Production of mixed acid anhydride and amide compound

Details Production of mixed acid anhydride and amide compound Production of mixed acid anhydride and amide compound

2001-06-01

2004-06-22

Raymond, Richard L. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S245000, C548S112000, C548S119000, C548S201000, C548S206000, C548S235000, C548S237000, C548S334500, C548S413000, C548S532000, C548S953000, C548S956000, C548S966000, C562S024000, C562S879000, C562S887000, C562S888000, C562S897000

Reexamination Certificate

active

06753431

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a selective production method of a mixed acid anhydride and a production method of an amide compound, which methods are useful in the production of pharmaceuticals and intermediates thereof.
DESCRIPTION OF RELATED ART
A mixed acid anhydride of a carboxylic acid derivative has been known as an intermediate for producing an amide compound. Said anhydride has been typically produced, for example, in a small scale production by quickly adding a carboxylic add activating agent to a mixed solution of a carboxylic acid such as an amino acid having a protected amino group and an organic base, and immediately thereafter, within a few minutes, reacted with amines to produce amides due to its instability to a longer reaction time (J. Amer. Chem. Soc., 89, 5012 (1967), and Org. Reaction, 12, 157 (1962)).
SUMMARY OF THE INVENTION
According to the present invention, a mixed acid anhydride can be selectively produced, and an amide compound can be produced in a good chemical or optical yield not only in a laboratory scale but also in an industrial scale of production where a longer reaction time is required.
The present invention provides
a method for producing a mixed acid anhydride of formula (1):
R
1
C(O)OY(O)
n
(R
2
)
p
  (1)
wherein R
1
, R
2
, Y, n and p denote the same as defined below, which comprises adding
a carboxylic acid of formula (2);
R
1
COOH  (2)
 wherein R
1
denotes
a hydrogen atom,
an optionally substituted saturated or unsaturated hydrocarbyl group, or
an optionally substituted hetero ring, and
an organic base to a solution of a carboxylic acid activating agent of formula (3);
(R
2
)
p
Y(O)
n
X  (3)
 wherein R
2
denotes
an optionally substituted alkyl group (e.g., C1-C6 chain, branched or cyclic alkyl group, which may be substituted with a halogen atom),
an optionally substituted aryl group (e.g., a phenyl which may be substituted with a halogen or C1-C3 alkyl group),
an optionally substituted chain or cyclic alkoxy group (e.g., C1-C6 chain or cyclic alkoxy group), or
an optionally substituted aryloxy group (e.g., a phenoxy group which may be substituted with a halogen or C1-C3 alkyl group),
Y denotes
a carbon atom, a phosphorus atom, or a sulfur atom,
X denotes
a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a cyano group or a group of formula:
 (R
2
)
p
Y(O)
n
O—,
 wherein
R
2
is the same as defined above,
n and p are an integer of 1 or 2; and
when Y is a carbon atom, n=1 and p=1,
when Y is a phosphorous atom, n=1 and p=2, and
when Y is sulfur atom, n=2 and p=1 and R
2
denotes an optionally substituted alkyl or aryl group; and
a method for producing an amide compound of formula (4);
 wherein
R
1
denotes the same group as described above,
R
3
and R
4
independently denote
a hydrogen atom,
an optionally substituted saturated or unsaturated hydrocarbyl group,
an optionally substituted hetero ring,
a protective group for an amino group, or
R
3
represents a group of formula: —OR
30
, or —NR
30
R
31
, wherein
R
30
represents an optionally substituted alkyl group, or an optionally substituted aryl group and R
31
represents a hydrogen atom or an optionally substituted aryl group, and
R
3
and R
4
may be bonded to form a ring, which comprises
reacting the mixed acid anhydride of formula (3) obtained as above, with an amine of formula (5);
NHR
3
R
4
  (5)
 wherein R
3
and R
4
independently denote the same group as described above.
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, the present invention will be described in detail.
First a description will be made to R
1
.
In the optionally substituted saturated or unsaturated hydrocarbyl group represented by R
1
and other groups, the saturated or unsaturated hydrocarbyl group means, unless otherwise specified hereinafter,
a straight, branched or cyclic alkyl group (e.g., C1-C18 alkyl group),
an alkenyl or cycloalkenyl group (e.g., C2-C5 alkenyl or C5-C6 cycloalkenyl),
an alkynyl group (e.g., C3-C4 alkynyl),
an aryl group, which includes a phenyl, tolyl, biphenyl and naphthyl group,
an aralkyl, arylalkenyl or arylalkynyl group, which respectively means a phenyl-, biphenyl- or naphthyl-substituted alkyl (e.g, C1-C4 alkyl such as methyl, ethyl, propyl, butyl), alkenyl (e.g., C2-C4 alkenyl such as vinyl, propenyl, methally), or alkynyl (e.g, C3-C4 alkylnyl such as propynyl, butynyl) group.
The hetero ring means a pyridyl group, a 1,3-oxazole group, a 1,3-thiazole group, a furyl group, a tetrahydrofuryl group, a thienyl group, an imidazole or alkyleneimine group (e.g., C2-C11) of which nitrogen atoms are protected by a protecting group, or the like hereinafter.
The straight, branched or cyclic alkyl group, the alkenyl or cycloalkenyl group, the alkynyl group, the aryl group, the aralkyl, arylalkenyl or arylalkynyl group and the hetero ring may be each substituted with
(a) a hydroxy group or a halogen atom, or
(b) an amino group of formula: R
11
R
12
N— and optionally further with
at least one group selected from
a carbamoyl group, a methylmercapto group,
a 4-pyrimidinone-3-yl group,
an alkyl(C1-C3)dithio group, of which alkyl is substituted with an amino and carboxyl groups,
a mercapto, guanidyl, carboxyl, hydroxy or imidazolyl group, wherein R
11
represents a hydrogen atom or an amino-protecting group, R
12
represents an amino-protecting group, or a group of formula: R
13
—CO,
wherein R
13
represents a saturated or unsaturated hydrocarbyl group or a hetero ring, as defined above, which may be substituted with
(c) a hydroxy group, or a halogen atom, or
(d) a group of formula: R
14
R
15
N— and optionally further with at least one group selected from
a carbamoyl group, a methylmercapto group,
an alkyl(C1-C3)dithio group, of which alkyl is substituted with an amino and carboxyl groups,
an amino, mercapto, guanidyl, carboxyl, hydroxy, imidazolyl group, wherein R
14
is an amino-protecting group, and R
15
represents a hydrogen atom, a saturated or unsaturated hydrocarbyl group, a hetero ring or an amino-protecting group,
provided that said amino, mercapto, guanidyl, carboxyl, hydroxy and imidazolyl groups which may present in R
1
, R
2
, R
3
and substituent groups contained therein are in a protected form.
First preferred group for R
1
is an alkyl (e.g, C1-C5) group substituted with
(b) an amino group of formula: R
11
R
12
N— and optionally further with
at least one group selected from
a carbamoyl group, a methylmercapto group,
a 4-pyrimidinone-3-yl group,
an alkyl(C1-C3)dithio group, of which alkyl is substituted with an amino and carboxyl groups,
a mercapto, guanidyl, carboxyl, hydroxy or imidazolyl group, wherein R
11
represents a hydrogen atom or an amino-protecting group, R
12
represents an amino-protecting group, or a group of formula: R
13
—CO,
wherein R
13
represents a saturated or unsaturated hydrocarbyl group or the hetero ring, as defined above, which may be substituted with
(c) a hydroxy group, or a halogen atom, or
(d) a group of formula: R
14
R
15
N— and optionally further with at least one group selected from
a carbamoyl group, a methylmercapto group,
an alkyl(C1-C3)dithio group, of which alkyl is substituted with an amino and carboxyl groups,
an amino, mercapto, guanidyl, carboxyl, hydroxy, imidazolyl group, wherein R
14
is an amino-protecting group, and R
15
represents a hydrogen atom or an amino-protecting group,
provided that said amino, mercapto, guanidyl, carboxyl, hydroxy and imidazolyl groups are in a protected form.
Specific examples of the optionally substituted (C1-C18) alkyl group include a methyl group, an ethyl group, a n-propyl group, a n-butyl group, a n-pentyl group, a n-hexyl group, a n-heptyl group, a n-octyl group, a n-nonyl group, a n-decyl group, a n-undecyl group, an n-dodecyl group, a n-tridecyl group, a n-tetradecyl group, a n-pentadecyl group, an n-hexadecyl group, an n-heptadecyl group, an octadecyl group, an isopropyl group, an isobutyl group, a 3-methylbutyl group, a 4-methylpentyl group,

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