U.S. patent application number 13/236585 was filed with the patent office on 2012-01-12 for process for the preparation of sulfomate-carboxylate derivatives.
This patent application is currently assigned to Shionogi & Co., Ltd.. Invention is credited to Toshiaki MASUI, Kazuhiro YOSHIDA.
Application Number | 20120010428 13/236585 |
Document ID | / |
Family ID | 37073356 |
Filed Date | 2012-01-12 |
United States Patent
Application |
20120010428 |
Kind Code |
A1 |
MASUI; Toshiaki ; et
al. |
January 12, 2012 |
PROCESS FOR THE PREPARATION OF SULFOMATE-CARBOXYLATE
DERIVATIVES
Abstract
Disclosed is a process for the preparation of Compound (III),
salt or solvate thereof by reacting Compound (I), salt or solvate
thereof with Compound (II) in a toluene solvent in the presence of
an additive such as water or an alcohol. Also disclosed is a
process for the preparation of Compound (IV) comprising hydrolyzing
the obtained Compound (III) if necessary, and then oxidizing.
##STR00001## In the formula, R.sup.1 is hydrogen, optionally
substituted lower alkyl, optionally substituted aryl or optionally
substituted aryl lower alkyl, and R.sup.2 is optionally substituted
lower alkyl, optionally substituted cycloalkyl or optionally
substituted aryl lower alkyl.
Inventors: |
MASUI; Toshiaki; (Amagasaki,
JP) ; YOSHIDA; Kazuhiro; (Osaka, JP) |
Assignee: |
Shionogi & Co., Ltd.
Osaka
JP
|
Family ID: |
37073356 |
Appl. No.: |
13/236585 |
Filed: |
September 19, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11909980 |
Sep 27, 2007 |
|
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|
PCT/JP2006/306616 |
Mar 30, 2006 |
|
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13236585 |
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Current U.S.
Class: |
562/507 |
Current CPC
Class: |
C07C 303/36 20130101;
C07C 2601/14 20170501; C07C 311/07 20130101; C07C 313/06 20130101;
C07C 303/36 20130101 |
Class at
Publication: |
562/507 |
International
Class: |
C07C 61/08 20060101
C07C061/08 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 31, 2005 |
JP |
2005-102678 |
Claims
1. A process for the preparation of a compound of the formula
(IVb): ##STR00018## wherein R.sup.2 is lower alkyl, or a salt
thereof, comprising hydrolyzing a compound of the formula (IIIa)
under alkaline condition: ##STR00019## wherein R.sup.1a is
optionally substituted lower alkyl, and R.sup.2 is lower alkyl, or
a salt thereof, to obtain a compound of the formula (IIIb):
##STR00020## wherein R.sup.2 is lower alkyl, or a salt thereof; and
oxidizing the obtained compound or salt thereof.
2. A compound of the formula (IIIb-1): ##STR00021## or a salt
thereof.
Description
[0001] This application is a Continuation application of copending
application Ser. No. 11/909,980 filed on Sep. 27, 2007, which is
the National Stage application under 35 U.S.C. .sctn.371 of
International Application No. PCT/JP2006/306616 filed Mar. 30, 2006
and claims priority benefits under 35 U.S.C. .sctn.119(a)-(d) of
foreign Application No. 2005-102678 filed in Japan on Mar. 31,
2005.
TECHNICAL FIELD
[0002] The present invention relates to a process for the
preparation of sulfamate-carboxylate derivatives.
BACKGROUND ART
[0003] Sulfamate-carboxylate derivatives are useful compounds as
synthetic materials or intermediates for medicine. For example,
they can be used as a synthetic intermediate of a compound having
NPYY5 receptor antagonistic activity described in Patent Document
1.
[0004] Patent Document 1 discloses a process for the preparation of
4-(2-methylpropane-2-sulfonylamino-1-cyclohexanecarboxylic acid
comprising subjecting 4-amino-1-cyclohexanecarboxylic acid methyl
ester and t-butylsulphinyl chloride to the coupling reaction in a
dichloromethane solvent, oxidizing the obtained compound, and then
hydrolyzing. It is difficult to use industrially this process,
because it is necessary that restricted-use dichloromethane is used
and the product is isolated by chromatography.
[0005] Patent Document 2 discloses a process for the preparation of
trans-4-(2-methylpropane-2-sulfonylamino-1-cyclohexanecarboxylic
acid comprising subjecting cis-4-amino-1-cyclohexanecarboxylic acid
methyl ester and t-butylsulphinyl chloride to the coupling reaction
in an ethyl acetate solvent, the oxidation reaction, transformation
to trans isomer, and then hydrolysis. This process was far from a
high-yielding preparation process as the yield from
cis-4-amino-1-cyclohexanecarboxylic acid to
trans-4-(2-methylpropane-2-sulfonylamino)cyclohexanecarboxylic acid
is 70% or less even if the loss in transformation to trans isomer
was excluded.
[0006] Additionally, the document discloses an example that
tetrahydrofuran is used in a coupling step. However, the process
was needed to improve as a process for the industrial preparation,
because it was necessary to isolate the reaction intermediates in
every step, operations were complicated and the preparation
efficiency was not high. [0007] [Patent Document 1] WO01/37826
[0008] [Patent Document 2] WO2003/076374
DISCLOSURE OF INVENTION
Problems to be Solved by the Invention
[0009] The object of the present invention is to provide an
efficient process for the preparation of sulfamate-carboxylate
derivatives which are useful as synthetic materials or
intermediates for medicine.
Means for Solving the Problem
[0010] The present invention is the followings.
(1) A process for the preparation of a compound of the formula
(III):
##STR00002##
wherein R.sup.1 is hydrogen, optionally substituted lower alkyl,
optionally substituted aryl or optionally substituted aryl lower
alkyl, and R.sup.2 is optionally substituted lower alkyl,
optionally substituted cycloalkyl or optionally substituted aryl,
salt or solvate thereof (hereinafter referred to as Compound
(III)), characterized by reacting a compound of the formula
(I):
##STR00003##
wherein R.sup.1 has the same meaning as defined above, salt or
solvate thereof (hereinafter referred to as Compound (I)), with a
compound of the formula (II):
##STR00004##
wherein R.sup.2 has the same meaning as defined above, and Hal is
halogen (hereinafter referred to as Compound (II)), in toluene
solvent in the presence of at least one of additives selected from
the group consisting of water, alcohol, dimethylformamide,
dimethylacetamide and dimethoxyethane. (2) The process for the
preparation of the above (1), wherein the additive is water or
isopropanol. (3) A process for the preparation of a compound of the
formula (IV):
##STR00005##
wherein R.sup.1 and R.sup.2 have the same meanings as defined
above, salt or solvate thereof (hereinafter referred to as Compound
(IV)), characterized by obtaining a compound of the formula (III),
salt or solvate thereof by the process of the above (1), and
oxidizing the obtained compound, salt or solvate thereof. (4) A
process for the preparation of a compound of the formula (IVb):
##STR00006##
wherein R.sup.2 has the same meaning as defined above, salt or
solvate thereof (hereinafter referred to as Compound (IVb)),
characterized by hydrolyzing a compound of the formula (IIIa):
##STR00007##
wherein R.sup.1a is optionally substituted lower alkyl, optionally
substituted aryl or optionally substituted aryl lower alkyl, and
R.sup.2 has the same meaning as defined above, salt or solvate
thereof (hereinafter referred to as Compound (IIIa)), to obtain a
compound of the formula (IIIb):
##STR00008##
wherein R.sup.2 has the same meaning as defined above, salt or
solvate thereof (hereinafter referred to as Compound (IIIb)), and
oxidizing the obtained compound, salt or solvate thereof. (5) The
process for the preparation of the above (4), characterized by
obtaining a compound of the formula (IIIa):
##STR00009##
wherein R.sup.1a and R.sup.2 have the same meanings as defined
above, salt or solvate thereof by the process of the above (1), and
using the obtained compound, salt or solvate thereof. (6) The
process for the preparation of the above (5), characterized by
reacting without isolating a compound of the formula (IIIa) or
(IIIb) or the salt to give a compound of the formula (IVb), salt or
solvate thereof. (7) A process for the preparation of a compound of
the formula (VI):
##STR00010##
wherein R.sup.2, R.sup.3 and Z have the same meanings as defined
above, pharmaceutically acceptable salt or solvate thereof
(hereinafter referred to as Compound (VI)), characterized by
obtaining a compound of the formula (IV) or (IVb), salt or solvate
thereof by the process of any one of the above (3) to (6), and
reacting the obtained compound, salt or solvate thereof with a
compound of the formula (V):
R.sup.3NH--Z (V)
wherein R.sup.3 is hydrogen or lower alkyl; Z is optionally
substituted lower alkyl, optionally substituted lower alkenyl,
optionally substituted amino, optionally substituted lower alkoxy,
optionally substituted carbocyclyl or optionally substituted
heterocyclyl, salt or solvate thereof (hereinafter referred to as
Compound (V)). (8) A compound of the formula (IIIb-1):
##STR00011##
salt or solvate thereof.
Effect of the Invention
[0011] A process for the preparation of the present invention can
be used to obtain safely and easily Compound (III) or (IV) in high
yield, and is useful for green chemistry.
BEST MODE FOR CARRYING OUT THE INVENTION
[0012] In this description, "lower alkyl" includes C1 to C10,
preferably C1 to C6, and more preferably C1 to C3 straight or
branched alkyl. Examples include methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,
isopentyl, neopentyl, hexyl, isohexyl, n-heptyl, isoheptyl,
n-octyl, isooctyl, n-nonyl and n-decyl. "Lower alkyl" of R.sup.1,
R.sup.1a or R.sup.3 is preferably methyl or ethyl. "Lower alkyl" of
R.sup.2 is preferably ethyl, isopropyl or t-butyl.
[0013] The lower alkyl part of "aryl lower alkyl", "halogeno lower
alkyl" or "hydroxy lower alkyl" is the same as the above "lower
alkyl".
[0014] Examples of substituents for "optionally substituted lower
alkyl" of Z include (1) halogen; (2) cyano; and (3) the following
groups (i) to (xvi): (i) hydroxy, (ii) lower alkoxy, (iii)
mercapto, (iv) lower alkylthio, (v) acyl, (vi) acyloxy, (vii)
carboxy, (viii) lower alkoxycarbonyl, (ix) imino, (x) carbamoyl,
(xi) thiocarbamoyl, (xii) lower alkylcarbamoyl, (xiii) lower
alkylthiocarbamoyl, (xiv) amino, (xv) lower alkylamino or (xvi)
heterocyclylcarbonyl, which may be optionally substituted by at
least one of groups selected from Substituent Group .beta. defined
below.
[0015] Examples of substituents for "optionally substituted lower
alkyl" of R.sup.1 or R.sup.1a include at least one of groups
selected from the group consisting of halogen, optionally protected
hydroxy, mercapto, lower alkoxy, lower alkenyl, di-lower
alkylamino, lower alkylthio, acyl, carboxy, lower alkoxycarbonyl,
carbamoyl, cyano, cycloalkyl phenoxyl and heterocyclyl.
[0016] Examples of substituents for "optionally substituted lower
alkyl" except for those of Z, R.sup.1 and R.sup.1a include at least
one of groups selected from Substituent Group .beta. defined
below.
[0017] "Lower alkenyl" includes C2 to C10, preferably C2 to C8 and
more preferably C3 to C6 straight or branched alkenyl having at
least one double bond at arbitrary positions. Examples include
vinyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl,
butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl,
isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl and decenyl.
[0018] Examples of substituents for "optionally substituted lower
alkenyl" include halogen, lower alkoxy, lower alkenyl, amino, lower
alkylamino, lower alkoxycarbonylamino, lower alkylthio, acyl,
carboxy, lower alkoxycarbonyl, carbamoyl, cyano, cycloalkyl,
phenyl, lower alkylphenyl, lower alkoxyphenyl, naphthyl and/or
heterocyclyl.
[0019] Examples of substituents for "optionally substituted amino"
include the below Substituent Group .beta., optionally substituted
benzoyl and/or optionally substituted heterocyclylcarbonyl (wherein
the substituent is hydroxy, lower alkyl, lower alkoxy and/or lower
alkylthio).
[0020] The lower alkyl part of "lower alkoxy", "lower alkylthio",
"lower alkylcarbamoyl", "lower alkylthiocarbamoyl", "lower
alkylamino", "di-lower alkylamino", "lower alkylsulfinyl", "lower
alkylsulfonyl", "lower alkylsulfamoyl", "lower alkoxycarbonyl",
"lower alkoxy lower alkyl", "hydroxy lower alkyl", "lower
alkoxycarbonylamino", "lower alkylphenyl", "lower alkoxyphenyl",
"halogeno lower alkyl", "phenyl lower alkoxy" or "phenyl lower
alkylthio" is the same as the above "lower alkyl".
[0021] Examples of substituents for "optionally substituted lower
alkoxy" include at least one of groups selected from the below
Substituent Group .beta.. Preferred is phenyl, lower alkylphenyl,
lower alkoxyphenyl, naphthyl or heterocyclyl.
[0022] "Acyl" includes (1) C1 to C10, preferably C1 to C6 and more
preferably C1 to C4 straight or branched alkylcarbonyl or
alkenylcarbonyl, (2) C4 to C9 and preferably C4 to C7
cycloalkylcarbonyl and (3) C7 to C11 arylcarbonyl. Examples include
formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl,
hexanoyl, acryloyl, propioloyl, methacryloyl, crotonoyl,
cyclopropylcarbonyl, cyclohexylcarbonyl, cyclooctylcarbonyl and
benzoyl.
[0023] The acyl part of "acyloxy" is the same as above.
[0024] The protecting group of "optionally protected hydroxy" or
"optionally protected hydroxy lower alkyl" includes all hydroxy
protecting groups usually used. Examples include acyl (e.g.,
acetyl, trichloroacetyl and benzoyl), lower alkoxycarbonyl (e.g.,
t-butoxycarbonyl), lower alkylsulfonyl (e.g., methanesulfonyl),
lower alkoxy lower alkyl (e.g., methoxymethyl) and trialkylsilyl
(e.g., t-butyldimethylsilyl).
[0025] "Halogen" includes fluorine, chlorine, bromine and iodine.
Especially preferred is Fluorine or chlorine.
[0026] The halogen part of "halogenophenyl" or "halogeno lower
alkyl" is the same as the above "halogen".
[0027] "Alkylenedioxy" includes methylenedioxy, ethylenedioxy,
trimethylenedioxy, tetramethylenedioxy, pentamethylenedioxy and
hexamethylenedioxy. Preferred is methylenedioxy or
ethylenedioxy.
[0028] "Carbocyclyl" includes "cycloalkyl", "cycloalkenyl",
"bicycloalkyl" and "aryl".
[0029] "Cycloalkyl" includes C3 to C8 and preferably C5 or C6
cyclic alkyl. Examples include cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
[0030] Examples of substituents for "optionally substituted
cycloalkyl" include at least one of groups selected from
Substituent Group .beta. defined below.
[0031] "Cycloalkenyl" includes the above cycloalkyl with at least
one of double bonds at arbitrary positions in the ring. Examples
include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl
and cyclohexadienyl.
[0032] "Bicycloalkyl" includes C5 to C8 alicyclic groups wherein
the two rings share two or more atoms and which are given by
removing one hydrogen from C5 to C8 alicyclic group. Examples
include bicyclo[2.1.0]pentyl, bicyclo[2.2.1]heptyl,
bicyclo[2.2.2]octyl and bicyclo[3.2.1]octyl.
[0033] "Aryl" includes monocyclic or polycyclic aromatic
carbocyclyl, and examples include phenyl, naphtyl, anthryl and
phenanthryl. It also includes aryl which is fused with another
non-aromatic carbocyclyl, and examples include indanyl, indenyl,
biphenylyl, acenaphtyl, tetrahydronaphtyl and fluorenyl. Especially
preferred is phenyl.
[0034] Examples of substituents for "optionally substituted
carbocyclyl" include at least one of groups selected from the below
Substituent Group .alpha. and .beta.. The "carbocyclyl" may be
substituted at arbitrary positions.
[0035] Examples of substituents for "optionally substituted aryl"
or "optionally substituted aryl lower alkyl" of R.sup.1 or R.sup.1a
include at least one of groups selected from the group consisting
of halogen, optionally protected hydroxy, mercapto, lower alkyl,
halogeno lower alkyl, hydroxy lower alkyl, lower alkoxy, lower
alkenyl, di-lower alkylamino, lower alkylthio, acyl, carboxy, lower
alkoxycarbonyl, carbamoyl, cyano, cycloalkyl, phenyl, phenoxyl,
lower alkyl phenyl, lower alkoxy phenyl, halogenophenyl, naphthyl
and heterocyclyl.
[0036] Examples of substituents for the other "optionally
substituted aryl" include at least one of groups selected from the
below Substituent Group .beta..
[0037] The cycloalkyl part of "cycloalkylcarbamoyl",
"cycloalkylsulfamoyl" or "cycloalkyloxy" is the same as the above
"cycloalkyl".
[0038] The aryl part of "arylsulfonyl" or "aryl lower alkyl" is the
same as the above "aryl".
[0039] "Heterocyclyl" includes heterocycle which contains at least
one hetero atom optionally selected from the group of O, S and N.
Examples include 5- to 6-membered heteroaryl such as pyrrolyl,
imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl,
pyrazinyl, triazolyl, triazinyl, tetrazolyl, isoxazolyl, oxazolyl,
oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl and
thienyl; fused bicyclic heterocyclyl such as indolyl, isoindolyl,
indazolyl, indolizinyl, indolinyl, isoindolinyl, quinolyl,
isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl,
naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzopyranyl,
benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl,
benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl,
isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl,
triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl,
quinazolinyl, naphthyridinyl, dihydropyridyl, tetrahydroquinolyl
and tetrahydrobenzothienyl; fused tricyclic heterocyclyl such as
carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxatiinyl,
phenoxazinyl and dibenzofuryl; non-aromatic heterocyclyl such as
dioxanyl, thiiranyl, oxiranyl, oxathiolanyl, azetidinyl, thianyl,
pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl,
pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, morpholinyl,
morpholino, thiomorpholinyl, thiomorpholino, dihydropyridyl,
tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiazolyl and
tetrahydroisothiazolyl.
[0040] Fused heterocyclyl which is fused with a ring other than
heterocycle (e.g., benzothiazolyl) may have a bonding radical on
any ring.
[0041] Preferred as heterocyclyl of Z is imidazolyl,
benzothiazolyl, isothiazolyl, benzopyranyl, morpholino, pyridyl,
quinolyl, pyrimidyl or the like.
[0042] Examples of substituents for "optionally substituted
heterocyclyl" are the same as the substituents for the above
substituted "carbocyclyl".
[0043] The heterocyclyl part of "heterocyclyloxy",
"heterocyclylthio", "heterocyclylcarbonyl" or
"heterocyclylsulfonyl" is the same as the above "heterocyclyl".
[0044] Substituent Group .alpha. is a group of (1) halogen; (2)
oxo; (3) cyano; (4) nitro; (5) imino optionally substituted by
lower alkyl or hydroxy; (6) the following groups (i) to (xxi): (i)
hydroxy, (ii) lower alkyl, (iii) lower alkenyl, (iv) lower alkoxy,
(v) carboxy, (vi) lower alkoxycarbonyl, (vii) acyl, (viii) acyloxy,
(ix) imino, (x) mercapto, (xi) lower alkylthio, (xii) carbamoyl,
(xiii) lower alkylcarbamoyl, (xiv) cycloalkylcarbamoyl, (xv)
thiocarbamoyl, (xvi) lower alkylthiocarbamoyl, (xvii) lower
alkylsulfinyl, (xviii) lower alkylsulfonyl, (xix) sulfamoyl, (xx)
lower alkylsulfamoyl and (xxi) cycloalkylsulfamoyl, which may be
optionally substituted by at least one of groups selected from
Substituent Group .beta.; (7) the following groups (i) to (v): (i)
cycloalkyl, (ii) cycloalkenyl, (iii) cycloalkyloxy, (iv) amino and
(v) alkylenedioxy, which may be optionally substituted by a
substituent selected from Substituent Group .beta., lower alkyl,
lower alkoxy-lower alkyl, optionally protected hydroxy-lower alkyl,
halogeno-lower alkyl, lower alkylsulfonyl and/or arylsulfonyl; and
(8) the following groups: (i) phenyl, (ii) naphtyl, (iii) phenoxy,
(iv) phenyl-lower alkoxy, (v) phenylthio, (vi) phenyl-lower
alkylthio, (vii) phenylazo, (viii) heterocyclyl, (ix)
heterocyclyloxy, (x) heterocyclylthio, (xi) heterocyclylcarbonyl
and (xii) heterocyclylsulfonyl, which may be optionally substituted
by a substituent selected from Substituent .beta., lower alkyl,
halogeno-lower alkyl and/or oxo.
[0045] Substituent Group .beta. is a group of halogen, optionally
protected hydroxy, mercapto, lower alkoxy, lower alkenyl, amino,
lower alkylamino, lower alkoxycarbonylamino, lower alkylthio, acyl,
carboxy, lower alkoxycarbonyl, carbamoyl, cyano, cycloalkyl,
phenyl, phenoxyl, lower alkylphenyl, lower alkoxyphenyl,
halogenophenyl, naphthyl and heterocyclyl.
[0046] A compound of the formula (I), (III), (IV) or (VI) in the
present invention may be the salt. Examples include salts of
inorganic acid such as hydrochloric acid, sulfuric acid, nitric
acid and phosphoric acid; salts of organic acid such as acetic
acid, formic acid, p-toluenesulfonic acid, methanesulfonic acid,
oxalic acid and citric acid; salts of organic base such as
ammonium, trimethylammonium and triethylammonium; salts of alkali
metal such as sodium and potassium; and salts of alkaline-earth
metal such as calcium and magnesium.
[0047] Compound (III) or (IV) can be prepared according to the
following processes.
Process A
##STR00012##
[0048] In the formula, R.sup.1 is hydrogen, optionally substituted
lower alkyl, optionally substituted aryl or optionally substituted
aryl lower alkyl, R.sup.2 is optionally substituted lower alkyl,
optionally substituted cycloalkyl or optionally substituted aryl,
and Hal is halogen.
(The First Step)
[0049] Compound (I) is reacted with sulfinylhalide Compound (II) in
toluene solvent in the presence of at least one of additives
selected from the group consisting of water, alcohol,
dimethylformamide, dimethylacetamide and dimethoxyethane, if
necessary, with base to give Compound (III).
[0050] The amount of Compound (II) can be about 1 mole equivalent
or more and preferably about 1.3 mole equivalents or more, and
about 3 mole equivalents or less and preferably about 1.5 mole
equivalents or less relative to 1 mole of Compound (I).
[0051] Examples of additives include water, methanol, ethanol,
isopropanol, n-propanol, n-butanol, t-butanol, dimethylformamide,
dimethylacetamide, dimethoxyethane and the mixture of 2 or 3 kinds
of additives selected from them. Preferred is water or
isopropanol.
[0052] It is preferable that the amount of the additive is decided
considering the amount of Compound (I) and (II), solubility,
stability against the additive and the like. For example, when the
weight of Compound (I) is v (g), the amount of the additive can be
about 0.5v (ml) or more and preferably about 1v (ml) or more, and
about 5v (ml) or less and preferably about 2v (ml) or less.
[0053] The amount of the toluene solvent is not especially limited.
The arbitrary amount to give a reactive solution or slurry can be
used. For example, when the weight of Compound (I) is v (g), the
amount of the solvent can be about 1v (ml) or more and preferably
about 2v (ml) or more. The maximum amount is not especially
limited, but about 10v (ml), preferably about 8v (ml) and more
preferably about 5v (ml) considering preparation efficiency.
[0054] Examples of bases include triethylamine, pyridin,
diisopropylethylamine, sodium hydroxide, potassium carbonate and
sodium hydrogencarbonate. The amount of the base is about 1 mole
equivalent or more and preferably about 2 mole equivalents or more,
and about 5 mole equivalents or less and preferably about 4 mole
equivalents or less relative to 1 mole of Compound (I).
[0055] Reaction can be carried out at -20.degree. C. to under
heating, preferably about -10 to 50.degree. C. and more preferably
about 0 to 20.degree. C., for about 5 minutes to 10 hours and
preferably about 1 to 3 hours.
[0056] The obtained Compound (III) may be isolated or provided to
the next step without isolating. When it is used in the next step
without isolating, there is an advantage that the works can be
carried out in succession.
[0057] As a solvent used in this step, toluene is especially
preferable, but acetic ester (ethyl acetate, methyl acetate,
isopropyl acetate or isobutyl acetate), tetrahydrofuran, benzene,
xylene, benzene chloride, dichloromethane or the like can be
used.
(The Second Step)
[0058] Compound (IV) is obtained by subjecting Compound (III) to
oxidation reaction in an appropriate solvent with an arbitrary
oxidizing agent by a well-known method.
[0059] A solvent can be selected considering property of a
substrate or an oxidizing agent or the like. Examples include
toluene, dimethylformamide, tetrahydrofuran and ethyl acetate.
[0060] The reaction solution obtained in the first step without
isolating Compound (III) can be subjected to oxidation reaction. In
case that Compound (III) in the reaction solution obtained in the
first step is a compound wherein R.sup.1 is hydrogen, it is
possible that Compound (III) is transformed to the salt, the water
is added thereto and the mixture is subjected to oxidation reaction
in an aqueous solution by a well-known method. Toluene same as
previous step or water is preferably used as a solvent.
[0061] The amount of the solvent is not limited. The arbitrary
amount to give a reactive solution or slurry can be used. For
example, when the weight of Compound (III) is v (g), the minimum
amount of the solvent is about 1v (ml), preferably about 2v (ml)
and more preferably about 3v (ml). The maximum amount is not
limited, but about 10v (ml), preferably about 8v (ml) and more
preferably about 5v (ml) considering preparation efficiency.
[0062] An arbitrary oxidizing agent can be used. Examples of
oxidizing agents include peracetic acid, m-chloroperbenzoic acid,
pertrifluoroacetic acid, sodium periodate, magnesium monoperoxy
phthalate (MMPP), potassium permanganate, sodium hyochlorite,
calcium hyochlorite, perchloric acid, chlorous acid, oxone (2
KHSO.sub.5.KHSO.sub.4.K.sub.2SO.sub.4) and O.sub.2. Preferred is
peroxide.
[0063] Peroxide can be used as hydrogen peroxide solution. As a
catalyst, ammonium molybdate tetrahydrate
((NH.sub.4).sub.6Mo.sub.7O.sub.24.4H.sub.2O), sodium tungstate, the
hydrate or the like can be used. The amount of superoxide can be
about 0.5 mole equivalent or more and preferably about 1 mole
equivalent or more, and about 3 mole equivalents or less and
preferably 2 mole equivalents or less relative to 1 mole of
Compound (III). The minimum amount of catalyst can be about 0.005
mole equivalent or more and preferably about 0.01 mole equivalent
or more, and about 0.1 mole equivalent or less and preferably about
0.06 mole equivalent or less relative to 1 mole of Compound
(III).
[0064] Reaction temperature is not limited, but usually about 0 to
100.degree. C. and preferably about 20 to 60.degree. C.
[0065] Reaction time is not limited, but usually about 1 to 24
hours and preferably about 1 to 5 hours
[0066] After finishing the reaction, the target compound, Compound
(IV), is crystallized by adding acid such as sulfuric acid or
hydrochloric acid at about 10 to 50.degree. C. and preferably about
20 to 30.degree. C., and stirring for about 15 minutes to 10 hours
and preferably about 30 minutes to 3 hours. And then, the target
compound, Compound (IV), can be obtained by washing, filtrating and
drying by a well-known method.
[0067] As shown in a comparative example described below, when
Compound (I) and (II) were reacted in the absence of an additive in
toluene solvent, preparation rate of the target compound, Compound
(III), remained around 50%. Furthermore, the present inventors
confirmed that preparation rates of Compound (III) were changed by
lot because the reactivity of Compound (I) changed by factors such
as crystal form. On the other hand, a process of the present
invention was preferably and stably carried out in all lots by
reacting Compound (I) and (II) in the presence of an additive and
the target compound, Compound (III), can be stably obtained with a
high preparation rate, about 95%.
[0068] The present inventors confirmed that the solubility of
Compound (I) in toluene was lower than that in ethyl acetate or
tetrahydrofuran in Patent Document 2. In this circumstance, people
skilled in the art should expect that it is usually difficult to
carry out the reaction. However, according to a process of the
present invention, the target compound could be obtained at very
high preparation rate by using an additive. Additionally, although
Compound (II) is unstable in water or the like, the reaction is
preferably carried out without degradation of Compound (II)
according to a process of the present invention.
[0069] Compared to processes described in Patent Document 1 or 2,
the present process is useful as a process for the industrial
preparation because the first step and the second step can be
carried out in succession and the target compound can be obtained
without dichloromethane or the like whose use is not
environmentally preferable.
Process B
[0070] When Compound (III) obtained by the first step of the above
Process A is a compound wherein R.sup.1 is optionally substituted
lower alkyl, optionally substituted aryl or optionally substituted
aryl lower alkyl, Compound (IIIb) can be obtained by subjecting to
the hydrolyzing step before the second step of the above Process A,
and then subjected to oxidation reaction.
##STR00013##
In the formula, R.sup.1a is optionally substituted lower alkyl,
optionally substituted aryl or optionally substituted aryl lower
alkyl, R.sup.2 is optionally substituted lower alkyl, optionally
substituted cycloalkyl or optionally substituted aryl, and Hal is
halogen.
(The First Step)
[0071] Compound (IIIa) is obtained by the same process as the first
step of the above Process A.
(The Second Step)
[0072] Compound (IIIb) is obtained by hydrolyzing Compound (IIIa)
in an appropriate solvent with arbitrary base and water by a
well-known method.
[0073] A solvent can be selected considering property of a
substrate or oxidizing agent or the like. Examples include toluene,
dimethylformamide, tetrahydrofuran, benzene, xylene, benzene
chloride and dichloromethane.
[0074] The amount of solvent is not limited. The arbitrary amount
to give a reactive solution or slurry can be used. For example,
when the weight of Compound (IIIa) is v (g), the minimum amount of
the solvent is about 1v (ml), preferably about 2v (ml) and more
preferably about 3v (ml). The maximum amount is not limited, but
about 10v (ml), preferably about 8v (ml) and more preferably about
5v (ml) considering preparation efficiency. Base and water are
added to the prepared solution as above.
[0075] Alternatively, base and water can be added to a reaction
solution without isolating Compound (IIIa) obtained by the first
step.
[0076] The additive amount of water is not especially limited. For
example, when the weight of Compound (IIIa) is v (g), the minimum
amount of added water is about 1v (ml), preferably about 2v (ml)
and more preferably about 3v (ml). The maximum amount is not
limited, but about 10v (ml), preferably about 8v (ml) and more
preferably about 5v (ml) considering preparation efficiency. When
Compound (IIIa) obtained in the first step is subjected to this
step as a reaction solution without isolating, the minimum amount
of added water is about half of and preferably about the same as
the volume of the reaction solution. The maximum amount is about 10
times and preferably about 3 times of the volume of the reaction
solution.
[0077] As a base, sodium hydroxide, sodium methoxide, potassium
hydroxide or the like can be used. The amount of the base can be
about 1 mole equivalent or more and preferably about 2 mole
equivalents or more, and about 5 mole equivalents or less and
preferably about 3 mole equivalents or less relative to 1 mole of
Compound (IIIa).
[0078] Reaction temperature is not limited, but usually about 0 to
80.degree. C. and preferably about 20 to 50.degree. C.
[0079] Reaction time is preferably about 1 to 24 hours and more
preferably about 1 to 10 hours.
[0080] Compound (IIIb) may be isolated from the water layer of the
obtained reaction solution or provided to the next step as water
layer without isolating. When it is used in the next step without
isolating, there is an advantage that the works can be carried out
in succession.
[0081] When peroxide is used as an oxidizing agent in the next
step, oxidation reaction can be preferably carried out by
neutralizing the reaction solution with acid such as sulfuric acid
and hydrochloric acid in advance.
(The Third Step)
[0082] The target compound, Compound (IVb), is obtained by the same
process as the second step of the above Process A.
[0083] Patent Document 2 described above discloses a method for
coupling Compound (I) and (II) to give Compound (IIIa), oxidizing
Compound (IIIa) to give Compound (IV) wherein R.sup.1 is lower
alkyl, and hydrolyzing after transforming Compound (IV) to trans
isomer to give Compound (IVb). According to this method, the yield
from Compound (Ia) to Compound (IVb) was around 50%. The yield
remained only 70% or less even if the loss in the transformation
step to trans isomer was excluded. Furthermore, the reaction was
carried out by isolating each reaction intermediate and changing
the reaction solvent to a different solvent such as ethyl acetate,
dimethylformamide, toluene or tetrahydrofuran.
[0084] The present inventors found that Compound (IIIa) was
degraded under the acid condition, and completed a method for
obtaining the target compound, Compound (IVb), with high yield,
around 90% (yield from Compound (I)), by subjecting to oxidation
reaction after alkaline hydrolysis. According to a process of the
present invention, the target compound can be efficiently and
safely obtained because steps from the first step to the third step
can be carried out in succession and dichloromethane or the like is
not used.
[0085] Compound (VI) can be prepared by reacting Compound (IVb)
obtained in the above Process A or B with Compound (V).
[0086] When a compound wherein R.sup.1 is optionally substituted
lower alkyl, optionally substituted aryl or optionally substituted
aryl lower alkyl, salt or solvate thereof (hereinafter referred to
as Compound (IVa)) can be obtained by the above Process A, the
compound is transformed to Compound (IVb) by hydrolyzing in
advance.
##STR00014##
In the formula, R.sup.1a is optionally substituted lower alkyl,
optionally substituted aryl or optionally substituted aryl lower
alkyl, R.sup.2 is optionally substituted lower alkyl, optionally
substituted cycloalkyl or optionally substituted aryl, R.sup.3 is
hydrogen or lower alkyl, and Z is optionally substituted lower
alkyl, optionally substituted lower alkenyl, optionally substituted
amino, optionally substituted lower alkoxy, optionally substituted
carbocyclyl or optionally substituted heterocyclyl.
[0087] Compound (VI) can be obtained by reacting Compound (V) with
Compound (IVb). This reaction can be carried out according to
amidation reaction described in the above Patent Document 1 or the
like.
[0088] For example, Compound (IVb) and an activator such as acid
halide (for example, thionyl chloride, oxalyl chloride, phosphorus
oxychloride or the like is used), acid anhydride or activated ester
of Compound (V) are reacted in an appropriate solvent at about 0 to
100.degree. C. for about 3 minutes to 10 hours.
[0089] As a solvent, tetrahydrofuran, dimethylformamide, diethyl
ether, dichloromethane, toluene, benzene, xylene, cyclohexane,
hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane,
dioxane, acetone, acetonitrile, water, the mixture solvent or the
like can be used. Preferred is toluene or tetrahydrofuran.
Additionally, if necessary, activator such as base (Preferred is
triethylamine, pyridine or the like), thionyl chloride, acid halide
(e.g., thionyl chloride, oxalyl chloride or phosphorus
oxychloride), acid anhydride or activated ester can be used.
[0090] As the alternative process, the target compound can be
obtained by reacting Compound (IVb) and (V) in an appropriate
solvent (e.g., tetrahydrofuran, dimethylformamide, diethyl ether,
dichloromethane, toluene, benzene, xylene, cyclohexane, hexane,
chloroform, ethyl acetate, butyl acetate, pentane, heptane,
dioxane, acetone, acetonitrile, water or the mixture solvent) in
the presence of a condensing agent at about 0 to 100.degree. C. for
about 3 minutes to 10 hours.
[0091] Examples of condensing agents include
1,1-carbonyldiimidazole, dicyclohexyl carbodiimide and water
soluble carbodiimide(1-ethyl-3-(3'-dimethylamino propyl)
carbodiimide).
[0092] Examples of the groups of Z are the followings.
##STR00015## ##STR00016##
[0093] Compound (VI) obtained as above is useful as a NPYY5
receptor antagonist.
[0094] This invention is further explained by the following
Examples, which are not intended to limit the scope of the present
invention.
Example 1
##STR00017##
[0095] Additive: Water
[0096] To hydrochloride of Compound (I-1) (10.00 g), were added
toluene (40 mL), triethylamine (10.72 g) and tap water (20 mL) and
the mixture was cooled to 3.degree. C. Compound (II-1) (7.45 g) was
added dropwise thereto at 3 to 6.degree. C. over 65 minutes. This
reaction solution was stirred at 0 to 10.degree. C. for about 60
minutes and then separated to obtain the upper layer (46.69 g)
(Compound (IIIa-1) in toluene solution). To this reaction solution,
were added tap water (40 mL) and 48% NaOH solution (10.03 g). The
mixture was stirred at about 40.degree. C. for 2 hours, and then
separated to obtain the lower layer. 20% sulsuluric acid solution
(17.54 g) was added dropwise thereto at 40 to 48.degree. C. to be
pH6.5 (Compound (IIIb-1) in the reaction solution). To this
reaction solution, was added sodium tungstate dihydrate (794 mg).
35% hydrogen peroxide solution (9.36 g) was added dropwise thereto
at 32 to 52.degree. C. over 61 minutes. This reaction solution was
stirred at about 40.degree. C. for 90 minutes. 18.12 g of a
solution that sodium sulfite (8.00 g) was dissolved in tap water
(100 g) was added dropwise thereto and the surplus superoxide was
removed. To this reaction solution, was added dropwise 20%
sulsuluric acid solution (12.32 g) at 40 to 45.degree. C. to be
pH3. The mixture was stirred at about 2.degree. C. for 120 minutes.
The reaction mixture was filtered, and then the filtrate was washed
with 30 mL of tap water. The undried crystal was collected and
dried under reduced pressure with heating (80.degree. C.) to give
11.41 g of Compound (IVb-1) (90.0% yield, based on hydrochloride of
Compound (I-1)).
Compound (IIIb-1)
[0097] .sup.1H-NMR (CDCl.sub.3, internal standard TMS, 300 MHz)
[0098] .delta. 1.05-1.20 (m, 2H), 1.21 (s, 9H), 1.54 (m, 2H), 2.09
(t, 4H, J=14 Hz), 2.28 (tt, 1H, J=12.0, 3.6 Hz), 3.18 (m, 1H), 3.30
(d, 1H, J=6.0 Hz)
[0099] Elemental analysis:
[0100] Calcd: C, 53.41; H, 8.56; N, 5.66; S, 12.96
[0101] Found: C, 53.21; H, 8.59; N, 5.85; S, 12.57
[0102] Melting point: Degrading over about 180.degree. C.
Example 2
Additive: Isopropanol
[0103] To hydrochloride of Compound (I-1) (7.00 g), were added
toluene (28 mL), triethylamine (7.50 g) and isopropanol (7 mL) and
the mixture was cooled to 3.degree. C. Compound (II-1) (5.21 g) was
added dropwise thereto at 2 to 8.degree. C. over 17 minutes. This
reaction solution was stirred at 0 to 10.degree. C. for about 60
minutes. Tap water (14 mL) was added thereto and separated to
obtain the upper layer (36.31 g) (Compound (IIIa-1) in toluene
solution). To this reaction solution, were added tap water (28 mL)
and 48% NaOH solution (7.02 g). The mixture was stirred at about
25.degree. C. for 4 hours, and then separated to obtain the lower
layer. 20% sulsuluric acid solution (12.73 g) was added dropwise
thereto at about room temperature to be pH7.5 (Compound (IIIb-1) in
the reaction solution). To this reaction solution, was added sodium
tungstate dihydrate (556 mg). 35% hydrogen peroxide solution (6.55
g) was added dropwise thereto at 40 to 43.degree. C. over 59
minutes. After stirring this reaction solution at about 40.degree.
C. for 120 minutes, 4.63 g of a solution that sodium sulfite (8.00
g) was dissolved in tap water (100 g) was added dropwise thereto
and the surplus superoxide was quenched. To this reaction solution,
was added dropwise 20% sulsuluric acid solution (8.39 g) at about
room temperature to be pH3. The mixture was stirred at about
2.degree. C. for about 30 minutes. The reaction mixture was
filtered, and then the filtrate was washed with 21 mL of tap water.
The undried crystal was collected and dried under reduced pressure
with heating (80.degree. C.) to give 7.86 g of Compound (IVb-1)
(88.5% yield, based on hydrochloride of Compound (I-1)).
Example 3
Additive: Methanol
[0104] To hydrochloride of Compound (I-1) (7.00 g), were added
toluene (35 mL), triethylamine (7.50 g) and methanol (7 mL) and the
mixture was cooled to 3.degree. C. Compound (II-1) (5.21 g) was
added dropwise thereto at 2 to 9.degree. C. over 48 minutes.
Triethylamine (7.50 g) was added thereto and Compound (II-1) (5.21
g) was added dropwise at 2 to 9.degree. C. Triethylamine (7.50 g)
was added thereto and Compound (II-1) (5.21 g) was added dropwise
at 2 to 9.degree. C. After stirring this reaction solution at 0 to
10.degree. C. for about 30 minutes, tap water (14 mL) was added
thereto and separated to obtain the upper layer (46.57 g) (Compound
(IIIa-1) in toluene solution). The preparation rate of Compound
(IIIa-1) was 94.5%.
[0105] The preparation rates of Compound (IIIa-1) in the above
Examples and a case that the additive was not added were
compared.
TABLE-US-00001 TABLE 1 The preparation The kind and rate (%) of The
amount of amount of Compound Additive the additive the solvent
(IIIa-1) Example 1 Water 2 V Toluene 4 V 94.6 Example 2 Isopropanol
1 V Toluene 4 V 98.8 Example 3 Methanol 1 V Toluene 5 V 94.5
Comparative No additive -- Toluene 5 V 52.7 example (1 V of the
amount of an additive means 1 mL relative to 1 g of the
substrate.)
[0106] To carry out the next reaction without isolating Compound
(IIIa-1), the preparation rate was calculated by quantitating the
reaction solution with HPLC without isolating the compound in all
cases.
[0107] It is cleared that the preparation rates of Compound
(IIIa-1) were considerably enhanced in the cases that an additive
was added compared to the case that an additive was not used.
INDUSTRIAL APPLICABILITY
[0108] A process of the present invention is useful as a process
for the industrial preparation because it can safely and
efficiently prepare Compound (III) and (IV).
* * * * *