub.2,
X.sup.3 is a leaving group, R.sup.4 is a hydrogen atom, a
hydrocarbon group optionally having substituents, a heterocyclic
group optionally having substituents, an alkoxy group optionally
having substituents, an aryloxy group optionally having
substituents or an amino group optionally having substituents, and
R.sup.5 is a cyclic hydrocarbon group optionally having
substituents or a heterocyclic group optionally having
substituents, or a salt thereof, which comprises reacting a
compound represented by the formula: ##STR82## wherein X.sup.3 and
R.sup.5 are as defined above, or a salt thereof, with a compound
represented by the formula: ##STR83## wherein G.sup.1 and R.sup.4
are as defined above, or a salt thereof.
Description
[0001] This application is a divisional of U.S. patent application
Ser. No. 10/939,293, now U.S. Pat. No. ______ issued ______, which
was a divisional of U.S. patent application Ser. No. 10/466,494,
now U.S. Pat. No. 6,833,457 issued Dec. 21, 2004, which was the
National Phase filing of International Patent Application No.
PCT/JP02/00304 filed Jan. 18, 2002.
TECHNICAL FIELD
[0002] The present invention relates to a benzylpiperidine compound
useful as a production intermediate for a cyclic amide compound and
the like used as a therapeutic agent for acquired immunodeficiency
syndrome and a production method thereof.
BACKGROUND ART
[0003] As synthetic methods of benzylpiperidine compounds, (i) a
method via reduction of carbonyl group (Wolff-Kishner reduction,
etc.) after Friedel-Crafts reaction and (ii) a method via olefin
synthesis reaction such as Wittig reaction and Horner-Emmons
reaction etc. as shown in the following are known. (i) The method
of A. Wick et al. (U.S. Pat. No. 4,690,931, 1987) ##STR2## (ii) The
paper of Z-L Zhou et al. (J. Org. Chem., 1999, vol. 64, p. 3763)
##STR3##
[0004] Of the benzylpiperidine compounds, particularly when a
compound where a carbamoyl group substitutes on the benzene ring is
to be synthesized, a method that goes through an olefin synthesis
reactions such as Wittig reaction and the like is advantageous in
that the position of substitution can be controlled easily.
However, it is not known that benzylpiperidine compounds
substituted by a carbamoyl group having an acidic hydrogen
disadvantageous to the reaction can be produced through those
reactions.
[0005] In addition, Takayanagi et al. (WO98/31661) obtained a
benzylpiperidine compound substituted by methoxycarbonyl group, and
thereafter converted the methoxycarbonyl group to a substituted
carbamoyl group.
[0006] When this example described in WO98/31661 and an azidation
reaction are combined, a carbamoyl-substituted benzylpiperidine
compound can be synthesized as shown by the following formulas.
##STR4## wherein HOBt is hydroxy-1H-benzotriazole and WSC is
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride.
[0007] However, the production method is complicated, and the
development of an industrially advantageous short-step production
method is necessary.
[0008] In view of the above, it is an object of the present
invention to provide an industrially advantageous short-step
production method of a benzylpiperidine compound wherein a
carbamoyl group substitutes on the benzene ring, and to provide a
novel synthetic intermediate for this production method.
DISCLOSURE OF THE INVENTION
[0009] In view of the above-mentioned aspects, the present
inventors have conducted intensive studies and, as a result, found
that the Horner-Emmons reaction between Compound (I) to be
described below, which is substituted by a carbamoyl group having
an acidic hydrogen disadvantageous to the reaction, and piperidone
Compound (II) to be described below unexpectedly proceeds in a good
yield, and the handling property during isolation and purification
of product can be markedly improved, and succeeded in synthesizing
benzylpiperidine Compound (VIII) to be described below from readily
available 4-(chloromethyl)benzoyl chloride by short steps via
Compound (I), which resulted in the completion of the present
invention.
[0010] The present inventors have found a novel production method
of Compound (IX) to be described below, which is used for leading
the benzylpiperidine Compound (VIII) obtained by the
above-mentioned reaction into Compound (X) to be described below,
which is useful as a pharmaceutical agent, which resulted in the
completion of the present invention.
[0011] Accordingly, the present invention relates to the following
(1) to (16). (1) A process for the preparation of a compound
represented by the formula: ##STR5## wherein [0012] R.sup.1 is a
hydrogen atom or an amino-protecting group and [0013] R.sup.2 is a
hydrogen atom, a hydrocarbon group optionally having substituents,
an alkoxy group optionally having substituents or a heterocyclic
group optionally having substituents, or a salt thereof, which
comprises reacting a compound represented by the formula: ##STR6##
wherein R.sup.3 is a lower alkyl group and R.sup.2 is as defined
above, or a salt thereof, with a compound represented by the
formula: ##STR7## wherein R.sup.1 is as defined above, or a salt
thereof. (2) A process for the preparation of a compound
represented by the formula: ##STR8## wherein [0014] R.sup.2 is a
hydrogen atom, a hydrocarbon group optionally having substituents,
an alkoxy group optionally having substituents or a heterocyclic
group optionally having substituents, and [0015] R.sup.3 is a lower
alkyl group, or a salt thereof, which comprises reacting a compound
represented by the formula: ##STR9## wherein X.sup.1 is a halogen
atom and R.sup.2 is as defined above, or a salt thereof, with a
trialkyl phosphite represented by the formula: ##STR10## wherein
R.sup.3 is as defined above. (3) A process for the preparation of a
compound represented by the formula: ##STR11## wherein [0016]
R.sup.1 is a hydrogen atom or an amino-protecting group and [0017]
R.sup.2 is a hydrogen atom, a hydrocarbon group optionally having
substituents, an alkoxy group optionally having substituents or a
heterocyclic group optionally having substituents, or a salt
thereof, which comprises reacting a compound represented by the
formula: ##STR12## wherein X.sup.1 is a halogen atom and R.sup.2 is
as defined above, or a salt thereof, with a trialkyl phosphite
represented by the formula: ##STR13## wherein R.sup.3 is a lower
alkyl group, and thereafter reacting with a compound represented by
the formula: ##STR14## wherein R.sup.1 is as defined above, or a
salt thereof. (4) The process of the above-mentioned (3), wherein
the compound represented by the formula (IV) or a salt thereof is
reacted with the trialkyl phosphite represented by the formula (V)
to give a compound represented by the formula: ##STR15## wherein
[0018] R.sup.2 is a hydrogen atom, a hydrocarbon group optionally
having substituents, an alkoxy group optionally having substituents
or a heterocyclic group optionally having substituents, and [0019]
R.sup.3 is a lower alkyl group, or a salt thereof. (5) A process
for the preparation of a compound represented by the formula:
##STR16## wherein [0020] R.sup.2 is a hydrogen atom, a hydrocarbon
group optionally having substituents, an alkoxy group optionally
having substituents or a heterocyclic group optionally having
substituents, or a salt thereof, which comprises: reacting a
compound represented by the formula: ##STR17## wherein X.sup.1 is a
halogen atom and X.sup.2 is a leaving group, with a compound
represented by the formula: R.sup.2NH.sub.2 (VII) wherein R.sup.2
is as defined above, or a salt thereof, to give a compound
represented by the formula: ##STR18## wherein R.sup.2 and X.sup.1
are as defined above, or a salt thereof; reacting the compound
represented by the formula (IV) or a salt thereof with a trialkyl
phosphite represented by the formula: ##STR19## wherein R.sup.3 is
a lower alkyl group; thereafter reacting with a compound
represented by the formula: ##STR20## wherein R.sup.1 is a hydrogen
atom or an amino-protecting group, or a salt thereof, to give a
compound represented by the formula: ##STR21## wherein R.sup.1 and
R.sup.2 are as defined above, or a salt thereof; and reducing and
thereafter where necessary deprotecting the compound represented by
the formula(III) or a salt thereof. (6) The process of the
above-mentioned (5) which comprises: reacting a compound
represented by the formula: ##STR22## wherein X.sup.1 and X.sup.2
are each a halogen atom, with a compound represented by the
formula: ##STR23## wherein R.sup.2 is a hydrogen atom, a
hydrocarbon group optionally having substituents, an alkoxy group
optionally having substituents or a heterocyclic group optionally
having substituents, or a salt thereof, to give a compound
represented by the formula: ##STR24## wherein R.sup.2 and X.sup.1
are as defined above, or a salt thereof; reacting the compound
represented by the formula (IV) or a salt thereof with a trialkyl
phosphite represented by the formula: ##STR25## wherein R.sup.3 is
a lower alkyl group, to give a compound represented by the formula:
##STR26## wherein R.sup.2 and R.sup.3 are as defined above, or a
salt thereof; reacting the compound represented by the formula (I)
or a salt thereof with a compound represented by the formula:
##STR27## wherein R.sup.1 is a hydrogen atom or an amino-protecting
group, or a salt thereof, to give a compound represented by the
formula: ##STR28## wherein R.sup.1 and R.sup.2 are as defined
above, or a salt thereof; and reducing and thereafter where
necessary deprotecting the compound represented by formula (III) or
a salt thereof (7) A process for the preparation of a compound
represented by the formula: ##STR29## wherein [0021] G.sup.1 is a
bond, CO or SO.sub.2, [0022] R.sup.2 is a hydrogen atom, a
hydrocarbon group optionally having substituents, an alkoxy group
optionally having substituents or a heterocyclic group optionally
having substituents, [0023] R.sup.4 is a hydrogen atom, a
hydrocarbon group optionally having substituents, a heterocyclic
group optionally having substituents, an alkoxy group optionally
having substituents, an aryloxy group optionally having
substituents or an amino group optionally having substituents, and
[0024] R.sup.5 is a cyclic hydrocarbon group optionally having
substituents or a heterocyclic group optionally having
substituents, which comprises: reacting a compound represented by
the formula: ##STR30## wherein X.sup.1 is a halogen atom and
X.sup.2 is a leaving group, with a compound represented by the
formula: ##STR31## wherein R.sup.2 is as defined above, or a salt
thereof, to give a compound represented by the formula: ##STR32##
wherein R.sup.2 and X.sup.1 are as defined above, or a salt
thereof; reacting the compound represented by the formula (IV) or a
salt thereof with a trialkyl phosphite represented by the formula:
##STR33## wherein R.sup.3 is a lower alkyl group; thereafter
reacting with a compound represented by the formula: ##STR34##
wherein R.sup.1 is a hydrogen atom or an amino-protecting group, or
a salt thereof, to give a compound represented by the formula:
##STR35## wherein R.sup.1 and R.sup.2 are as defined above, or a
salt thereof; reducing and thereafter where necessary deprotecting
the compound represented by the formula (III) or a salt thereof to
give a compound represented by the formula: ##STR36## wherein
R.sup.2 is as defined above, or a salt thereof; and reacting the
compound represented by the formula (VIII') or a salt thereof with
a compound represented by the formula: ##STR37## wherein X.sup.3 is
a leaving group and G.sup.1, R.sup.4 and R.sup.5 are as defined
above, or a salt thereof. (8) The process of any of the
above-mentioned (2) to (7), wherein the compound represented by the
formula (IV) or a salt thereof is reacted with the compound
represented by the formula (V) in the presence of alkali metal
iodide. (9) The process of the above-mentioned (8), wherein the
alkali metal iodide is potassium iodide. (10) The process of the
above-mentioned (1), (3), (4), (5), (6) or (7), wherein the
compound represented by the formula (II) or a salt thereof is
reacted in the presence of a base. (11) The process of the
above-mentioned (10), wherein the base is t-butoxide of an alkali
metal. (12) The process of the above-mentioned (11), wherein the
base is potassium t-butoxide. (13) A process for the preparation of
a compound represented by the formula: ##STR38## wherein [0025]
G.sup.1 is a bond, CO or SO.sub.2, [0026] X.sup.3 is a leaving
group, [0027] R.sup.4 is a hydrogen atom, a hydrocarbon group
optionally having substituents, a heterocyclic group optionally
having substituents, an alkoxy group optionally having
substituents, an aryloxy group optionally having substituents or an
amino group optionally having substituents, and [0028] R.sup.5 is a
cyclic hydrocarbon group optionally having substituents or a
heterocyclic group optionally having substituents, or a salt
thereof, which comprises reacting a compound represented by the
formula: ##STR39## wherein X.sup.3 and R.sup.5 are as defined
above, or a salt thereof, with a compound represented by the
formula: ##STR40## wherein G.sup.1 and R.sup.4 are as defined
above, or a salt thereof. (14) A process for the preparation of a
compound represented by the formula: ##STR41## wherein [0029]
G.sup.1 is a bond, CO or SO.sub.2, [0030] R.sup.2 is a hydrogen
atom, a hydrocarbon group optionally having substituents, an alkoxy
group optionally having substituents or a heterocyclic group
optionally having substituents, [0031] R.sup.4 is a hydrogen atom,
a hydrocarbon group optionally having substituents, a heterocyclic
group optionally having substituents, an alkoxy group optionally
having substituents, an aryloxy group optionally having
substituents or an amino group optionally having substituents, and
[0032] R.sup.5 is a cyclic hydrocarbon group optionally having
substituents or a heterocyclic group optionally having
substituents, or a salt thereof, which comprises reacting a
compound represented by the formula: ##STR42## wherein X.sup.3 is a
leaving group and R.sup.5 is as defined above, or a salt thereof,
with a compound represented by the formula: ##STR43## wherein
G.sup.1 and R.sup.4 are as defined above, or a salt thereof, to
give a compound represented by the formula: ##STR44## wherein
G.sup.1, X.sup.3, R.sup.4 and R.sup.5 are as defined above, or a
salt thereof, and reacting the compound represented by the formula
(IX) or a salt thereof with a compound represented by the formula:
##STR45## wherein R.sup.2 is as defined above, or a salt thereof.
(15) The process of the above-mentioned (14), wherein R.sup.2 is a
hydrogen atom, R.sup.4 is a methyl group, R.sup.5 is a phenyl group
having 1 or 2 substituents selected from the group consisting of a
halogen atom and a methyl group, G.sup.1 is a carbonyl, and X.sup.3
is a chlorine atom. (16) A compound represented by the formula:
##STR46##
[0033] As the `halogen atom` denoted by the above-mentioned X.sup.1
and X.sup.2', for example, chlorine atom, bromine atom, iodine atom
and the like can be mentioned.
[0034] As the `leaving group` denoted by X.sup.2, for example, a
halogen atom (e.g., chlorine atom, bromine atom, iodine atom,
etc.), an alkyl or arylsulfonyloxy group (e.g., methanesulfonyloxy,
ethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, etc.)
and the like can be mentioned.
[0035] As the `amino-protecting group` denoted by R.sup.1, any
protecting group can be used as long as it does not inhibit the
reaction, and carbamate protecting groups (e.g., benzyloxycarbonyl
group, t-butoxycarbonyl group, etc.), amide protecting groups
(e.g., formyl group, etc.), aminoacetal protecting groups (e.g.,
benzyloxymethyl group, etc.), benzyl protecting groups (e.g.,
benzyl group, etc.) and the like are preferably used. Of these,
benzyl group, benzyloxycarbonyl group and t-butoxycarbonyl group
are particularly preferable.
[0036] As the `hydrocarbon group` of the `hydrocarbon group
optionally having substituents` denoted by R.sup.2, lower alkyl
groups (e.g., C.sub.1-6 alkyl group such as methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl etc. and the
like), cycloalkyl groups (e.g., C.sub.3-6 cycloalkyl group such as
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc. and the
like), aryl groups (e.g., C.sub.6-10 aryl group such as phenyl,
1-naphthyl, 2-naphthyl etc. and the like), aralkyl groups (e.g.,
C.sub.7-10 aralkyl group such as benzyl, phenethyl and the like,
preferably phenyl-C.sub.1-4 alkyl group, etc.), and the like can be
mentioned.
[0037] As the `alkoxy group` of the `alkoxy group optionally having
substituents` denoted by R.sup.2, for example, C.sub.1-6 alkoxy
groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,
isobutoxy, sec-butoxy, t-butoxy and the like, and the like can be
mentioned.
[0038] As the `heterocyclic group` of the `heterocyclic group
optionally having substituents` denoted by R.sup.2, aromatic
heterocyclic groups and saturated or unsaturated non-aromatic
heterocyclic groups, containing, as an atom constituting the ring
system (ring atom), at least one of 1 to 3 kinds of hetero atoms,
which is selected from oxygen atom, sulfur atom, nitrogen atom and
the like, can be mentioned. As the aromatic heterocyclic group, for
example, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl,
1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl,
1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,
1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl,
pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, isobenzofuranyl,
benzothienyl, indolyl, isoindolyl, 1H-indazolyl, benzindazolyl,
benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, benzopyranyl,
1,2-benzisothiazolyl, benzodioxolyl, benzimidazolyl,
2,1,1-benzoxadiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl,
cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl,
naphthyridinyl, purinyl, pteridinyl, carbazolyl,
.alpha.-carbolinyl, .beta.-carbolinyl, .gamma.-carbolinyl,
acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl,
phenoxathiinyl, thianthrenyl, phenathridinyl, phenathrolinyl,
indolizinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl,
pyrazolo[3,4-b]pyridyl, imidazo[1,2-a]pyridyl,
imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl,
imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl,
1,2,4-triazolo[4,3-b]pyridazinyl and the like can be mentioned, and
as the saturated or unsaturated non-aromatic heterocyclic groups,
for example, oxiranyl, azetidinyl, oxetanyl, thietanyl,
pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidinyl,
tetrahydropyranyl, morpholinyl, thiomorpholinyl and piperazinyl and
the like can be mentioned.
[0039] As the `substituent` of the `hydrocarbon group optionally
having substituents`, `alkoxy group optionally having substituents`
and `heterocyclic group optionally having substituents`, for
example, (1) hydroxyl group, (2) amino group, (3) mono- or
di-substituted amino group [e.g., mono- or di-substituted amino
group substituted by 1 or 2 substituents selected from C.sub.1-6
alkyl group (methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl,
n-pentyl, n-hexyl), C.sub.1-6 alkanoyl (e.g., acetyl, propionyl,
butyryl, etc.), C.sub.7-13 arylcarbonyl (e.g., benzoyl, naphthoyl,
etc.) and C.sub.1-6 alkylsulfonyl (methylsulfonyl, ethylsulfonyl,
propylsulfonyl, butylsulfonyl, pentylsulfonyl, etc.)], (4) halogen
atom (e.g., fluorine, chlorine, bromine, iodine, etc.), (5) nitro
group, (6) cyano group, (7) C.sub.1-6 alkyl group (methyl, ethyl,
n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, n-hexyl, etc.)
optionally substituted by halogen atom (e.g., fluorine, chlorine,
bromine, iodine, etc.) or (8) C.sub.1-6 alkoxy group (e.g.,
methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy,
n-pentyloxy, n-hexyloxy, etc.) optionally substituted by halogen
atom (e.g., fluorine, chlorine, bromine, iodine, etc.), and the
like can be mentioned.
[0040] As the R.sup.2, C.sub.1-2 alkyl such as methyl, ethyl and
the like and a hydrogen atom are preferable.
[0041] As the lower alkyl group denoted by R.sup.3, for example,
those having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl,
isopropyl and the like, can be mentioned, with preference given to
methyl and ethyl.
[0042] The production methods of the present invention are
explained in the following.
Production of Compound (III)
[0043] A compound represented by the formula (III) or a salt
thereof can be produced by reacting a compound represented by the
formula (I) or a salt thereof with a piperidone compound of the
formula (II) or a salt thereof.
[0044] When --NHR.sup.2 of the compound of the formula (I) has a
basic group such as an amino group and the like, an acid addition
salt, for example, a salt such as inorganic acid salts (e.g.,
hydrochloride, sulfate, hydrobromide, phosphate, etc.), organic
acid salts (e.g., acetate, trifluoroacetate, succinate, maleate,
fumarate, propionate, citrate, tartrate, lactate, oxalate,
methanesulfonate, p-toluenesulfonate, etc.) and the like can be
formed. As the salt of the compound of the formula (I), these salts
can be used.
[0045] In the following, a compound represented by the formula (I)
and a salt thereof are simply referred to as Compound (I). In
addition, the compounds represented by the formula (II) and the
formula (III) can form a salt, and as such salt, those similar to
the salts of the compound of the above-mentioned formula (I) can be
mentioned. In the following, the compound represented by the
formula (II) and a salt thereof are simply referred to as Compound
(II), and the compound represented by the formula (III) and a salt
thereof are simply referred to as Compound (III). Compound (III),
wherein R.sup.1 is a benzyl group, R.sup.2 is a hydrogen atom, and
the carbamoyl group is linked to the para-position, and a salt
thereof, is novel (a compound represented by the aforementioned
formula (III') and a salt thereof, which are hereinafter simply
referred to as Compound (III')).
[0046] The reaction between Compound (I) and Compound (II) is
generally carried out in a solvent in the presence of a base. As
the solvent, any solvent can be used as long as the reaction is not
inhibited. For example, amides (e.g., N,N-dimethylformamide,
N,N-dimethylacetamide, N-methylpyrrolidone, etc.) and nitrites
(e.g., acetonitrile, etc.) are preferably used. These solvents can
be used alone or as a mixture of two or more kinds thereof.
[0047] As the base, for example, alkali metal alkoxides having 1 to
4 carbon atoms such as t-butoxide of alkali metal (e.g., potassium
t-butoxide, sodium t-butoxide), sodium methoxide, sodium ethoxide
and the like can be mentioned. Of these, t-butoxide of alkali metal
is preferable, and potassium t-butoxide is particularly
preferable.
[0048] The Compound (II) is used in an amount of generally 0.5 mole
to 5 moles, preferably 0.8 mole to 3 moles, per 1 mole of Compound
(I). The amount of the base to be used is generally 1 mole to 10
moles, preferably 1 mole to 3 moles, per 1 mole of Compound
(I).
[0049] The reaction temperature is generally -20.degree. C. to
150.degree. C., preferably 0.degree. C. to 50.degree. C., and the
reaction time is generally 10 min. to 12 hrs., preferably 30 min.
to 5 hrs.
Production of Compound (I)
[0050] The Compound (I) can be produced by reacting a compound
represented by the formula (IV) or a salt thereof with a compound
represented by the formula (V) [hereinafter to be referred to as
Compound (V)]. The compound represented by the formula (IV) can
form a salt and as such salt, those similar to the salt of the
compound represented by the above-mentioned formula (I) can be
mentioned. In the following, a compound represented by the formula
(IV) and a salt thereof are simply referred to as Compound
(IV).
[0051] The reaction between Compound (IV) and Compound (V) is
carried out generally in the presence of a solvent and as such
solvent, any solvent can be used as long as it does not inhibit the
reaction. For example, amides (e.g., N,N-dimethylformamide,
N,N-dimethylacetamide, N-methylpyrrolidone, etc.), nitrites (e.g.,
acetonitrile, etc.), and alcohols (e.g., methanol, ethanol,
propanol, etc.) are preferably used. These solvents can be used
alone or in a mixture of two or more kinds thereof.
[0052] The Compound (V) is used in an amount of generally 1 mole to
10 moles, preferably 1 mole to 5 moles, per 1 mole of Compound
(IV). To promote this reaction, for example, an alkali metal iodide
such as potassium iodide, sodium iodide and the like is desirably
used concurrently. Of these, potassium iodide is particularly
preferably used concurrently. Said alkali metal iodide is used in
an amount of generally 0.1 mole to 5 moles, preferably 0.5 mole to
3 moles, per 1 mole of Compound (IV).
[0053] This reaction is generally carried out at a reaction
temperature of 20.degree. C. to 150.degree. C., preferably
50.degree. C. to 100.degree. C., generally for 30 min. to 24 hrs.,
preferably 1 hr. to 5 hrs. The phosphonic acid ester (Compound (I))
obtained by this reaction may be isolated, but may be conveniently
applied to the subsequent Horner-Emmons reaction with Compound (II)
as it is or after evaporation of the solvent. When Compound (I) is
applied for the production of the above-mentioned Compound (III)
without isolation, the reagents to be used may be used in an amount
within the above-mentioned range, while assuming that Compound (I)
has been obtained quantitatively from Compound (IV).
Production of Compound (IV)
[0054] The Compound (IV) can be produced by reacting a compound
represented by the formula (VI) [hereinafter to be referred to as
Compound (VI), and a compound represented by the formula (VI'),
which is a Compound (VI) wherein X.sup.2 is a halogen atom, and a
salt thereof are hereinafter to be simply referred to as Compound
(VI')] with an amine compound represented by the formula (VII) or a
salt thereof. The compound represented by the formula (VII) can
form a salt and as such salt, those similar to the salt of the
compound represented by the above-mentioned formula (I) can be
mentioned. In the following, a compound represented by the formula
(VII) and a salt thereof are simply referred to as Compound
(VII).
[0055] This reaction is generally carried out in a solvent and as
such solvent, any solvent can be used as long as it does not
inhibit the reaction. For example, hydrocarbons (e.g., n-hexane,
n-heptane, benzene, toluene, xylene, etc.), halogenated
hydrocarbons (e.g., dichloromethane, etc.), ethers (e.g., diethyl
ether, diisopropyl ether, ethylene glycol dimethyl ether,
tetrahydrofuran, dioxane, etc.), amides (e.g.,
N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone,
etc.), esters (e.g., ethyl acetate, methyl acetate, etc.), nitrites
(e.g., acetonitrile, etc.), sulfoxides (e.g., dimethyl sulfoxide,
etc.), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone,
cyclohexanone, etc.), alcohols (e.g., methanol, ethanol, propanol,
etc.), water and the like can be included. Of these, hydrocarbons
(e.g., n-hexane, n-heptane, benzene, toluene, xylene, etc.), ethers
(e.g., diethyl ether, diisopropyl ether, ethylene glycol dimethyl
ether, tetrahydrofuran, dioxane, etc.), amides (e.g.,
N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone,
etc.), esters (e.g., ethyl acetate, methyl acetate, etc.), nitrites
(e.g., acetonitrile, etc.), and ketones (e.g., acetone, 2-butanone,
4-methyl-2-pentanone, cyclohexanone, etc.) are preferable. These
solvents can be used alone or in a mixture of two or more kinds
thereof.
[0056] The amount of the Compound (VII) to be used is generally 1
mole to 30 moles, preferably 1 mole to 10 moles, per 1 mole of
Compound (VI). Compound (VII) may be used in an aqueous
solution.
[0057] In this reaction, a base may be present to control the
reaction speed, dissolution property and the like. As the base, for
example, sodium hydroxide, potassium hydroxide, sodium
hydrogencarbonate, sodium carbonate, potassium carbonate, potassium
t-butoxide, triethylamine, diisopropylethylamine
diisopropylethylamide, pyridine, dimethylaminopyridine,
1,8-diazabicyclo[5,4,0]-7-undecene and the like are preferable. The
base is used generally in an amount of 1 mole to 100 moles,
preferably 1 mole to 30 moles, per 1 mole of Compound (VI) and may
be used in an aqueous solution.
[0058] This reaction is carried out generally at a reaction
temperature of -20.degree. C. to 150.degree. C., preferably
0.degree. C. to 50.degree. C., for generally 10 min. to 12 hrs.,
preferably 1 hr. to 3 hrs.
[0059] Compound (VI) can be easily available as a commercial
product. Compound (IV) is also commercial available.
Production of Compound (VIII)
[0060] By reduction of Compound (III), a compound represented by
the formula: ##STR47## wherein R.sup.1' is a hydrogen atom or an
amino-protecting group, and R.sup.2 is a hydrogen atom, a
hydrocarbon group optionally having substituents, an alkoxy group
optionally having substituents or a heterocyclic group optionally
having substituents, or a salt thereof can be obtained, which is
deprotected as necessary to give Compound (VIII'). As the
amino-protecting group for R.sup.1, those similar to the
amino-protecting group for R.sup.1 can be mentioned. The compound
represented by the formula (VIII) can form a salt, and as such
salt, those similar to the salt of the compound represented by the
above-mentioned formula (I) can be mentioned. In the following, a
compound represented by the formula (VIII) and a salt thereof are
simply referred to as Compound (VIII). In Compound (VIII), a
compound wherein R.sup.1 is a hydrogen atom and a salt thereof (a
compound represented by the aforementioned formula (VIII') and a
salt thereof) are hereinafter simply referred to as Compound
(VIII').
[0061] The reduction of Compound (III) is generally conducted in a
solvent and as such solvent, any solvent can be used as long as it
does not inhibit the reaction. For example, alcohols (e.g.,
methanol, ethanol, propanol, etc.) and ethers (e.g.,
tetrahydrofuran, etc.) are preferably used. These may be used alone
or in a mixture of two or more kinds thereof. In addition, hydrogen
chloride, acetic acid and the like may be used together with these
solvents.
[0062] For this reduction, hydrogenation reaction is generally
preferably used and, for example, palladium carbon, platinum
carbon, platinum oxide and the like are used as a catalyst. The
catalyst is generally used in an amount of 0.1 wt % to 100 wt %,
preferably 0.5 wt % to 50 wt %, of the weight of Compound (III).
The hydrogen pressure is preferably approximately 0.1 MPa to 10
MPa, which may be an open system.
[0063] This reaction is generally carried out at 0.degree. C. to
100.degree. C., preferably 20.degree. C. to 70.degree. C., for 1 to
12 hrs., preferably 30 min. to 5 hrs.
[0064] By the reduction of Compound (III) wherein R.sup.1 is an
amino-protecting group, Compound (VIII) wherein R.sup.1 is an
amino-protecting group and the same as R.sup.1 can be obtained.
When a compound of the formula (III) wherein R.sup.1 is an
amino-protecting group is used, the protected amino group for
R.sup.1 may be simultaneously deprotected depending on the means of
reduction to give Compound (VIII) wherein R.sup.1 is a hydrogen
atom, i.e., Compound (VIII'). For example, when a compound wherein
R.sup.1 is benzyl or N-benzyloxycarbonyl is used as Compound (III),
and reduction is conducted using palladium carbon as a catalyst,
deprotection takes place simultaneously with the reduction, whereby
Compound (VIII) wherein R.sup.1' is a hydrogen atom, i.e., Compound
(VIII') can be obtained. When a compound wherein R.sup.1 is
t-butoxycarbonyl is used as Compound (III), and when platinum
carbon or platinum oxide is used as a catalyst, Compound (VIII)
wherein R.sup.1' is the same as R.sup.1 can be obtained.
[0065] When a compound wherein R.sup.1' is a hydrogen atom, namely,
Compound (VIII'), is to be produced as Compound (VIII), the
compound can be obtained by deprotection after reduction of
Compound (III). This deprotection can be generally carried out
under, for example, hydrolysis conditions using an aqueous solution
of mineral acid such as hydrochloric acid, sulfuric acid and the
like, and the like. That is, by reaction using 1 equivalent to 100
equivalents of an acid relative to Compound (III) at 0.degree. C.
to 100.degree. C. for 1 to 12 hrs., deprotection is conveniently
conducted.
[0066] Any compound used for the above-mentioned methods or any
compound obtained thereby, and salts thereof can be converted to
each other by a method known per se or a method analogous
thereto.
[0067] Compound (VIII) that can be obtained by the above-mentioned
methods is, for example, reacted with a compound represented by the
formula: ##STR48## wherein G.sup.1 is a bond, CO or SO.sub.2,
X.sup.3 is a leaving group, R.sup.4 is a hydrogen atom, a
hydrocarbon group optionally having substituents, a heterocyclic
group optionally having substituents, an alkoxy group optionally
having substituents, an aryloxy group optionally having
substituents or an amino group optionally having substituents, and
R.sup.5 is a cyclic hydrocarbon group optionally having
substituents or a heterocyclic group optionally having
substituents, or a salt thereof to give a compound represented by
the formula: ##STR49## wherein each symbol is as defined above, or
a salt thereof, which is useful as a therapeutic agent of acquired
immunodeficiency syndrome.
[0068] As the `leaving group` denoted by X.sup.3, for example,
halogen atoms (e.g., chlorine atom, bromine atom, iodine atom,
etc.), alkyl or arylsulfonyloxy groups (e.g., methanesulfonyloxy,
ethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, etc.)
and the like can be mentioned. Of these, chlorine atom is
particularly preferable.
[0069] As the `hydrocarbon group` of the `hydrocarbon group
optionally having substituents` denoted by R.sup.4, for example,
chain aliphatic hydrocarbon group, alicyclic hydrocarbon group,
aryl group and the like can be mentioned. Preferred are chain
aliphatic hydrocarbon group and alicyclic hydrocarbon group.
[0070] As the chain aliphatic hydrocarbon group, for example,
linear or branched chain aliphatic hydrocarbon groups such as alkyl
group, alkenyl group, alkynyl group and the like can be mentioned,
with preference given to alkyl group. As the alkyl group, for
example, C.sub.1-10 alkyl groups (preferably C.sub.1-6 alkyl, etc.)
such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, 1-methylpropyl,
n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl,
3,3-dimethylbutyl, 3,3-dimethylpropyl, 2-ethylbutyl, n-heptyl,
1-methylheptyl, 1-ethylhexyl, n-octyl, 1-methylheptyl, nonyl and
the like, and the like can be mentioned. As the alkenyl group, for
example, C.sub.2-6 alkenyl groups such as vinyl, allyl,
isopropenyl, 2-methylallyl, 1-propenyl, 2-methyl-1-propenyl,
1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl,
2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl,
3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl,
3-hexenyl, 4-hexenyl, 5-hexenyl and the like, and the like can be
mentioned. As the alkynyl group, for example, C.sub.2-6 alkynyl
groups such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl,
2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl,
4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl
and the like can be mentioned.
[0071] As the alicyclic hydrocarbon group, for example, saturated
or unsaturated alicyclic hydrocarbon groups such as cycloalkyl
group, cycloalkenyl group, cycloalkanedienyl group and the like can
be mentioned, with preference given to cycloalkyl group. As the
cycloalkyl group, for example, C.sub.3-9 cycloalkyl (preferably
C.sub.3-8 cycloalkyl, etc.) such as cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and
the like, and the like, and fused rings such as 1-indanyl,
2-indanyl and the like can be mentioned. As the cycloalkenyl group,
for example, C.sub.3-6 cycloalkenyl groups such as
2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl,
3-cyclohexen-1-yl, 1-cyclobuten-1-yl, 1-cyclopenten-1-yl and the
like, and the like can be mentioned. As the cycloalkanedienyl
group, for example, C.sub.4-6 cycloalkadienyl groups such as
2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl,
2,5-cyclohexadien-1-yl and the like, and the like can be
mentioned.
[0072] As the aryl group, monocyclic or condensed polycyclic
aromatic hydrocarbon groups can be mentioned. For example,
C.sub.6-14 aryl groups such as phenyl, naphthyl (e.g., 1-naphthyl,
2-naphthyl), anthryl, phenanthryl, acenaphthylenyl, indanyl (e.g.,
4-indanyl, 5-indanyl) and the like, and the like are preferable,
and phenyl, 1-naphthyl, 2-naphthyl and the like are particularly
preferable.
[0073] As the `substituent` of the `hydrocarbon group optionally
having substituents` denoted by R.sup.4, for example, optionally
substituted alkyl group, optionally substituted alkenyl group,
optionally substituted alkynyl group, optionally substituted aryl
group, optionally substituted cycloalkyl group, optionally
substituted cycloalkenyl group, optionally substituted heterocyclic
group, optionally substituted amino group, optionally substituted
imidoyl group, optionally substituted amidino group, optionally
substituted hydroxyl group, optionally substituted thiol group,
optionally esterified carboxyl group, optionally substituted
carbamoyl group, optionally substituted thiocarbamoyl group,
optionally substituted sulfamoyl group, halogen atoms (e.g.,
fluorine, chlorine, bromine, iodine and the like, preferably
chlorine, bromine, etc.), cyano group, nitro group, sulfonic
acid-derived acyl group, carboxylic acid-derived acyl group,
optionally substituted alkylsulfinyl group, optionally substituted
arylsulfinyl group and the like can be mentioned, wherein 1 to 5
(preferably 1 to 3) of these optional substituents may substitute
at substitutable positions.
[0074] As the aryl group of the `optionally substituted aryl group`
as the substituent, for example, C.sub.6-14 aryl groups such as
phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl and the
like, and the like can be mentioned. As used herein, as the
substituent of the aryl group, lower alkoxy group optionally
substituted by halogen (e.g., C.sub.1-6 alkoxy group such as
methoxy, ethoxy, propoxy and the like, halogen-substituted
C.sub.1-4 alkoxy group such as fluoromethoxy, difluoromethoxy,
trifluoromethoxy, 1,1-difluoroethoxy, 2,2-difluoroethoxy,
3,3-difluoropropoxy, 2,2,3,3,3-pentafluoropropoxy and the like,
etc.), aryloxy optionally having substituents (e.g., phenoxy,
4-fluorophenoxy, 2-carbamoylphenoxy, etc.), halogen atoms (e.g.,
fluorine, chlorine, bromine, iodine, etc.), lower alkyl groups
optionally having substituents (e.g., unsubstituted C.sub.1-6 alkyl
groups such as methyl, ethyl, propyl and the like,
halogen-substituted C.sub.1-4 alkyl group such as fluoromethyl,
difluoromethyl, trifluoromethyl, 1,1-difluoroethyl,
2,2-difluoroethyl, 3,3-difluoropropyl, 2,2,3,3,3-pentafluoropropyl
and the like, etc.), C.sub.3-8 cycloalkyl (e.g., cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.), amino
group, mono-substituted amino (e.g., carbamoylamino,
methylsulfonylamino, methylamino, ethylamino, propylamino, etc.),
di-substituted amino (e.g., dimethylamino, diethylamino,
N-methyl-N-methylsulfonylamino, di(methylsulfonyl)amino, etc.),
carbamoyl group optionally substituted by C.sub.1-6 alkyl (e.g.,
butylcarbamoyl, etc.), formyl, C.sub.2-6 alkanoyl group (e.g.,
acetyl, propionyl, butyryl and the like), C.sub.6-14 aryl group
(e.g., phenyl, naphthyl, etc.), C.sub.6-14 aryl-carbonyl (e.g.,
benzoyl, naphthoyl, etc.), C.sub.7-13 aralkyl-carbonyl (e.g.,
benzylcarbonyl, naphthylmethylcarbonyl, etc.), hydroxyl group,
alkanoyloxy (e.g., C.sub.2-5 alkanoyloxy such as acetyloxy,
propionyloxy, butyryloxy and the like), C.sub.7-13
aralkyl-carbonyloxy (e.g., benzylcarbonyloxy, etc.), nitro group,
optionally substituted sulfamoyl group (unsubstituted sulfamoyl
group, N-methylsulfamoyl, etc.), optionally substituted arylthio
group (e.g., phenylthio, 4-methylphenylthio, etc.),
--N.dbd.N-phenyl, cyano group, amidino group, optionally esterified
carboxyl group (free carboxyl group, C.sub.1-4 alkoxy-carbonyl such
as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl and the like,
etc.), C.sub.1-6 alkylthio, C.sub.1-6 alkylsulfinyl, C.sub.1-6
alkylsulfonyl, C.sub.6-14 arylthio, C.sub.6-14 arylsulfinyl,
C.sub.6-14 arylsulfonyl, heterocyclic group optionally having
substituents (e.g., pyridyl, thienyl, tetrazolyl, morpholinyl,
oxazolyl and the like, as well as those recited as the
`heterocyclic group optionally having substituents` denoted by
R.sup.5 in the following) and the like can be mentioned. One or two
of these optional substituents may substitute at substitutable
positions.
[0075] As the cycloalkyl group of the `optionally substituted
cycloalkyl group` as the substituent, for example, C.sub.3-7
cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl and the like, and the like can be
mentioned. Here, as the substituent of the cycloalkyl group, a
similar number of those similar to the substituent of the
aforementioned `optionally substituted aryl group` can be
mentioned.
[0076] As the cycloalkenyl group of the `optionally substituted
cycloalkenyl group` as the substituent, for example, C.sub.3-6
cycloalkenyl groups such as cyclopropenyl, cyclobutenyl,
cyclopentenyl, cyclohexenyl and the like, and the like can be
mentioned. Here, as the substituent of the optionally substituted
cycloalkenyl group, a similar number of those similar to the
substituent of the aforementioned `optionally substituted aryl
group` can be mentioned.
[0077] As the alkyl group of the `optionally substituted alkyl
group` as a substituent, for example, C.sub.1-6 alkyl such as
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,
t-butyl, n-pentyl, isopentyl, neopentyl, 1-methylpropyl, n-hexyl,
isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl,
3,3-dimethylpropyl and the like, and the like can be mentioned.
Here, as the substituent of the alkyl group, a similar number of
those similar to the substituent of the aforementioned `optionally
substituted aryl group` can be mentioned.
[0078] As the alkenyl group of the `optionally substituted alkenyl
group` as a substituent, for example, C.sub.2-6 alkenyl group such
as vinyl, allyl, isopropenyl, 2-methylallyl, 1-propenyl,
2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl,
2-ethyl-1-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl,
1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,
4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl,
5-hexenyl and the like, and the like can be mentioned. Here, as the
substituent of the alkenyl group, a similar number of those similar
to the substituent of the aforementioned `optionally substituted
aryl group` can be mentioned.
[0079] As the alkynyl group of the `optionally substituted alkynyl
group` as a substituent, for example, C.sub.2-6 alkynyl group such
as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,
3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl,
1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and the like
can be mentioned. Here, as the substituent of the alkynyl group, a
similar number of those similar to the substituent of the
aforementioned `optionally substituted aryl group` can be
mentioned.
[0080] As the heterocyclic group of the `optionally substituted
heterocyclic group` as a substituent, an aromatic heterocyclic
group, a saturated or unsaturated non-aromatic heterocyclic group
(aliphatic heterocyclic group) and the like, which contain, as an
atom constituting the ring (ring atom), at least one (preferably 1
to 4, more preferably 1 or 2) of 1 to 3 kinds (preferably 1 or 2
kinds) of hetero atoms, which is selected from oxygen atom, sulfur
atom and nitrogen atom, and the like can be mentioned.
[0081] As the substituent of the `optionally substituted amino
group`, `optionally substituted imidoyl group`, `optionally
substituted amidino group`, `optionally substituted hydroxyl group`
and `optionally substituted thiol group`, as a substituent, for
example, lower alkyl groups (e.g., C.sub.1-6 alkyl group such as
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl,
hexyl and the like, etc.), optionally substituted aryl groups
(e.g., phenyl, 4-methylphenyl etc.), acyl groups (e.g., C.sub.1-6
alkanoyl such as formyl, acetyl, propionyl, pivaloyl etc.),
arylcarbonyl (e.g., benzoyl etc.), substituted sulfonyl (e.g.,
alkylsulfonyl such as C.sub.1-6 alkylsulfonyl (e.g.,
methylsulfonyl, ethylsulfonyl and the like), C.sub.6-14
arylsulfonyl (e.g., p-toluenesulfonyl etc.), aminosulfonyl,
methylaminosulfonyl, dimethylaminosulfonyl etc.), optionally
halogenated C.sub.1-6 alkoxy-carbonyl (e.g.,
trifluoromethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl,
trichloromethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl etc.)) and
the like can be mentioned.
[0082] The `amino group` of the `optionally substituted amino
group` as a substituent may be substituted by, besides the
above-mentioned substituents, optionally substituted imidoyl groups
(e.g., C.sub.1-6 alkylimidoyl, formylimidoyl, amidino etc.) and the
like, and in some cases, two substituents together with a nitrogen
atom form a cyclic amino group. As the cyclic amino group in such
cases, for example, 3- to 8-membered (preferably 5- or 6-membered)
cyclic amino and the like, such as 1-azetidinyl; 1-pyrrolidinyl;
piperidino (1-piperidinyl); morpholino (4-morpholinyl);
1-piperazinyl; 1-piperazinyl optionally having lower alkyl groups
(e.g., C.sub.1-6 alkyl groups such as methyl, ethyl, propyl,
isopropyl, butyl, t-butyl, pentyl, hexyl and the like, etc.),
aralkyl groups (e.g., C.sub.7-10 aralkyl groups such as benzyl,
phenethyl and the like, etc.), aryl groups (e.g., C.sub.6-10 aryl
groups such as phenyl, 1-naphthyl, 2-naphthyl and the like, etc.)
and the like at the 4-position; and the like can be mentioned.
[0083] As the `optionally substituted carbamoyl group`,
N-mono-substituted carbamoyl group and N,N-di-substituted carbamoyl
group can be mentioned besides the unsubstituted carbamoyl.
[0084] The `N-mono-substituted carbamoyl group` means a carbamoyl
group having one substituent on a nitrogen atom, and as the
substituent, for example, lower alkyl groups (e.g., C.sub.1-6 alkyl
groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
t-butyl, pentyl, hexyl and the like, etc.), cycloalkyl groups
(e.g., C.sub.3-6 cycloalkyl groups such as cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl and the like, etc.), aryl groups (e.g.,
C.sub.6-10 aryl groups such as phenyl, 1-naphthyl, 2-naphthyl and
the like, etc.), aralkyl groups (e.g., C.sub.7-10 aralkyl groups
such as benzyl, phenethyl and the like, preferably phenyl-C.sub.1-4
alkyl group etc.), heterocyclic groups (e.g., those similar to the
`heterocyclic group` as a substituent of the aforementioned
`optionally substituted hydrocarbon group` denoted by R.sup.1, and
the like) can be mentioned. The lower alkyl group, cycloalkyl
group, aryl group, aralkyl group and heterocyclic group may have a
substituent, and as the substituent, for example, hydroxyl group,
optionally substituted amino group [said amino group may have, as
substituent, 1 or 2 of, for example, lower alkyl groups (e.g.,
C.sub.1-6 alkyl groups such as methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, t-butyl, pentyl, hexyl and the like, etc.), acyl
groups (e.g., C.sub.1-6 alkanoyl (e.g., formyl, acetyl, propionyl,
pivaloyl etc.), arylcarbonyl (e.g., benzoyl etc.), C.sub.1-6
alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl etc.)) and the
like], halogen atoms (e.g., fluorine, chlorine, bromine, iodine
etc.), nitro group, cyano group, lower alkyl groups (e.g.,
C.sub.1-6 alkyl groups such as methyl, ethyl, n-propyl, isopropyl,
n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the
like, and the like, with particularly preference given to methyl,
ethyl, etc.) optionally substituted by 1 to 5 halogen atoms (e.g.,
fluorine, chlorine, bromine, iodine etc.), lower alkoxy groups
(e.g., C.sub.1-6 alkoxy groups such as methoxy, ethoxy, n-propoxy,
isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the
like, and the like, with particularly preference given to methoxy,
ethoxy and the like) optionally substituted by 1 to 5 halogen atoms
(e.g., fluorine, chlorine, bromine, iodine etc.), and the like can
be mentioned. These substituents may be the same or different and 1
or 2 or 3 (preferably 1 or 2) thereof preferably substitute.
[0085] The `N,N-di-substituted carbamoyl group` means a carbamoyl
group having two substituents on the nitrogen atom, wherein the two
substituents on the nitrogen atom may be the same or different.
Examples of one of the substituents include those similar to the
substituents of the above-mentioned `N-mono-substituted carbamoyl
group`, and examples of the other of the substituents include lower
alkyl groups (e.g., C.sub.1-6 alkyl groups such as methyl, ethyl,
propyl, isopropyl, butyl, t-butyl, pentyl, hexyl and the like
etc.), C.sub.3-6 cycloalkyl groups (e.g., cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl etc.), C.sub.7-10 aralkyl groups (e.g.,
benzyl, phenethyl and the like, preferably phenyl-C.sub.1-4 alkyl
group etc.) and the like can be mentioned. In addition, two
substituents may form a cyclic amino group together with a nitrogen
atom, and as the cyclic aminocarbonyl group in such case, for
example, 3- to 8-membered (preferably 5- or 6-membered) cyclic
amino-carbonyl such as 1-azetidinylcarbonyl;
1-pyrrolidinylcarbonyl; 1-piperidinylcarbonyl;
4-morpholinylcarbonyl; 1-piperazinylcarbonyl; 1-piperazinylcarbonyl
having, at the 4-position, lower alkyl groups (e.g., C.sub.1-6
alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl,
t-butyl, pentyl, hexyl and the like, etc.), aralkyl groups (e.g.,
C.sub.7-10 aralkyl groups such as benzyl, phenethyl and the like,
etc.), aryl groups (e.g., C.sub.6-10 aryl groups such as phenyl,
1-naphthyl, 2-naphthyl and the like, etc.) and the like; and the
like, and the like can be mentioned.
[0086] As the substituent of the `optionally substituted
thiocarbamoyl group`, those similar to the substituent of the
aforementioned `optionally substituted carbamoyl group` can be
mentioned.
[0087] As the `sulfamoyl group optionally having substituents`,
unsubstituted sulfamoyl as well as N-mono-substituted sulfamoyl
group and N,N-di-substituted sulfamoyl group can be mentioned.
[0088] The `N-mono-substituted sulfamoyl group` means a sulfamoyl
group having one substituent on the nitrogen atom. As the
substituent, those similar to the substituent of the
N-mono-substituted carbamoyl group can be mentioned.
[0089] The `N,N-di-substituted sulfamoyl group` means a sulfamoyl
group having two substituents on the nitrogen atom. As the
substituent, those similar to the substituent of the
N,N-di-substituted carbamoyl group can be mentioned.
[0090] As the `optionally esterified carboxyl group`, free carboxyl
group as well as, for example, lower alkoxycarbonyl group,
aryloxycarbonyl group, aralkyloxycarbonyl group and the like can be
mentioned.
[0091] As the `lower alkoxycarbonyl group`, for example, C.sub.1-6
alkoxy-carbonyl groups such as methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
isobutoxycarbonyl, sec-butoxycarbonyl, t-butoxycarbonyl,
pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl and
the like and the like can be mentioned. Of these, C.sub.1-3
alkoxy-carbonyl groups such as methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl and the like, and the like are preferable.
[0092] As the `aryloxycarbonyl group`, for example, C.sub.6-12
aryloxy-carbonyl groups such as phenoxycarbonyl,
1-naphthoxycarbonyl, 2-naphthoxycarbonyl and the like, and the like
are preferable.
[0093] As the `aralkyloxycarbonyl group`, for example, C.sub.7-14
aralkyloxy-carbonyl groups such as benzyloxycarbonyl,
phenethyloxycarbonyl and the like (preferably C.sub.6-10
aryl-C.sub.1-2 alkoxy-carbonyl, etc.), and the like are
preferable.
[0094] The `aryloxycarbonyl group` and `aralkyloxycarbonyl group`
may have a substituent, and as the substituent, a similar number of
those similar to the substituent of the aryl group and aralkyl
group as examples of the substituent of the aforementioned
`N-mono-substituted carbamoyl group` can be used.
[0095] As the `sulfonic acid-derived acyl group` as a substituent,
one wherein hydrocarbon group is linked with sulfonyl, and the like
can be mentioned, with preference given to acyl such as C.sub.1-10
alkylsulfonyl, C.sub.2-6 alkenylsulfonyl, C.sub.2-6
alkynylsulfonyl, C.sub.3-9 cycloalkylsulfonyl, C.sub.3-9
cycloalkenylsulfonyl, C.sub.6-14 arylsulfonyl, C.sub.7-10
aralkylsulfonyl and the like can be mentioned. Specific examples of
C.sub.1-10 alkyl include methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl and the like. As
the C.sub.2-6 alkenyl, for example, vinyl, allyl, 1-propenyl,
isopropenyl, 2-butenyl, 3-butenyl, 2-hexenyl and the like can be
mentioned. As the C.sub.2-6 alkynyl, for example, ethynyl,
2-propynyl, 2-butynyl, 5-hexynyl and the like can be mentioned. As
the C.sub.3-9 cycloalkyl, for example, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cyclooctyl and the like can be mentioned.
As the C.sub.3-9 cycloalkenyl, for example, 1-cyclopenten-1-yl,
2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 3-cyclohexen-1-yl,
3-cycloocten-1-yl and the like can be mentioned. As the C.sub.6-14
aryl, phenyl, 1-naphthyl, 2-naphthyl and the like can be mentioned.
As the C.sub.7-10 aralkylsulfonyl, for example, benzyl, phenethyl
and the like can be mentioned.
[0096] These hydrocarbon groups linked with sulfonyl may have a
substituent, and as the substituent, for example, hydroxyl group,
optionally substituted amino groups [said amino group may have 1 or
2 substituents from, for example, lower alkyl groups (e.g.,
C.sub.1-6 alkyl groups such as methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, t-butyl, pentyl, hexyl and the like, etc.), acyl
groups (e.g., C.sub.1-6 alkanoyl (e.g., formyl, acetyl, propionyl,
pivaloyl etc.), arylcarbonyl (e.g., benzoyl etc.), C.sub.1-6
alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl etc.)) and the
like], halogen atoms (e.g., fluorine, chlorine, bromine, iodine
etc.), nitro group, cyano group, lower alkyl group (e.g., C.sub.1-6
alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like, and
the like, particularly preferably methyl, ethyl and the like)
optionally substituted by 1 to 5 halogen atoms (e.g., fluorine,
chlorine, bromine, iodine etc.), lower alkoxy group (e.g.,
C.sub.1-6 alkoxy group such as methoxy, ethoxy, n-propoxy,
isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the
like, and the like, particularly preferably methoxy, ethoxy and the
like) optionally substituted by 1 to 5 halogen atoms (e.g.,
fluorine, chlorine, bromine, iodine etc.), and the like can be
mentioned. These substituents may be the same or different and 1 or
2 or 3 (preferably 1 or 2) thereof preferably substitute.
[0097] As the `carboxylic acid-derived acyl group` as a
substituent, one wherein hydrogen atom or a substituent that the
aforementioned `N-mono-substituted carbamoyl group` has on a
nitrogen atom is bonded to carbonyl and the like can be mentioned.
Preferred are acyl such as C.sub.1-6 alkanoyl such as formyl,
acetyl, trifluoroacetyl, propionyl, butyryl, isobutyryl, pivaloyl
and the like, arylcarbonyl such as benzoyl and the like, and the
like can be mentioned.
[0098] As the alkyl of the `optionally substituted alkylsulfinyl
group` as a substituent, for example, lower alkyl groups such as
C.sub.1-6 alkyl groups (e.g., methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, t-butyl, pentyl, hexyl etc.) and the like can be
mentioned.
[0099] As the aryl of the `optionally substituted arylsulfinyl
group` as a substituent, for example, C.sub.6-14 aryl groups such
as phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl and the
like and the like can be mentioned.
[0100] As the `substituent` of the `optionally substituted
alkylsulfinyl group` and `optionally substituted arylsulfinyl
group`, lower alkoxy groups (e.g., C.sub.1-6 alkoxy groups such as
methoxy, ethoxy, propoxy and the like, etc.), halogen atoms (e.g.,
fluorine, chlorine, bromine, iodine etc.), lower alkyl groups
(e.g., C.sub.1-6 alkyl groups such as methyl, ethyl, propyl and the
like, etc.), amino group, hydroxyl group, cyano group, amidino
group and the like can be mentioned. One or two of these optional
substituents may be substituted at substitutable positions.
[0101] As the `heterocyclic group optionally having substituents`
denoted by R.sup.4, those similar to the `heterocyclic group
optionally having substituents` denoted by the following R.sup.5
can be mentioned.
[0102] As the `alkoxy group` of the `alkoxy group optionally having
substituents` denoted by R.sup.4, for example, C.sub.1-6 alkoxy
such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,
isobutoxy, sec-butoxy, t-butoxy and the like are preferable. As the
`substituent`, for example, lower alkyl (e.g., C.sub.1-6 alkyl such
as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl,
n-hexyl and the like), cycloalkyl groups (e.g., C.sub.3-6
cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl and the like, etc.), aryl groups (e.g., C.sub.6-10 aryl
groups such as phenyl, 1-naphthyl, 2-naphthyl and the like, etc.),
aralkyl groups (e.g., C.sub.7-10 aralkyl groups such as benzyl,
phenethyl and the like, preferably phenyl-C.sub.1-4 alkyl group,
etc.), heterocyclic groups (e.g., those similar to `heterocyclic
group` as a substituent of the above-mentioned `hydrocarbon group`
optionally having substituent` denoted by R.sup.4, etc.) and the
like can be mentioned.
[0103] The lower alkyl group, cycloalkyl group, aryl group, aralkyl
group and heterocyclic group may have a substituent, and as the
substituent, for example, hydroxyl group, optionally substituted
amino group [said amino group may have 1 or 2 substituents from,
for example, lower alkyl groups (e.g., C.sub.1-6 alkyl groups such
as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl,
pentyl, hexyl and the like etc.), acyl groups (e.g., C.sub.1-6
alkanoyl such as formyl, acetyl, propionyl, pivaloyl and the like,
arylcarbonyl such as benzoyl and the like, C.sub.1-6 alkylsulfonyl
such as methylsulfonyl, ethylsulfonyl and the like, etc.) and the
like], halogen atoms (e.g., fluorine, chlorine, bromine, iodine,
etc.), nitro group, cyano group, lower alkyl group optionally
substituted by 1 to 5 halogen atoms (e.g., fluorine, chlorine,
bromine, iodine, etc.), lower alkoxy group optionally substituted
by 1 to 5 halogen atoms (e.g., fluorine, chlorine, bromine, iodine,
etc.) and the like can be mentioned. As the lower alkyl group, for
example, C.sub.1-6 alkyl groups such as methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, hexyl and
the like, and the like can be mentioned, particularly methyl, ethyl
and the like are preferable. As the lower alkoxy group, for
example, C.sub.1-6 alkoxy groups such as methoxy, ethoxy,
n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy
and the like, and the like can be mentioned, with particular
preference given to methoxy, ethoxy and the like. These
substituents are the same or different and 1 or 2 or 3 (preferably
1 or 2) thereof are preferably used for substitution.
[0104] As the `aryl group` of the `aryloxy group optionally having
substituents` denoted by R.sup.4, for example, C.sub.6-14 aryl
groups such as phenyl, naphthyl, anthryl, phenanthryl,
acenaphthylenyl and the like, and the like can be mentioned. As the
`substituent`, lower alkoxy groups (e.g., C.sub.1-6 alkoxy groups
such as methoxy, ethoxy, propoxy and the like, etc.), halogen atoms
(e.g., fluorine, chlorine, bromine, iodine, etc.), lower alkyl
groups (e.g., C.sub.1-6 alkyl groups such as methyl, ethyl, propyl
and the like, etc.), amino group, hydroxyl group, cyano group,
amidino group and the like can be mentioned. One or two of these
optional substituents may substitute at substitutable
positions.
[0105] As the `substituent` of the `amino group optionally having
substituents` denoted by R.sup.4, for example, lower alkyl groups
(e.g., C.sub.1-6 alkyl groups such as methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl and the like,
etc.), acyl groups (e.g., C.sub.1-6 alkanoyls such as formyl,
acetyl, propionyl, pivaloyl, etc., arylcarbonyl (e.g., benzoyl,
etc.)), optionally halogenated C.sub.1-6 alkoxy-carbonyl (e.g.,
trifluoromethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl,
trichloromethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, etc.) and
the like can be mentioned. The `amino group` of the `amino group
optionally having substituents` denoted by R.sup.4 may be
substituted by optionally substituted imidoyl group (e.g.,
C.sub.1-6 alkylimidoyl, formylimidoyl, amidino, etc.) and the like.
In some cases, two substituents form a cyclic amino group together
with nitrogen atom, as the cyclic amino group in such case, for
example, 3-to 8-membered (preferably 5- or 6-membered) cyclic amino
groups such as 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl,
4-morpholinyl, 1-piperazinyl and 1-piperazinyl optionally having,
at the 4-position, lower alkyl groups (e.g., C.sub.1-6 alkyl groups
such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl,
hexyl and the like, etc.), aralkyl groups (e.g., C.sub.7-10 aralkyl
groups such as benzyl, phenethyl and the like, etc.), aryl groups
(e.g., C.sub.6-10 aryl groups such as phenyl, 1-naphthyl,
2-naphthyl and the like, etc.) and the like, and the like, and the
like can be mentioned.
[0106] As R.sup.4, C.sub.1-3 alkyl, phenyl optionally having
substituents, 3-pyridyl, 4-pyridyl and the like are preferable.
Particularly, methyl group is preferable.
[0107] As the `cyclic hydrocarbon group` of the `cyclic hydrocarbon
group optionally having substituents` denoted by R.sup.5, alicyclic
hydrocarbon group, aryl group and the like can be mentioned.
[0108] As the alicyclic hydrocarbon group, for example, saturated
or unsaturated alicyclic hydrocarbon groups such as cycloalkyl
group, cycloalkenyl group, cycloalkanedienyl group and the like can
be mentioned. Preferred is cycloalkyl group. As the cycloalkyl
group, for example, C.sub.3-9 cycloalkyl (preferably C.sub.3-8
cycloalkyl, etc.) such as cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and the like, and
the like, and fused rings such as 1-indanyl, 2-indanyl and the
like, can be mentioned. As the cycloalkenyl group, for example,
C.sub.3-6 cycloalkenyl groups such as 2-cyclopenten-1-yl,
3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl,
1-cyclobuten-1-yl, 1-cyclopenten-1-yl and the like, and the like
can be mentioned. As the cycloalkanedienyl group, for example,
C.sub.4-6 cycloalkadienyl groups such as 2,4-cyclopentadien-1-yl,
2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl and the like, and
the like can be mentioned.
[0109] As the aryl group, for example, monocyclic or condensation
polycyclic aromatic hydrocarbon groups can be mentioned, with
preference given to C.sub.6-14 aryl groups such as phenyl,
naphthyl, anthryl, phenanthryl, acenaphthylenyl, 4-indanyl,
5-indanyl and the like, and the like. Of these, phenyl, 1-naphthyl,
2-naphthyl and the like are particularly preferable.
[0110] As the `substituent` of the `cyclic hydrocarbon group
optionally having substituents` denoted by R.sup.5, those mentioned
as the `substituent` of the aforementioned `hydrocarbon group
optionally having substituents` denoted by R.sup.4 can be
mentioned. When the cyclic hydrocarbon group is an alicyclic
hydrocarbon group, for example, phenyl group, phenyl group
optionally substituted by C.sub.1-6 alkyl such as tolyl group and
the like, naphthyl group and the like can be mentioned. When the
cyclic hydrocarbon group is an aryl group, for example, halogen
atoms (e.g., chlorine atom, fluorine atom, etc.), C.sub.1-6 alkyl
groups (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
t-butyl, pentyl, hexyl, etc.), C.sub.1-6 alkoxy groups (e.g.,
methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, etc.), C.sub.3-6
cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, etc.), halogenated C.sub.1-6 alkyl groups (e.g.,
trifluoromethyl, etc.), halogenated C.sub.1-6 alkoxy groups (e.g.,
trifluoromethyloxy, etc.), C.sub.1-6 alkylthio groups (e.g.,
methylthio, ethylthio, etc.), C.sub.1-6 alkylsulfonyl groups (e.g.,
methylsulfonyl, ethylsulfonyl, etc.), cyano group, nitro group and
the like can be mentioned.
[0111] As the `heterocyclic group` of the `heterocyclic group
optionally having substituents` denoted by R.sup.5, for example,
aromatic heterocyclic group and saturated or unsaturated
non-aromatic heterocyclic group (aliphatic heterocyclic group),
containing, as a ring-constituting atom (ring atom), at least 1
(preferably 1 to 4, more preferably 1 or 2) of 1 to 3 kinds
(preferably 1 or 2 kinds) of hetero atoms, which is selected from
oxygen atom, sulfur atom and nitrogen atom, and the like, and the
like can be mentioned.
[0112] As the aromatic heterocyclic group, aromatic monocyclic
heterocyclic groups (e.g., 5- or 6-membered aromatic monocyclic
heterocyclic groups such as furyl, thienyl, pyrrolyl, oxazolyl,
isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl,
1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,
1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl,
pyrimidinyl, pyrazinyl, triazinyl and the like) and aromatic fused
heterocycle groups [e.g., 8- to 12-membered aromatic fused
heterocycle groups such as benzofuranyl, isobenzofuranyl,
benzothienyl, indolyl, isoindolyl, 1H-indazolyl, benzindazolyl,
benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, benzopyranyl,
1,2-benzisothiazolyl, benzodioxolyl, benzimidazolyl,
2,1,1-benzoxadiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl,
cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl,
naphthyridinyl, purinyl, pteridinyl, carbazolyl,
.alpha.-carbolinyl, .beta.-carbolinyl, .gamma.-carbolinyl,
acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl,
phenoxathiinyl, thianthrenyl, phenathridinyl, phenathrolinyl,
indolizinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl,
pyrazolo[3,4-b]pyridyl, imidazo[1,2-a]pyridyl,
imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl,
imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl,
1,2,4-triazolo[4,3-b]pyridazinyl and the like (preferably a
heterocycle wherein the aforementioned 5- or 6-membered aromatic
monocyclic heterocyclic group is condensed with a benzene ring or a
heterocycle wherein the same or different two heterocycles of the
aforementioned 5- or 6-membered aromatic monocyclic heterocyclic
group are condensed)] and the like can be mentioned.
[0113] As the non-aromatic heterocyclic group, for example, 3-to
8-membered (preferably 5- or 6-membered) saturated or unsaturated
(preferably saturated) non-aromatic heterocyclic groups (aliphatic
heterocyclic groups) such as oxiranyl, azetidinyl, oxetanyl,
thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidinyl,
tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl and
the like, and the like can be mentioned.
[0114] As the `substituent` of the `heterocyclic group optionally
having substituents` denoted by R.sup.5, those mentioned as the
`substituent` of the aforementioned `hydrocarbon group optionally
having substituents` denoted by R.sup.4 can be mentioned.
[0115] As the R.sup.5, phenyl groups optionally having substituents
are preferable. Of these, a phenyl group having 1 or 2 substituents
selected from the group consisting of halogen atom and methyl group
is particularly preferable.
[0116] As the G.sup.1, carbonyl (CO) is preferable.
[0117] The compound represented by the formula (IX) can form a
salt, and as such salt, those similar to the salts of the compound
represented by the formula (I) can be mentioned. In the following,
a compound represented by the formula (IX) and a salt thereof are
simply referred to as Compound (IX).
[0118] The reaction between Compound (VIII) and Compound (IX) can
be carried out according to the method described in ORGANIC
FUNCTIONAL GROUP PREPARATIONS, the second edition, ACADEMIC PRESS,
INC.
[0119] This reaction is generally carried out in a solvent inert to
the reaction. As such solvent, alcohol solvent, ether solvent,
halogen solvent, aromatic solvent, acetonitrile,
N,N-dimethylformamide (DMF), acetone, methyl ethyl ketone, dimethyl
sulfoxide (DMSO) and the like can be used alone or in a mixture. Of
these, acetonitrile, dimethylformamide, acetone, ethanol and the
like are preferable.
[0120] Compound (VIII) is generally used in an amount of 0.8 mole
to 1.5 moles, preferably 1 mole to 1.3 moles, per 1 mole of
Compound (IX). The reaction temperature is generally from room
temperature to 100.degree. C., preferably 30.degree. C. to
90.degree. C., and the reaction time is generally 0.5 hr. to 1
day.
[0121] In this reaction, 1 to 5 equivalents of a base is generally
added relative to Compound (IX), but it is not necessarily
essential. As such base, 1) strong bases such as hydrides of alkali
metal or alkaline earth metal (e.g., lithium hydride, sodium
hydride, potassium hydride, calcium hydride, etc.), amides of
alkali metal or alkaline earth metal (e.g., lithium amide, sodium
amide, lithium diisopropylamide, lithium dicyclohexylamide, lithium
hexamethyl disilazide, sodium hexamethyl disilazide, potassium
hexamethyl disilazide, etc.), lower alkoxides of alkali metal or
alkaline earth metal (e.g., sodium methoxide, sodium ethoxide,
potassium t-butoxide, etc.) and the like, 2) inorganic bases such
as hydroxides of alkali metal or alkaline earth metal (e.g., sodium
hydroxide, potassium hydroxide, lithium hydroxide, barium
hydroxide, etc.), carbonates of alkali metal or alkaline earth
metal (e.g., sodium carbonate, potassium carbonate, cesium
carbonate, etc.), hydrogencarbontes of alkali metal or alkaline
earth metal (e.g., sodium hydrogencarbonate, potassium
hydrogencarbonate, etc.) and the like, 3) organic bases such as
amines of triethylamine, diisopropylethylamine, N-methylmorpholine,
dimethylaminopyridine, DBU (1,8-diazabicyclo[5.4.0]-7-undecene),
DBN (1,5-diazabicyclo[4.3.0]non-5-ene) and the like, basic
heterocyclic compounds such as pyridine imidazole, 2,6-lutidine and
the like, and the like can be mentioned.
[0122] To promote the reaction, for example, alkali metal iodides
such as potassium iodide, sodium iodide and the like are desirably
co-used. Of these, co-use of potassium iodide is particularly
preferable. The alkali metal iodide is generally used in an amount
of 0.1 mole to 5 moles, preferably 0.5 mole to 3 moles, per 1 mole
of Compound (IX).
[0123] As the salt of the compound of the formula (X), acid
addition salts such as inorganic acid salts (e.g., hydrochloride,
sulfate, hydrobromide, phosphate, etc.), organic acid salts (e.g.,
acetate, trifluoroacetate, succinate, maleate, fumarate,
propionate, citrate, tartrate, lactate, oxalate, methanesulfonate,
p-toluenesulfonate, etc.) and the like, salts with bases (e.g.,
alkali metal salts such as potassium salt, sodium salt, lithium
salt and the like, alkaline earth metal salts such as calcium salt,
magnesium salt and the like, salts with organic bases such as
ammonium salt, trimethylamine salt, triethylamine salt,
t-butyldimethylamine salt, dibenzylmethylamine salt,
benzyldimethylamine salt, N,N-dimethylaniline salt, pyridine salt,
quinoline salt and the like) may be formed.
[0124] In the following, a compound represented by the formula (X)
and a salt thereof are simply referred to as Compound (X).
[0125] The Compound (IX) used as a starting material in this
reaction can be synthesized by using a compound represented by the
formula: ##STR50## wherein R.sup.6 is a carboxyl group, a sulfonic
acid group or a salt thereof or a reactive derivative thereof, and
other symbols are as defined above, or a salt thereof, as a
starting material according to a conventionally known method. In
some cases, the compound represented by the formula (XIII) can form
a salt, and such salt, those similar to the salts of the compound
represented by the formula (I), as well as acid addition salts such
as inorganic acid salts (e.g., hydrochloride, sulfate,
hydrobromide, phosphate, etc.), organic acid salts (e.g., acetate,
trifluoroacetate, succinate, maleate, fumarate, propionate,
citrate, tartrate, lactate, oxalate, methanesulfonate,
p-toluenesulfonate, etc.) and the like can be mentioned. In the
following, a compound represented by the formula (XIII) and a salt
thereof are simply referred to as Compound (XIII). In Compound
(XIII), a compound, wherein R.sup.6 is a carboxyl group, or a salt
thereof corresponds to a compound represented by the aforementioned
the formula (XII) or a salt thereof. In the following, a compound
represented by the formula (XII) and a salt thereof are simply
referred to as Compound (XII). Of the Compound (XIII), Compound
(XII) is preferable.
[0126] As the reactive derivative of carboxy group denoted by
R.sup.6, for example, a reactive derivative such as acid halide,
acid azide, acid anhydride, mixed acid anhydride, active amide,
active ester, active thio ester, isocyanate and the like is
subjected to acylation reaction. As the acid halide, for example,
acid chloride, acid bromide and the like can be mentioned.
[0127] As the mixed acid anhydride, for example, mono C.sub.1-6
alkyl carbonate mixed acid anhydride (e.g., mixed acid anhydride of
free acid and monomethyl carbonate, monoethyl carbonate,
monoisopropyl carbonate, monoisobutyl carbonate, mono-t-butyl
carbonate, monobenzyl carbonate, mono (p-nitrobenzyl) carbonate,
monoallyl carbonate and the like), C.sub.1-6 aliphatic carboxylic
mixed acid anhydride (e.g., mixed acid anhydride of free acid and
acetic acid, trichloroacetic acid, cyanoacetic acid, propionic
acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid,
pivalic acid, trifluoroacetic acid, trichloroacetic acid,
acetoacetic acid and the like), C.sub.7-12 aromatic carboxylic
mixed acid anhydride (e.g., mixed acid anhydride of free acid and
benzoic acid, p-toluic acid, p-chlorobenzoic acid and the like),
organic sulfonic mixed acid anhydride (e.g., mixed acid anhydride
of free acid and methanesulfonic acid, ethanesulfonic acid,
benzenesulfonic acid, p-toluenesulfonic acid and the like) and the
like can be mentioned.
[0128] As the active amide, for example, amide with
nitrogen-containing heterocyclic compound [e.g., acid amide of free
acid and pyrazole, imidazole, benzotriazole and the like, wherein
these nitrogen-containing heterocyclic compounds are optionally
substituted by C.sub.1-6 alkyl groups (e.g., methyl, ethyl, etc.),
C.sub.1-6 alkoxy groups (e.g., methoxy, ethoxy, etc.), halogen
atoms (e.g., fluorine, chlorine, bromine, etc.), oxo groups, thioxo
group, C.sub.1-6 alkylthio groups (e.g., methylthio, ethylthio,
etc.) and the like] and the like can be mentioned.
[0129] As the active ester, any that can be used for this object in
the field of .beta.-lactam and peptide syntheses can be used. For
example, organic phosphoric acid ester (e.g., diethoxyphosphoric
acid ester, diphenoxyphosphoric acid ester, etc.), as well as
p-nitrophenyl ester, 2,4-dinitrophenyl ester, cyanomethyl ester,
pentachlorophenyl ester, N-hydroxysuccinimide ester,
N-hydroxyphthalimide ester, 1-hydroxybenzotriazole ester,
6-chloro-1-hydroxybenzotriazole ester, 1-hydroxy-1H-2-pyridone
ester and the like can be mentioned.
[0130] As the active thio ester, for example, ester with aromatic
heterocycle thiol compound [e.g., 2-pyridylthiol ester,
2-benzothiazolylthiol ester and the like, wherein these
heterocycles are optionally substituted by C.sub.1-6 alkyl groups
(e.g., methyl, ethyl, etc.), C.sub.1-6 alkoxy groups (e.g.,
methoxy, ethoxy, etc.), halogen atoms (e.g., fluorine, chlorine,
bromine, etc.), C.sub.1-6 alkylthio groups (e.g., methylthio,
ethylthio, etc.) and the like] can be mentioned.
[0131] As the `reactive derivative of sulfonic acid group` denoted
by R.sup.6, for example, sulfonyl halides (e.g., sulfonyl chloride,
sulfonyl bromide, etc.), sulfonylazide, acid anhydrides thereof and
the like can be mentioned.
[0132] The Compound (IX) can be produced, for example, by reacting
Compound (XII) with a compound represented by the formula:
##STR51## or a salt thereof. The compound represented by the
formula (XI) can form a salt, and as such salt, those similar to
the salt of the compound represented by the formula (I) can be
mentioned. In the following, a compound represented by the formula
(XI) and a salt thereof are simply referred to as Compound
(XI).
[0133] The reaction between Compound (XII) and Compound (XI) is
generally carried out via a reactive derivative of carboxyl group,
and the reactive derivative may or may not be isolated. As the
reactive derivative of carboxyl group, those mentioned above can be
used. Generally, acid chloride is used, which is comparatively
easily prepared and advantageous in cost.
[0134] The solvent to be used for this reaction may be any as long
as it does not inhibit the reaction. For example, hydrocarbons
(e.g., n-hexane, n-heptane, benzene, toluene, xylene etc.),
halogenated hydrocarbons (e.g., dichloromethane etc.), ethers
(e.g., diethyl ether, diisopropyl ether, ethylene glycol dimethyl
ether, tetrahydrofuran, dioxane etc.), amides (e.g.,
N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone
etc.), esters (e.g., ethyl acetate, methyl acetate etc.), nitriles
(e.g., acetonitrile etc.), sulfoxides (e.g., dimethyl sulfoxide
etc.), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone,
cyclohexanone, etc.) and the like can be mentioned. Of these,
hydrocarbons (e.g., n-hexane, n-heptane, benzene, toluene, xylene
etc.), ethers (e.g., diethyl ether, diisopropyl ether, ethylene
glycol dimethyl ether, tetrahydrofuran, dioxane etc.), amides
(e.g., N,N-dimethylformamide, N,N-dimethylacetamide,
N-methylpyrrolidone etc.), esters (e.g., ethyl acetate, methyl
acetate etc.), nitriles (e.g., acetonitrile etc.) and ketones
(e.g., acetone, 2-butanone, 4-methyl-2-pentanone, cyclohexanone
etc.) are preferable. These solvents may be used alone or in a
mixture of two or more kinds.
[0135] The Compound (XII) is generally used in an amount of 1 mole
to 3 moles, preferably 1 mole to 2 moles, per 1 mole of Compound
(XI). The reaction between Compound (XII) and Compound (XI) is
carried out generally at -20.degree. C. to 100.degree. C.,
preferably 0.degree. C. to 30.degree. C., for 30 min. to 6 hrs.,
preferably 1 hr. to 3 hrs.
[0136] For conversion of --COOH group to --COCl group, thionyl
chloride and the like are preferably and used generally in an
amount of 1 mole to 30 moles, preferably 1 mole to 10 moles, per 1
mole of Compound (XII). For isolation of acid chloride, it may be
used in around 30 moles also as a solvent, and when the reaction
with Compound (XI) is continued without isolation of an acid
chloride, it is more preferably used in 1 mole to 2 moles. This
conversion is performed generally at -20.degree. C. to 100.degree.
C., preferably 0.degree. C. to 60.degree. C., for 5 min. to 6 hrs.,
preferably 10 min. to 3 hrs.
[0137] The Compound (XII) can be obtained easily from, for example,
commercially available isonipecotic acid derivatives by alkylation
reaction, acylation reaction, sulfonylation and the like known per
se, and some may be available as commercial products. The Compound
(XI) can be obtained from commercially available or known aniline
derivative by a method known per se, such as N-alkylation and the
like.
[0138] The compound or a salt thereof obtained by the
above-mentioned method can be isolated or purified by, for example,
a means such as solvent extraction, concentration under reduced
pressure, crystallization, recrystallization, distillation,
chromatography and the like.
[0139] The compound or a salt thereof obtained by the
above-mentioned method can be used in the next step as a reaction
mixture or without thorough purification.
[0140] In the invention of the above-mentioned (3)-(7), when
Compound (IV) is reacted with Compound (V), Compound (I) is
produced in the reaction mixture. The Compound (I) can be led to
Compound (III) without isolation but by reaction with Compound
(II).
[0141] The Compound (X) can be used together with other
prophylactic or therapeutic agents of HIV infectious diseases
(particularly, prophylactic or therapeutic agent of AIDS). In this
case, these drugs are separately or simultaneously, admixed with
pharmacologically acceptable carriers, excipients, binders,
diluents and the like for forming a preparation and can be
administered orally or parenterally as a pharmaceutical composition
for the prophylaxis or treatment of HIV infectious diseases. When
drugs are independently prepared, the separately prepared agents
can be administered upon mixing by the use of diluent and the like
when in use, but each preparation separately prepared may be
administered simultaneously or in a staggered manner to a single
subject. A kit product for administration upon mixing separately
prepared drugs using a diluent and the like when in use (e.g.,
injection kit containing ampoules each containing powder drug, a
diluent to dissolve two or more drugs in admixture when in use and
the like, etc.), a kit product for simultaneous or staggered
separate administration of separately prepared drugs to a single
subject (e.g., a tablet kit for independent, simultaneous or
staggered administration of two or more tablets containing each
drug placed in the same or different bag(s) having, where
necessary, a column to indicate the time of administration of the
drug, etc.) and the like may be prepared.
[0142] Specific examples of the prophylactic or therapeutic agent
of HIV infectious diseases to be used together with Compound (X)
include nucleic acid reverse transcription enzyme inhibitors such
as zidovudine, didanosine, zalcitabine, lamivudine, stavudine,
abacavir, adefovir, adefovir dipivoxil, fozivudine tidoxil and the
like; non-nucleic acid reverse transcription enzyme inhibitors such
as nevirapine, delavirdine, efavirenz, loviride, immunocal,
oltipraz and the like, including pharmaceutical agents having an
anti-oxidization action such as immunocal, oltipraz and the like;
protease inhibitors such as saquinavir, ritonavir, indinavir,
nelfinavir, amprenavir, palinavir, lasinavir and the like; and the
like.
[0143] As the nucleic acid reverse transcription enzyme inhibitors,
zidovudine, didanosine, zalcitabine, lamivudine, stavudine,
abacavir and the like are preferable, and as the non-nucleic acid
reverse transcription enzyme inhibitors, nevirapine, delavirdine,
efavirenz and the like are preferable. As the protease inhibitors,
saquinavir, ritonavir, indinavir, nelfinavir, amprenavir and the
like are preferable.
[0144] The Compound (X) can be also used in combination with the
above-mentioned protease inhibitors, nucleic acid reverse
transcription enzyme inhibitors and the like, as well as, for
example, CXCR4 antagonists (e.g., AMD-8664, etc.), which are T cell
oriented HIV-1 second receptors, CD4 antagonist, entry inhibitors
(e.g., T-20, FP-21399, etc.) that inhibit invasion of viruses into
host cells by acting on the surface antigens of HIV-1, integrase
inhibitors that inhibit incorporation of virus DNA into host
chromosomes, Tat inhibitors that inhibit transcription of virus DNA
to mRNA by acting on Tat, which is an HIV-1 transcription factor,
and HIV-1 vaccines.
[0145] The Compound (X) that can be obtained from Compound (VIII)
by the method of the present invention has a CCR antagonistic
action, particularly potent CCR5 antagonistic action, and is low
toxic. Therefore, it can be used as a prophylactic or therapeutic
agent such as a prophylactic or therapeutic agent of various HIV
infectious diseases in humans, such as AIDS, and a suppressant of
the disease state of AIDS, a prophylactic or therapeutic agent of
multiple sclerosis, a prophylactic or therapeutic agent of graft
versus host reaction, a prophylactic or therapeutic agent of
chronic rheumatism and the like. Compound (X) can be administered
orally or parenterally as a pharmaceutical preparation made from
starting materials conventionally used for pharmaceutical
preparations such as excipient, diluent, extender and the like.
[0146] The daily dose of Compound (X) varies depending on the
conditions and body weight of patients and the administration
method. In the case of oral administration, the dose of the active
ingredient [Compound (X)] is ca. 5 to 1000 mg, preferably ca.
10-600 mg, more preferably ca. 10-300 mg, particularly preferably
ca. 15-150 mg, for an adult (body weight 50 kg), which is
administered once or in 2 or 3 portions a day.
[0147] When Compound (X) and a reverse transcription enzyme
inhibitor and/or a protease inhibitor are used in combination, the
dose of the reverse transcription enzyme inhibitor or protease
inhibitor is appropriately determined from the range of, for
example, not less than about 1/200 to 1/2 and not more than about 2
to 3 times the typical dose. In addition, when 2 or more kinds of
pharmaceutical agents are used in combination, and one
pharmaceutical agent affects the metabolism of the other
pharmaceutical agent(s), the dose of each pharmaceutical agent is
appropriately adjusted, but in general, the dose of single
administration of each pharmaceutical agent is used.
EXAMPLES
[0148] The present invention is explained in more detail in the
following by referring to Reference Examples and Examples. The
present invention is not limited in any way by these examples.
[0149] In the present specification, by the `room temperature` is
meant a range of 20-30.degree. C. and approximately 25.degree. C.,
and by the `overnight` is meant about 15 hrs.
Example 1
Production of 4-(chloromethyl)benzamide
[0150] ##STR52##
[0151] To a mixture of 28% aqueous ammonia (19.3 g, 317 mmol, 4.0
eq) and toluene (30 mL) was dropwise added a 4-chloromethylbenzoyl
chloride (15.0 g, 79.3 mmol)/toluene (30 mL) solution under
ice-cooling. The mixture was stirred at room temperature for 1 hr.
and under ice-cooling for 1 hr. The crystals were collected by
filtration, washed with water (9 mL) and toluene (9 mL), and dried
in vacuo at 40.degree. C. to give the title compound (13.36 g,
yield 99.3%) as white crystals.
[0152] .sup.1H-NMR (300 MHz, CDCl.sub.3).delta.: 1.37(3H, t, J=7.1
Hz), 2.05(2H,quint,J=6.7 Hz), 2.54(2H,t,J=6.7 Hz), 2.60(3H,s),
3.19(2H,t,J=6.7 Hz), 4.33(2H,q,J=7.1 Hz)
Example 2
[0153] Diethyl 4-carbamoylbenzylphosphonate ##STR53##
[0154] The compound (44.83 g, 0.264 mol) obtained in Example 1,
triethyl phosphite (53.21 g, 0.320 mol), potassium iodide (39.4 g,
0.237 mol) and acetonitrile (224 mL) were charged and stirred under
reflux for 4 hrs. The reaction mixture was allowed to return to
room temperature, and water (336 mL) was added. The mixture was
concentrated under reduced pressure, and the residue (315 g) was
stirred at room temperature for 1 hr. and under ice-cooling for 1
hr. The crystals were collected by filtration, washed with cold
water (20 mL) and dried in vacuo at 40.degree. C. for 7 hrs. to
give the title compound (66.79 g, yield 93.2%) as slightly yellow
crystals.
[0155] .sup.1H-NMR (300 MHz, CDCl.sub.3).delta.: 1.27(6H,t,J=7.1
Hz), 3.22(2H,t,J=11.0 Hz), 3.99-4.10(4H,m), 7.37-7.85(4H,m).
Example 3
Production of 4-(1-benzylpiperidin-4-ylidenemethyl)benzamide
[0156] ##STR54##
[0157] The compound (25.0 g, 0.147 mol) obtained in Example 1,
triethyl phosphite (29.4 g, 0.177 mol), potassium iodide (22.0 g,
0.133 mol) and acetonitrile (125 mL) were charged and stirred under
reflux for 3 hrs. The reaction mixture was allowed to return to
room temperature, and concentrated under reduced pressure. To the
residue were added N,N-dimethylformamide (100 mL) and
1-benzyl-4-piperidone (30.6 g, 0.162 mol), and the mixture was
stirred under ice-cooling. Potassium t-butoxide (23.1 g, 0.206 mol)
was added in 3 portions at 15 min. intervals. The reaction mixture
was stirred at room temperature for 45 min. Water (400 mL) was
dropwise added under ice-cooling, and the mixture was stirred for
30 min. Crystals were collected by filtration, washed with cold
water (180 mL) and dried in vacuo at 40.degree. C. to give the
title compound (38.7 g, yield 85.2%) as pale-yellow powdery
crystals.
[0158] .sup.1H-NMR (300 MHz, CDCl.sub.3).delta.: 2.40-2.57(8H,m),
3.54(2H,s), 6.04(2H,br.s,NH.sub.2), 6.29(1H,s),
7.25-7.77(9H,m).
Example 4
Production of 4-(4-piperidylmethyl)benzamide --
[0159] ##STR55##
[0160] The compound (4267.9 g, 13.929 mol) obtained in Example 3,
10% palladium carbon (889.4 g, ca. 50% water-containing product)
and methanol (38.4 L) were charged, and a hydrogenation reaction
was conducted at normal pressure at 50.degree. C. for 5 hrs. After
the reaction, the reaction mixture was separated by filtration
without cooling to remove the insoluble material and washed with
methanol (3 L). The reaction mixture was concentrated under reduced
pressure to about 10 L, and ethyl acetate (15 L) was added,
followed by concentration again under reduced pressure to about 10
L, which step was conducted twice. The residue (ca. 10 L) was
stirred under reflux for 2 hrs., and cooled to room temperature.
The crystals were collected by filtration, washed with ethyl
acetate (2 L) and dried in vacuo at 40.degree. C. to give the title
compound (2619.2 g, yield 86.1%) as white crystals.
[0161] .sup.1H-NMR (300 MHz, CDCl.sub.3).delta.: 1.14-1.19(2H,m),
1.59-1.63(3H,m), 2.49-2.59(4H,m), 3.03-3.07(2H,m),
7.21-7.75(4H,m).
Reference Example 1
Production of 4-(1-benzylpiperidin-4-ylidenemethyl)benzamide
[0162] ##STR56##
[0163] 4-Cyanobenzyl bromide (4.90 g, 25.0 mmol), triethyl
phosphite (4.77 mL, 27.5 mmol) and toluene (4.9 mL) were charged,
and the mixture was stirred with heating under reflux for 3 hrs.,
while distilling away the solvent at normal pressure. The mixture
was allowed to return to room temperature, and concentrated under
reduced pressure to give a colorless transparent oil which
solidified by standing. N-benzylpiperidone (4.73 g, 25.0 mmol),
ethanol (35 mL), water (451 mg, 25.0 mmol) and potassium hydroxide
(pellet, 7.01 g, 125 mmol) were added successively, and the mixture
was stirred at room temperature for 30 min. to give a yellow
solution. The solution was stirred at 65-70.degree. C. for 2 hrs.
and cooled to 60.degree. C. to allow precipitation of crystals to
give a yellow suspension. Iced water (200 mL) was added, and the
mixture was stirred at 0-5.degree. C. After dissolution once, a
yellow suspension was formed. The suspension was stirred at
0-5.degree. C. for 30 min. and the crystals were collected by
filtration and dried in vacuo at 40.degree. C. to give the title
compound (3.30 g, yield 43.0%) as white crystals.
[0164] .sup.1H-NMR (300 MHz, CDCl.sub.3).delta.: 2.40-2.57(8H,m),
3.54 (2H,s), 6.04 (2H,br.s,NH.sub.2), 6.29 (1H,s), 7.25-7.77
(9H,m).
Example 5
Production of 4-(4-piperidylmethyl)benzamide
[0165] ##STR57##
[0166] The compound (0.919 g, 3.00 mmol) obtained in Reference
Example 1, 10% palladium carbon (0.192 g, ca. 50% water-containing
product) and methanol (9.2 mL) were charged, and the mixture was
stirred vigorously under hydrogen atmosphere at 50.degree. C. for 3
hrs. Insoluble materials were filtered off, and the residue was
washed with methanol (2.0 mL) and concentrated under reduced
pressure to give the title compound (0.642 g, yield 98%) as a white
dry solid.
[0167] .sup.1H-NMR (300 MHz, CDCl.sub.3).delta.: 1.14-1.19(2H,m),
1.59-1.63(3H,m), 2.49-2.59(4H,m), 3.03-3.07(2H,m),
6.10(2H,br.s,NH.sub.2), 7.21-7.75(4H,m).
Reference Example 2
Production of 4-(4-piperidylidenemethyl)benzamide
[0168] ##STR58##
[0169] 4-Cyanobenzyl bromide (49.0 g, 250 mmol), triethyl phosphite
(45.7 g, 275 mmol) and toluene (49 mL) were charged, and the
mixture was stirred and heated under reflux for 3 hrs., while
distilling away the solvent at normal pressure. Then, the mixture
was allowed to return to room temperature and concentrated under
reduced pressure to give a colorless transparent oil. 4-Piperidone
hydrochloride monohydrate (46.1 g, 300 mmol), ethanol (350 mL) and
potassium hydroxide (pellet, 70.1 g, 1250 mmol) were added
successively, and the mixture was stirred at room temperature for
30 min. and at 65-70.degree. C. for 4 hrs. to give a pale-yellow
suspension. Water (0.5 L) was added to the suspension at
20-25.degree. C., and the mixture was extracted with ethyl acetate
(2.0 L) and ethyl acetate-ethanol (17:3, 2.0 L). The obtained
organic layers were combined, washed with saturated brine (1.0 L)
and concentrated under reduced pressure. To the resulting residue
was added ethyl acetate (150 mL), and the mixture was stirred at
0-5.degree. C. for 30 min. The crystals were collected by
filtration and dried to give a pale-yellow solid. 2-Propanol (140
mL) was added thereto, and the mixture was stirred at room
temperature for 30 min. and further at 0-5.degree. C. for 30 min.
The crystals were collected by filtration and dried to give the
title compound (17.3 g, yield 41.4%) as pale-yellow crystals.
[0170] .sup.1H-NMR (300 MHz, CDCl.sub.3).delta.: 2.32-2.48 (4H,m),
2.83-2.99 (4H,m), 6.00 (2H,br.s,NH.sub.2), 6.29 (1H,s), 7.23-7.78
(4H,m).
Example 6
Production of 4-(4-piperidylmethyl)benzamide
[0171] ##STR59##
[0172] The compound (1.93 g, 8.92 mmol) obtained in Reference
Example 2, 10% palladium carbon (50% wet, 569 mg) and
tetrahydrofuran (39 mL) were charged, and the mixture was
vigorously stirred under a hydrogen atmosphere at 35-40.degree. C.
for 1 hr. Insoluble materials were filtered off while hot, and the
resulting filtrate was washed with tetrahydrofuran (39 mL),
concentrated under reduced pressure to give the title compound
(1.93 g, yield 98.7%) as white crystals.
[0173] .sup.1H-NMR (300 MHz, CDCl.sub.3).delta.: 1.14-1.19 (2H,m),
1.59-1.63 (3H,m), 2.49-2.59 (4H,m), 3.03-3.07 (2H,m), 6.10
(2H,br.s,NH.sub.2), 7.21-7.75 (4H,m).
Reference Example 3
Ethyl 1-mesyl-4-piperidinecarboxylate
[0174] ##STR60##
[0175] Ethyl isonipecotinate (1.0 g, 6.36 mmol), acetone (5 mL) and
triethylamine (0.97 mL, 6.99 mmol) were charged and stirred under
ice-cooling. Methanesulfonyl chloride (0.54 mL, 7.02 mmol) was
dropwise added, and the mixture was stirred at room temperature for
2 hrs. Water (10 mL) was added dropwise, and the mixture was
stirred at room temperature for 30 min. and under ice-cooling for 1
hr. The crystals were collected by filtration, washed with
ice-cooling acetone-water (1:3) (2 mL) and water (4 mL), and dried
in vacuo at 40.degree. C. for 9 hrs. to give the title compound
(1.31 g, yield 87.3%) as white crystals.
[0176] .sup.1H-NMR (300 MHz, CDCl.sub.3).delta.: 1.24 (3H,t,J=7.1
Hz), 1.78-1.87 (2H,m), 1.97-2.02 (2H,m),2.38-2.41 (1H,m), 2.76
(3H,s), 2.79-2.88 (2H,m), 3.61-3.67 (2H,m), 4.23 (2H,q,J=7.1
Hz).
Reference Example 4
1-Mesyl-4-piperidinecarboxylic acid
[0177] ##STR61##
[0178] The compound (132.4 g, 563 mmol) obtained in Reference
Example 3 and sodium hydroxide (28.4 g, 710 mmol)/water (348 ML)
solution were charged, and the mixture was stirred at room
temperature for 3 hrs. The reaction mixture was ice-cooled and
conc. hydrochloric acid (65 mL, 780 mmol) was dropwise added. The
mixture was stirred under ice-cooling for 1 hr. The crystals were
collected by filtration, washed with water (100 mL) and dried in
vacuo at 40.degree. C. for 9 hrs. to give the title compound (112.7
g, yield 96.6%) as white crystals.
[0179] .sup.1H-NMR (300 MHz, DMSO).delta.: 1.49-1.60 (2H,m),
1.86-1.92 (2H,m), 2.2-2.4 (1H,m), 2.72-2.80 (2H,m), 2.82 (3H,s),
3.42-3.48 (2H,m).
Reference Example 5
1-Mesyl-4-piperidinecarbonyl chloride
[0180] ##STR62##
[0181] The compound (20.0 g, 96.5 mmol) obtained in Reference
Example 4 and thionyl chloride (46.2 g, 388 mmol) were charged, and
the mixture was gradually heated to 50.degree. C. over 1.5 hrs and
stirred at 50.degree. C. for 2 hrs. The mixture was allowed to
return to room temperature, and diisopropyl ether (84 mL) was added
dropwise. The reaction mixture was stirred at room temperature for
1 hr. and under ice-cooling for 1 hr. The crystals were collected
by filtration, washed with diisopropyl ether (30 mL) and dried in
vacuo at room temperature for 7 hrs. to give the title compound
(20.8 g, yield 95.5%) as white crystals.
[0182] .sup.1H-NMR (300 MHz, CDCl.sub.3).delta.: 1.88-1.96(2H,m),
2.15-2.21(2H,m), 2.78(3H,s), 2.85-2.94(3H,m), 3.64-3.69(2H,m).
Reference Example 6
3,4-Dichloro-N-formylaniline
[0183] ##STR63##
[0184] 3,4-Dichloroaniline (1000.0 g, 6.172 mol) and formic acid
(585 g, 12.7 mol) were charged, and the mixture was stirred at
90.degree. C. for 1 hr. Water (1.5 L) was dropwise added with
heating, and then the mixture was gradually cooled to allow
precipitation of the crystals. The mixture was stirred at room
temperature for 30 min., and the crystals were collected by
filtration. The crystals were washed with water (1.2 L) and dried
in vacuo at 40.degree. C. for 8 hrs. to give the title compound
(1160.8 g, yield 99.0%) as pale-brown crystals.
[0185] .sup.1H-NMR (300 MHz,DMSO).delta.: 7.18-7.97(3H,m),
8.32-8.85(1H,m), 10.46(1H,br.s,NH).
Reference Example 7
3,4-Dichloro-N-(3-chloropropyl)aniline hydrochloride
[0186] ##STR64##
[0187] The compound (1160 g, 6.104 mol) obtained in Reference
Example 6, acetone (5.8 L), potassium carbonate (2.53 kg, 18.31
mol) and 1-bromo-3-chloropropane (1.81 L, 18.31 mol) were charged,
and the mixture was stirred under reflux for 14 hrs. Water (8.7 L)
and ethyl acetate (2.9 L) were added, and the mixture was
partitioned. To the aqueous layer was added ethyl acetate (2.9 L)
for extraction. The obtained organic layers were combined and
washed with water (5.8 L) and saturated brine (5.8 L). The mixture
was concentrated under reduced pressure to give a brown oily
substance (1743.8 g). 2-Propanol (5.8 L) was added to this oily
substance (1743.8 g), and conc. hydrochloric acid (1089 mL, 12.2
mol) was dropwise added over 30 min. at room temperature. The
mixture was stirred at 60.degree. C. for 1 hr. By ice-cooling, the
crystals were precipitated, and the mixture was stirred under
ice-cooling for 1.5 hrs. The crystals were collected by filtration,
washed with diisopropyl ether (580 ml) and dried in vacuo at
40.degree. C. for 9 hrs. to give the title compound (1509.1 g,
yield 89.9%) as yellowish brown crystals.
[0188] .sup.1H-NMR (300 MHz, DMSO).delta.: 1.91-2.00 (2H,m), 3.12
(2H,t,J=6.8 Hz), 3.69 (2H,t,J=6.8 Hz), 6.69-7.32 (3H,m).
Reference Example 8
N-(3-Chloropropyl)-N-(3,4-dichlorophenyl)-1-mesyl-4-piperidine
carboxamide
[0189] ##STR65##
[0190] The compound (900.0 g, 3.273 mol) obtained in Reference
Example 7 and 1-methyl-2-piperidone (4.5 L) were charged, and the
mixture was stirred at room temperature for dissolution.
[0191] The compound (369 g, 1.635 mol.times.3) obtained in
Reference Example 5 was added under water-cooling at 22-27.degree.
C. at 30 min. intervals. After the addition, the mixture was
stirred at room temperature for 1.5 hrs. Water (13.5 L) was
dropwise added under ice-cooling, and the mixture was stirred at
room temperature for 1.5 hrs. The crystals were collected by
filtration, washed with water (9 L) and dried in vacuo at
50.degree. C. for 26 hrs. to give the title compound (1372.7 g,
yield 98.1%) as white crystals.
[0192] .sup.1H-NMR (300 MHz, CDCl.sub.3).delta.: 1.64-1.71 (2H,m),
1.80-2.02 (4H,m), 2.15-2.28 (1H,m), 2.54 (2H,t,J=10.9 Hz), 2.70
(3H,s), 3.51 (2H, t, J=6.5 Hz), 3.65-3.77 (4H,m), 7.00-7.52
(3H,m).
Reference Example 9
N-[3-[4-(4-Carbamoylbenzyl)-1-piperidyl]propyl]-N-(3,4-dichlorophenyl)-1-m-
esyl-4-piperidine carboxamide
[0193] ##STR66##
[0194] The compound (1350.0 g, 3.156 mol) obtained in Reference
Example 8, potassium iodide (529.1 g, 3.187 mol), anhydrous
potassium carbonate (1744.7 g, 12.624 mol), compound (757.8 g,
3.471 mol) obtained in Example 4, N,N-dimethylformamide (6.75 L)
and acetonitrile (6.75 L) were charged, and the mixture was stirred
at 80-85.degree. C. for 2.5 hrs. The mixture was allowed to return
to room temperature, and water (27 L) was dropwise added. The
mixture was stirred at room temperature for 30 min. and then under
ice-cooling for 1 hr. The crystals were collected by filtration,
and washed with water (13.5 L). After drying in vacuo at 50.degree.
C., acetonitrile (17.2 L) was charged, and the mixture was stirred
under reflux for 2 hrs. The mixture was allowed to return to room
temperature and stirred for 1 hr. The crystals were collected by
filtration and washed with acetonitrile (2 L). Acetonitrile (14 L)
was again charged to the wet crystals, and the mixture was stirred
under reflux for 2 hrs. The mixture was allowed to return to room
temperature and stirred for 1 hr. The crystals were collected by
filtration and washed with acetonitrile (1.1 L). After drying in
vacuo at 50.degree. C., acetone (35.4 L) and water (8.85 L) were
added, and the mixture was heated for dissolution. The mixture was
gradually cooled until the crystals started to precipitate and aged
while retaining the temperature for 1.5 hrs. The mixture was cooled
under ice-cooling for 1.5 hrs. The crystals were collected by
filtration, washed with ice-cooled acetone-water (1:2) (1.8 L) and
dried in vacuo at 50.degree. C. to give the title compound (1221.7
g, yield 63.5%) as white crystals.
[0195] .sup.1H-NMR (300 MHz, CDCl.sub.3).delta.: 1.22-1.26 (2H,m),
1.56-1.69 (7H,m), 1.78-1.91 (4H,m), 2.24-2.29 (3H,m), 2.56-2.58
(4H,m), 2.73 (3H,s), 2.79-2.82 (2H,m), 3.62-3.74 (4H,m), 7.00-7.74
(7H,m).
Reference Example 10
1-Acetyl-4-piperidinecarboxylic acid
[0196] ##STR67##
[0197] Isonipecotic acid (129.2 g, 1.00 mol) was dissolved in water
(390 mL), and acetic anhydride (153.1 g, 1.50 mol) was added
dropwise under ice-cooling for about 10 min. (dropwise addition at
15-18.degree. C. for about 10 min.). After stirring at
55.+-.5.degree. C. for 2 hrs., the mixture was allowed to cool to
room temperature and stirred under ice-cooling for 1 hr. The
precipitated crystals were collected by filtration, washed with
cold diisopropyl ether (125 mL.times.2) and dried under reduced
pressure at 40.degree. C. for 8 hrs. to give the title compound
(129.1 g, yield 75.4%).
[0198] .sup.1H-NMR (300 MHz, CDCl.sub.3).delta.: 4.40 (1H, dt,
J=13.4 Hz), 3.79 (1H, dt, J=13.6 Hz), 3.17 (1H, dt, J=13.9 Hz),
2.87 (1H, dt, J=Hz), 2.62-2.55 (3H, s), 2.01-1.94 (2H, m),
1.75-1.65 (2H, m)
Reference Example 11
1-Acetyl-4-piperidinecarbonyl chloride
[0199] ##STR68##
[0200] To thionyl chloride (685 mL) was added the compound (85.6 g,
0.50 mol) obtained in Reference Example 10, and the mixture was
stirred at room temperature for 2 hrs. The precipitated crystals
were collected by filtration, washed with diisopropyl ether (250
mL.times.2) and dried under reduced pressure at 30.degree. C. for 8
hrs. to give the title compound (84.4 g, yield:89.0%).
[0201] .sup.1H-NMR (300 MHz, CDCl.sub.3).delta.: 1.70-1.90 (2H, m),
2.05-2.26 (2H, m), 2.26 (3H, s), 2.90-3.25 (4H,m), 3.95-4.30 (2H,
br), exchange proton in the range of about 3.5-4.5 ppm (2H, br)
Reference Example 12
3-Chloro-N-(3-chloropropyl)-4-methylaniline hydrochloride
[0202] ##STR69## 3-Chloro-4-methylaniline (10.0 g, 70.6 mmol),
1-bromo-3-chloropropane (34.7 mL, 55.6 g, 353 mmol) and
triethylamine (21.4 g, 212 mmol) were charged. The mixture was
stirred at 25-28.degree. C. for 24 hrs. Water (50 mL) and methyl
ethyl ketone (25 mL) were added for partitioning. The organic layer
was washed twice with water (50 mL). Conc. hydrochloric acid (35
mL, 5.7 eq) was dropwise added to the organic layer under
ice-cooling. The mixture was stirred at room temperature for 1 hr.
The crystals were collected by filtration, washed with diisopropyl
ether (10 mL) and dried in vacuo at 50.degree. C. to give the title
compound (14.12 g, yield 78.5%) as pale-yellow crystals.
[0203] .sup.1H-NMR (300 MHz, DMSO).delta.: 2.11 (2H,quint,J=6.9
Hz), 2.28 (3H,s), 3.29 (2H,t,J=7.3 Hz), 3.76 (2H,t,J=6.5 Hz),
7.16-7.37 (3H,m).
Reference Example 13
1-Acetyl-N-(3-chloro-4-methylphenyl)-N-(3-chloropropyl)-4-piperidine
carboxamide
[0204] ##STR70##
[0205] The compound (3.06 g, 12.0 mmol) obtained in Reference
Example 12 and N-methylpyrrolidone (15 mL) were charged and, after
dissolution, the compound (1.14 g, 6.00 mmol) obtained in Reference
Example 11 was added 3 times every 30 min. (total 1.5 equivalents)
to give a yellow suspension. The suspension was stirred at
20-26.degree. C. for 1 hr., and water (45 mL) was added at
10-20.degree. C. to once give a yellow solution, followed by
precipitation of a small amount of an oil. A seed crystal was
added, and the crystals were gradually precipitated. After stirring
at 20-26.degree. C. for 2 hrs., the crystals were collected by
filtration, washed with water (6.0 mL) and dried to give the title
compound (3.88 g, yield 87.1%) as white crystals.
[0206] .sup.1H-NMR (300 MHz, CDCl.sub.3).delta.: 1.61-1.77(4H,m),
1.96-2.05(5H,m), 2.33-2.44(5H,m), 2.84-2.90(1H,m), 3.51-3.56(2H,t),
3.74-3.80(3H,m), 4.49-4.54(1H,d), 6.96-7.33(3H,m).
Reference Example 14
1-Acetyl-N-[3-[4-(4-carbamoylbenzyl)-1-piperidyl]propyl]-N-(3-chloro-4-met-
hylphenyl)-4-piperidine carboxamide
[0207] ##STR71##
[0208] The compound (1.11 g, 3.00 mmol) obtained in Reference
Example 13, the compound (0.720 g, 3.30 mmol) obtained in Example
5, N,N-dimethylformamide (5.5 mL) and acetonitrile (5.5 mL) were
charged, and potassium carbonate (1.66 g, 12.0 mmol) and potassium
iodide (0.598 g, 3.60 mmol) were successively added thereto to give
a white suspension. The suspension was stirred at 70-75.degree. C.
for 2 hrs., and water (22 mL) was dropwise added at 20-25.degree.
C. The mixture was extracted with ethyl acetate (11 mL.times.2) and
washed with brine (saturated brine 3 mL+water 8 mL), which was
followed by solvent substitution with acetonitrile (11 mL) to allow
precipitation of crystals. The mixture was stirred at 20-25.degree.
C. for 1 hr. and at 0-5.degree. C. for 1 hr., then the crystals
were collected by filtration, washed with acetonitrile (1
mL.times.2) and dried to give the title compound (1.00 g, yield
60.3%) as white crystals.
[0209] .sup.1H-NMR (300 MHz, CDCl.sub.3).delta.: 1.23-1.28(2H,m),
1.55-1.89(11H,m), 2.04(3H,s), 2.23-2.42(7H,m), 2.55-2.58(2H,m),
2.80-2.84(3H,m), 3.61-3.67(2H,t), 3.73-3.78(1H,m), 4.47-4.53(1H,m),
6.00(2H,br.s,NH.sub.2), 6.94-7.74(7H,m).
Example 7
Production of 4-(4-piperidylidenemethyl)benzamide
[0210] ##STR72##
[0211] The compound (0.50 g, 1.84 mmol) obtained in Example 2,
1-benzyl-4-piperidone (418 mg, 2.21 mmol, 1.2 eq) and
N,N-dimethylformamide (3.5 ml) were charged, and the mixture was
stirred under ice-cooling. Potassium t-butoxide (455 mg, 4.06 mmol,
2.2 eq) was added, and the mixture was stirred at room temperature
for 4 hrs. Water (10 ml) was dropwise added under ice-cooling, and
the mixture was stirred for 1 hr. The crystals were collected by
filtration, washed with water (3 ml) and dried in vacuo at
50.degree. C. to give the title compound (453 mg, yield 79.9%) as
slightly yellow crystals.
[0212] .sup.1H-NMR (300 MHz, CDCl.sub.3): 2.40-2.57(8H,m),
3.54(2H,s), 6.04(2H,br.s,NH.sub.2), 6.29(1H,s),
7.25-7.77(9H,m).
Reference Example 15
Production of 1-acetyl-4-piperidinecarboxylic acid
[0213] ##STR73##
[0214] Isonipecotic acid (10.0 g, 0.078 mol) and ethyl acetate
(30.0 ml) were charged at room temperature. Acetic anhydride (11.9
g, 1.50 eq) was dropwise added over about 10 min. while retaining
not more than 20.degree. C. After stirring at 55.+-.5.degree. C.
for 2 hrs., the mixture was allowed to cool to room temperature
over 1 hr., ice-cooled and stirred at not higher than 10.degree. C.
for 1 hr. The precipitated crystals were collected by filtration
and washed with diisopropyl ether (10 ml.times.2) and dried in
vacuo at 50.degree. C. to give the title compound (11.9 g, yield
89.8%) as white crystals.
[0215] .sup.1H-NMR (300 MHz, DMSO).delta.: 1.32-1.51(2H,m),
1.76-1.84(2H,m), 1.98(3H,s), 2.43-2.50(1H,m), 2.65-2.68(1H,m),
3.04-3.12(1H,m), 3.71-3.75(1H,m), 4.16-4.20(1H,m).
Example 8
Production of
1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-chloropropyl)-4-piperidine
carboxamide
[0216] ##STR74##
[0217] The compound (863 g, 5.04 mol, 1.2 eq) obtained in Reference
Example 10 and N-methylpyrrolidone (6.4 L) were charged, and the
mixture was stirred at room temperature for dissolution. Thionyl
chloride (600 g, 5.04 mol, 1.2 eq) was dropwise added under
ice-cooling (inner temperature 4-12.degree. C.), and the mixture
was stirred under ice-cooling for 1 hr. Thereto was added compound
(1069 g, 4.20 mol) obtained in Reference Example 12, and the
mixture was stirred at room temperature for 2 hrs. The reaction
mixture was poured into iced water (12.8 L). A seed crystal was
added, and the mixture was stirred at room temperature. After
precipitation of crystals, water (6.4 L) was added dropwise, and
the mixture was stirred overnight at room temperature. The mixture
was stirred under ice-cooling for 2 hrs. The crystals were
collected by filtration, washed with water (5 L) and dried in vacuo
at 50.degree. C. to give the title compound (1350 g, yield 86.6%)
as white crystals.
[0218] .sup.1H-NMR (300 MHz, CDCl.sub.3).delta.: 1.61-1.80 (4H,m),
1.96-2.03(2H,m), 2.05(3H,s), 2.33-2.39(2H,m), 2.43(3H,s), 3.53
(2H,t,J=6.6 Hz), 3.75-3.80(3H,m), 4.49-4.53 (1H,m),6.96-7.33
(3H,m).
Example 9
1-Acetyl-N-[3-[4-(4-carbamoylbenzyl)-1-piperidyl]propyl]-N-(3-chloro-4-met-
hylphenyl)-4-piperidine carboxamide
[0219] ##STR75##
[0220] The compound (1237.0 g, 3.332 mol) obtained in Example 8,
potassium iodide (608.3 g, 3.665 mol, 1.1 eq), anhydrous potassium
carbonate (1381.4 g, 9.995 mol, 3.0 eq), the compound (800.0 g,
3.665 mol, 1.1 eq) obtained in Example 4 and acetonitrile (12.37 L)
were charged, and the mixture was stirred under reflux
(81-82.degree. C.) for 4 hrs. The mixture was allowed to return to
room temperature, and added to cold water (24.74 L), to which ethyl
acetate (12.37 L) was added for partitioning. The organic layer was
washed with 10% aqueous sodium chloride solution (24.74 L).
Magnesium sulfate was added to the organic layer at not higher than
20.degree. C., and after stirring for 10 min., filtered off. The
organic layer was concentrated under reduced pressure and
acetonitrile (1.24 L) was added to the concentrated residue. The
mixture was heated for dissolution. The mixture was cooled to room
temperature, and a seed crystal was added. t-Butyl methyl ether
(3.50 L) was added, and the mixture was stirred overnight at room
temperature. Because the crystals did not precipitate, t-butyl
methyl ether (1.00 L) was added dropwise, and the mixture was
stirred overnight at room temperature. After confirmation of
precipitation, t-butyl methyl ether (6.50 L) was added, and the
mixture was ice-cooled and aged at not higher than 10.degree. C.
for 1.5 hrs. The crystals were collected by filtration and washed
with acetonitrile-t-butyl methyl ether (0.1:1.9) (2.47 L). The
obtained crystals were suspended in pure water (12.37 L), and the
suspension was stirred at room temperature for 1 hr. The crystals
were collected by filtration, washed with pure water (3.71 L) and
dried in vacuo at 50.degree. C. to give the title compound as
slightly yellow crystals (1216 g, yield 66.2%).
[0221] The obtained slightly yellow crystals (1196.0 g, 2.162 mol),
acetone (2.99 L, 2.5 v/w) and pure water (5.98 L, 5.0 v/w) were
charged. The mixture was heated to 60.degree. C. for dissolution.
The mixture was allowed to return to room temperature, a seed
crystal was added, and the mixture was stirred overnight. After
confirmation of precipitation, water (5.980 L, 5.0 v/w) was added,
and the mixture was stirred at room temperature for 1 hr., and
under ice-cooling for 1 hr. The crystals were collected by
filtration, washed with water (2.00 L) and dried in vacuo at
50.degree. C. to give the title compound as white crystals (1146.5
g, recovery 95.9%). The obtained white crystals (1076.0 g), ethanol
(1.00 L) and ethyl acetate (2.00 L mL) were charged, and the
mixture was heated for dissolution. After confirmation of
dissolution, the mixture was dust-removed by filtration, and washed
with ethanol (76 ml) and ethyl acetate (152 ml). The temperature
was raised, and dissolution was confirmed under reflux. t-Butyl
methyl ether (2.15 L) and a seed crystal (0.5 g) were successively
added, and after heating under reflux for 1 hr., the mixture was
gradually cooled and stirred overnight at room temperature. After
confirmation of precipitation, t-butyl methyl ether (4.30 L) was
added dropwise, and the mixture was stirred at room temperature for
1 hr. and under ice-cooling for 1 hr. The crystals were collected
by filtration, washed with t-butyl methyl ether (2.15 L) and dried
in vacuo at 50.degree. C. to give the title compound (1007 g,
recovery 93.6%).
[0222] .sup.1H-NMR (300 MHz, CDCl.sub.3).delta.: 1.19-1.27 (2H,m),
1.56-2.00 (11H,m), 2.04 (3H,s), 2.24-2.39 (4H,m), 2.42 (3H,s),
2.55-2.57 (2H,m), 2.80-2.88 (3H,m), 3.61-3.78 (3H,m), 4.48-4.52
(1H,m), 6.94-7.74 (7H,m).
Example 10
1-Acetyl-N-[3-[4-(4-carbamoylbenzyl)-1-piperidyl]propyl]-N-(3-chloro-4-met-
hylphenyl)-4-piperidine carboxamide
[0223] ##STR76##
[0224] The compound (7.43 g, 20.0 mmol) obtained in Example 8, the
compound (4.80 g, 22.0 mmol) obtained in Example 4, anhydrous
potassium carbonate (8.29 g, 60.0 mmol), potassium iodide (3.65 g,
22.0 mmol) and acetonitrile (74 ml) were charged, and the mixture
was heated under reflux for 4 hrs. The mixture was allowed to
return to room temperature, poured into water (150 ml) and
extracted with ethyl acetate (74 ml). The organic layer was washed
with 10% brine (150 ml), magnesium sulfate (7.4 g) was added, and
the mixture was stirred for 10 min. Insoluble materials were
filtered off, and the filtrate was washed with ethyl acetate (7.4
ml) and concentrated under reduced pressure until the filtrate
became about 15 ml. Acetonitrile (7.4 ml), diisopropyl ether (22
ml) and a seed crystal were added, and the mixture was stirred
overnight at room temperature to allow precipitation. Diisopropyl
ether (22 ml) was added, and the mixture was stirred at room
temperature for 30 min. and at 0-10.degree. C. for 1 hr. Then the
crystals were collected by filtration and washed with
acetonitrile-diisopropyl ether (1:3 mixture, 14 ml). The obtained
crystals were suspended in water (74 ml) by stirring, collected by
filtration, washed with water (15 ml) and dried in vacuo at
50.degree. C. to give the title compound as pale-brown crystals
(7.4 g, yield 66.9%).
[0225] Acetone (18.5 ml) and water (37.0 ml) were added to the
obtained pale-brown crystals (7.4 g), and the mixture was dissolved
by heating. A seed crystal was added at 20-30.degree. C., and the
mixture was stirred overnight at room temperature to allow
precipitation. When water (37.0 ml) was added, an oily substance
floated, and when stirred at room temperature for 1.5 hrs.,
crystallization occurred. The mixture was stirred at room
temperature for 1 hr. and at 0-10.degree. C. for 1 hr. The crystals
were collected by filtration, washed with water (15 ml) and dried
in vacuo at 50.degree. C. to give the title compound as slightly
brown crystals (6.86 g, recovery 92.7%).
[0226] The obtained slightly brown crystals (10.0 g), ethanol (10.0
ml) and ethyl acetate (10.0 ml) were charged, and the mixture was
heated for dissolution (ca. 70.degree. C.). After confirmation of
dissolution, and the mixture was gradually cooled. Diisopropyl
ether (10.0 ml) and a seed crystal were successively added at about
60.degree. C., and the mixture was stirred overnight at about
50.degree. C. After confirmation of precipitation, diisopropyl
ether (40.0 ml) was added dropwise over 30 min., and the mixture
was stirred overnight at room temperature. The mixture was stirred
under ice-cooling for 1 hr., and the crystals were collected by
filtration, washed with a mixture of diisopropyl ether (10.0 ml)
and ethyl acetate (2.0 ml) and dried in vacuo at 50.degree. C. to
give the title compound (8.54 g, recovery 85.4%) as nearly white
crystals.
[0227] .sup.1H-NMR (300 MHz, CDCl.sub.3).delta.: 1.19-1.27 (2H,m),
1.56-2.00 (11H,m), 2.04 (3H,s), 2.24-2.39 (4H,m), 2.42 (3H,s),
2.55-2.57 (2H,m), 2.80-2.88 (3H,m), 3.61-3.78 (3H,m), 4.48-4.52
(1H,m), 6.94-7.74 (7H,m).
Example 11
1-Acetyl-N-[3-[4-(4-carbamoylbenzyl)-1-piperidyl]propyl]-N-(3-chloro-4-met-
hylphenyl)-4-piperidine carboxamide
[0228] ##STR77##
[0229] The compound (18.6 g, 50.0 mmol) obtained in Example 8, the
compound (12.0 g, 55.0 mmol) obtained in Example 4, anhydrous
potassium carbonate (20.7 g, 150 mmol), potassium iodide (9.13 g,
55.0 mmol) and acetonitrile (186 ml) were charged, and the mixture
was heated under reflux for 5 hrs. The mixture was allowed to
return to room temperature, poured into water (372 ml) and
extracted with ethyl acetate (186 ml). The organic layer was washed
with 10% brine (372 ml). Magnesium sulfate (18.6 g) was added, and
the mixture was stirred for 10 min. Insoluble materials were
filtered off, and the filtrate was washed with ethyl acetate (18.6
ml) and concentrated under reduced pressure until the filtrate
became about 37 ml. Acetonitrile (18.3 ml), heptane (18.0 ml),
ethyl acetate (18.6 ml) and a seed crystal were added, and the
mixture was stirred at room temperature for 1 hr. to allow
precipitation. Heptane (28.0 ml) and ethyl acetate (28.0 ml) were
added, and the mixture was stirred at room temperature overnight,
and at 0-5.degree. C. for 1 hr. The crystals were collected by
filtration and washed with ethyl acetate-heptane (1:2 mixture, 18.6
ml). The obtained crystals were suspended in water (186 ml) by
stirring, collected by filtration, washed with water (18.6 ml) and
dried in vacuo at 50.degree. C. to give the title compound as
nearly white crystals (17.2 g, yield 62.2%).
[0230] Acetone (40.5 ml) and water (81.0 ml) were added to the
obtained nearly white crystals (16.2 g), and the mixture was heated
for dissolution. A seed crystal was added at 20-30.degree. C., and
the mixture was stirred at room temperature overnight to allow
precipitation. Water (81.0 ml) was added, and the mixture was
stirred at room temperature for 2 hrs. and at 0-5.degree. C. for 1
hr. The crystals were collected by filtration, washed with water
(16 ml) and dried in vacuo at 50.degree. C. to give the title
compound as nearly white crystals (15.4 g, recovery 95.1%).
[0231] Ethanol (12.0 ml) and ethyl acetate (12.0 ml) were added to
the obtained nearly white crystals (15.0 g), and the mixture was
heated for dissolution, filtrated while hot and washed with
ethanol-ethyl acetate (1:1 mixture, 6.0 ml). Heptane (15.0 ml) and
a seed crystal were added at 40-50.degree. C., and the mixture was
stirred at 40-50.degree. C. for 17 hrs. The mixture was gradually
cooled and stirred at room temperature for 1 hr. Heptane (60.0 ml)
was added dropwise over 30 min. The mixture was stirred at room
temperature for 3 hrs. and at 0-5.degree. C. for 1 hr. The crystals
were collected by filtration, washed with heptane-ethyl acetate
(5:1 mixture, 18.0 ml) and dried in vacuo at 50.degree. C. to give
the title compound (13.9 g, recovery 92.7%) as nearly white
crystals.
[0232] .sup.1H-NMR (300 MHz, CDCl.sub.3)61.19-1.27(2H,m),
1.56-2.00(11H,m), 2.04(3H,s), 2.24-2.39(4H,m), 2.42(3H,s),
2.55-2.57(2H,m), 2.80-2.88(3H,m), 3.61-3.78(3H,m), 4.48-4.52(1H,m),
6.94-7.74(7H,m).
INDUSTRIAL APPLICABILITY
[0233] According to the method of the present invention,
benzylpiperidine compounds useful as synthesis starting materials
of pharmaceutical agents, agricultural chemicals and the like can
be produced conveniently by a short step.
[0234] This application is based on a patent application No.
2001-010354 filed in Japan, the contents of which are hereby
incorporated by reference.
* * * * *