U.S. patent application number 11/767298 was filed with the patent office on 2008-12-25 for esters of pentahydroxyhexylcarbamoyl alkanoic acids.
Invention is credited to Bernd Junker, Javier Manero.
Application Number | 20080319221 11/767298 |
Document ID | / |
Family ID | 40137195 |
Filed Date | 2008-12-25 |
United States Patent
Application |
20080319221 |
Kind Code |
A1 |
Junker; Bernd ; et
al. |
December 25, 2008 |
Esters of Pentahydroxyhexylcarbamoyl Alkanoic Acids
Abstract
Provided are compounds of formula A and formula I: A compound of
formula A: ##STR00001## wherein n is an integer from 6 to 17 and a
compound of formula I: ##STR00002##
Inventors: |
Junker; Bernd; (Frankfurt,
DE) ; Manero; Javier; (Frankfurt, DE) |
Correspondence
Address: |
FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER;LLP
901 NEW YORK AVENUE, NW
WASHINGTON
DC
20001-4413
US
|
Family ID: |
40137195 |
Appl. No.: |
11/767298 |
Filed: |
June 22, 2007 |
Current U.S.
Class: |
560/170 |
Current CPC
Class: |
C07B 2200/07 20130101;
C07C 233/18 20130101 |
Class at
Publication: |
560/170 |
International
Class: |
C07C 229/00 20060101
C07C229/00 |
Claims
1. A compound of formula A: ##STR00083## wherein n is an integer
from 6 to 17.
2. A compound of formula I: ##STR00084##
Description
[0001] Provided are certain compounds set forth below, certain
processes for the preparation of esters of
pentahydroxyhexylcarbamoyl alkanoic acids, and certain uses
therefore.
[0002] Benzyl pentahydroxyhexylcarbamoylundecanoate has the formula
I
##STR00003##
and is an intermediate in the preparation of the compound of
formula II
##STR00004##
which in turn is an intermediate in the synthesis of the compound
of formula III
##STR00005##
which is described in U.S. Pat. No. 7,205,290 as having, for
example, cholesterol-lowering properties.
[0003] Provided generally is a process for preparing a compound of
formula A
##STR00006##
wherein n is an integer from 6 to 17 comprising
[0004] a) reacting a compound of formula B
##STR00007##
with a compound of VI
##STR00008##
wherein
[0005] Hal is chosen from Br, Cl, and l, and
[0006] R1 is an alkyl radical which has from 1 to 18 carbon atoms
and in which [0007] at least one --CH.sub.2-- group of the alkyl
radical is optionally replaced by at least one group chosen from
--O--, --CO--, --CH.dbd.CH--, --C.ident.C--, and aryl groups, and
[0008] the alkyl radical is optionally substituted by at least one
halogen chosen from F, Cl, Br, and l,
[0009] to form a compound of formula C
##STR00009##
and
[0010] b) reacting the compound of formula C with glucamine to form
the compound of formula A.
[0011] In an exemplary embodiment is provided a process for
preparing a compound of formula I
##STR00010##
comprising
[0012] a) reacting a compound of formula IV
##STR00011##
with a compound of formula VI
##STR00012##
wherein
[0013] Hal is chosen from Br, Cl, and l, and
[0014] R1 is an alkyl radical which has from 1 to 18 carbon atoms
and in which [0015] at least one --CH.sub.2-- group of the alkyl
radical is optionally replaced by at least one group chosen from
--O--, --CO--, --CH.dbd.CH--, --C.ident.C--, and aryl groups, and
[0016] the alkyl radical is optionally substituted by at least one
halogen chosen from F, Cl, Br, and l,
[0017] to form a compound of formula V
##STR00013##
and
[0018] b) reacting the compound of formula V with D-glucamine to
form the compound of formula I.
[0019] Also provided is a process for preparing a compound of
formula I
##STR00014##
comprising
[0020] a) reacting a compound of formula IV
##STR00015##
with a compound of formula VI
##STR00016##
wherein Hal is chosen from Br, Cl, and l, and [0021] R1 is an alkyl
radical which has from 1 to 18 carbon atoms and in which at least
one --CH.sub.2-- group of the alkyl radical is optionally replaced
by at least one group chosen from --O--, --CO--, --CH.dbd.CH--,
--C.ident.C--, and aryl groups, and [0022] the alkyl radical is
optionally substituted by at least one halogen chosen from F, Cl,
Br, and l,
[0023] to form a compound of formula V
##STR00017##
[0024] b) reacting the compound of formula V with monobenzyl ester
of dodecanedioic acid of formula IV to form a compound of formula
VIII
##STR00018##
[0025] c) reacting the compound of formula VIII with D-glucamine to
form the compound of formula I.
[0026] Also provided is a process of preparing a compound of
formula I
##STR00019##
comprising converting a compound of formula V
##STR00020##
to the compound of formula I.
[0027] Also provided is a process of preparing a compound of
formula I
##STR00021##
comprising converting a compound of formula Va
##STR00022##
to the compound of formula I.
[0028] Also provided is a process for preparing a compound of
formula Va
##STR00023##
comprising reacting a compound of formula IV
##STR00024##
with a compound of formula VIa
##STR00025##
wherein Hal is chosen from Br, Cl, and l to form a compound of
formula Va.
[0029] Also provided is a process for preparing a compound of
formula I
##STR00026##
comprising reacting a compound of formula Va
##STR00027##
with D-glucamine to form the compound of formula I.
[0030] Also provided is a process for preparing a compound of
formula VIII
##STR00028##
comprising
[0031] a) reacting a compound of formula IV
##STR00029##
with a compound of formula VIa
##STR00030##
wherein Hal is chosen from Br, Cl, and l, to form a compound of
formula Va
##STR00031##
and,
[0032] b) reacting the compound of formula Va with a compound of
formula IV to form the compound of formula VIII.
[0033] Also provided is a process for preparing a compound of
formula I
##STR00032##
comprising reacting a compound of formula VIII
##STR00033##
with D-glucamine to form the compound of formula I.
[0034] Also provided is a compound of formula I
##STR00034##
[0035] Also provided is a compound of formula A
##STR00035##
wherein n is an integer from 6 to 17.
[0036] Also provided is a compound of formula V
##STR00036##
[0037] Also provided is a compound of formula Va
##STR00037##
[0038] Also provided is a compound of formula VIII
##STR00038##
[0039] Other aspects and embodiments will be apparent to those
skilled in the art from the following detailed description.
[0040] As used herein, the following words and phrases are
generally intended to have the meanings as set forth below, except
to the extent that the context in which they are used indicates
otherwise.
[0041] As used herein, an alkyl radical is a straight-chain or
branched hydrocarbon chain having from one to eighteen carbon
atoms, e.g. methyl, ethyl, isopropyl, n-butyl, isobutyl,
tert-butyl, hexyl, heptyl, octyl.
[0042] As used herein, an aryl radical is a phenyl, naphthyl, or
biphenyl radical in which at least one CH group is optionally
replaced by O, N, or S. The aryl radicals are optionally
substituted by at least one suitable group, e.g.: F, Cl, Br, l,
CF.sub.3, NO.sub.2, CN, COO(C.sub.1-C.sub.6)alkyl,
CON[(C.sub.1-C.sub.6)alkyl].sub.2, cycloalkyl,
(C.sub.1-C.sub.10)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, O--(C.sub.1-C.sub.6)-alkyl,
O--(C.sub.2-C.sub.6)-alkenyl, O--(C.sub.2-C.sub.6)-alkynyl,
O--CO--(C.sub.1-C.sub.6)-alkyl, O--CO--(C.sub.1-C.sub.6)-aryl,
O--CO--(C.sub.1-C.sub.6)-heterocycle,
SO.sub.2N[(C.sub.1-C.sub.6)-alkyl].sub.2,
S--(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2.
[0043] As described herein, "glucamine" refers to a compound
according to the formula:
##STR00039##
a stereoisomer thereof, or a salt thereof. A specific glucamine is
D-glucamine represented by the formula:
##STR00040##
[0044] As used herein, the term "reacting" is intended to represent
bringing the chemical reactants together under conditions such as
to cause the chemical reaction indicated to take place.
[0045] As use herein, the term "converting" is intended to
represent changing one compound into another, for example
converting a compound of formula I into a compound of formula
II.
[0046] The compounds described herein may be present in crystalline
or amorphous solid forms. Those crystalline forms may include
polymorphs and solvates, such as hydrates.
[0047] Provided is a process for preparing a compound of formula
I
##STR00041##
comprising
[0048] a) reacting a compound of formula IV
##STR00042##
with a compound of formula VI
##STR00043##
wherein
[0049] Hal is chosen from Br, Cl, and l, and
[0050] R1 is an alkyl radical which has from 1 to 18 carbon atoms
and in which [0051] at least one --CH.sub.2-- group of the alkyl
radical is optionally replaced by at least one group chosen from
--O--, --CO--, --CH.dbd.CH--, --C.ident.C--, and aryl groups, and
[0052] the alkyl radical is optionally substituted by at least one
halogen chosen from F, Cl, Br, and l, to form a compound of formula
V
##STR00044##
[0052] and
[0053] b) reacting the compound of formula V with D-glucamine to
form the compound of formula I.
[0054] In some exemplary embodiments, the compound of formula VI is
chosen from alkylcarboxylic halides and alkyl haloformates. In some
exemplary embodiments, the compound of formula VI is isobutyl
chloroformate.
[0055] In some exemplary embodiments, Hal is Cl.
[0056] In some exemplary embodiments, R1 is chosen from methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methyloxy,
ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy,
tert-butyloxy, and benzyloxy. In some exemplary embodiments, R1 is
isobutyloxy.
[0057] In some exemplary embodiments, in step a), the compound of
formula IV is dissolved in a suitable solvent or solvent mixture in
the presence of a suitable base at from -30.degree. C. to
70.degree. C., such as from -10.degree. C. to 40.degree. C.,
further such as from -5.degree. C. to 0.degree. C. A compound of
formula IV may be added over a period of 30-150 minutes, such as
60-120 minutes, to a solution of a compound of formula VI. In some
exemplary embodiments, the solution of a compound of formula VI may
be cooled to from -10.degree. C. to 30.degree. C., such as from -10
to 0.degree. C.
[0058] In some exemplary embodiments, in step a), a solution of a
compound of formula VI in a suitable solvent or solvent mixture
which is cooled to from -10.degree. C. to 30.degree. C., such as
from -10.degree. C. to 0.degree. C., is added to a compound of
formula IV and a suitable base in a suitable solvent or solvent
mixture at from -30.degree. C. to 70.degree. C., such as from
-10.degree. C. to 40.degree. C., further such as from -5.degree. C.
to 0.degree. C., over a period of 30-150 minutes, such as 60-120
minutes.
[0059] In some exemplary embodiments, in step a), the reaction
mixture is stirred at from -10.degree. C. to 40.degree. C., such as
from -10.degree. C. to 0.degree. C., for from 15-150 minutes, such
as 30-120 minutes. The reaction mixture may then either be used
directly in the subsequent reaction or the product formed is
isolated. In some exemplary embodiments, the reaction mixture is
used directly. In some exemplary embodiments, the compound of
formula V is isolated by evaporation of the solvent(s) under
reduced pressure. In some exemplary embodiments, the reaction
mixture is washed with water before the evaporation.
[0060] In some exemplary embodiments, the suitable base used in
step a) is chosen from tertiary amines such as triethylamine,
ethyldimethylamine, ethyldiisopropylamine, tributylamine,
N-ethylmorpholine, tetramethylethylenediamine, guanidine, and alkyl
guanidines. In some exemplary embodiments, the suitable base is
chosen from triethylamine and ethyldiisopropylamine.
[0061] In some exemplary embodiments, the suitable solvent used in
step a) is chosen from aprotic organic solvents such as toluene,
chlorobenzene, dichloromethane, ethyl acetate, butyl acetate,
diisobutyl ether, diisopropyl ether, tetrahydrofuran,
2-methyltetrahydrofuran, dimethylformamide, N-methylpyrrolidone,
and methyl ethyl ketone. In some exemplary embodiments, the
suitable solvent is chosen from ethyl acetate and butyl acetate. In
some exemplary embodiments, a mixture of solvents is used.
[0062] In some exemplary embodiments, in step b), D-glucamine is
added a little at a time over a period of from 5-60 minutes, such
as 15-30 minutes, to a solution of a compound of formula V and a
suitable base in a suitable solvent or solvent mixture at from
-10.degree. C. to 40.degree. C., such as from -5.degree. C. to
0.degree. C.
[0063] In some exemplary embodiments, the suitable base used in
step b) is chosen from tertiary amines such as triethylamine,
ethyldimethylamine, ethyldiisopropylamine, tributylamine,
N-ethylmorpholine, tetramethylethylenediamine, guanidine, and alkyl
guanidines. In some exemplary embodiments, the suitable base is
chosen from triethylamine and ethyidiisopropylamine.
[0064] In some exemplary embodiments, the suitable solvent used in
step b) is chosen from aprotic organic solvents such as toluene,
chlorobenzene, dichloromethane, ethyl acetate, butyl acetate,
diisobutyl ether, diisopropyl ether, tetrahydrofuran,
2-methyltetrahydrofuran, dimethylformamide, N-methylpyrrolidone,
and methyl ethyl ketone. In some embodiments, the suitable solvent
is chosen from ethyl acetate and butyl acetate. In some exemplary
embodiments, a mixture of solvents is used.
[0065] In some exemplary embodiments, the reaction mixture of step
b) is stirred for a further period of from 5-120 minutes, such as
30-60 minutes, at from -10.degree. C. to 40.degree. C., such as
from -5.degree. C. to 0.degree. C., subsequently for a further 5-20
hours, such as 12 hours, at from 0 to 30.degree. C., such as from
15.degree. C. to 20.degree. C., and subsequently washed with water
at 10.degree. C. to 80.degree. C., such as 50.degree. C. to
70.degree. C., and further such as 60.degree. C. The mixture is
subsequently cooled to a temperature sufficient to induce
crystallization of the compound of formula I, such as 20.degree. C.
In some exemplary embodiments, the compound of formula I is
purified by recrystallization.
[0066] Also provided is a process for preparing a compound of
formula I
##STR00045##
comprising
[0067] a) reacting a compound of formula IV
##STR00046##
with a compound of formula VI
##STR00047##
wherein Hal is chosen from Br, Cl, and l, and
[0068] R1 is an alkyl radical which has from 1 to 18 carbon atoms
and in which [0069] at least one --CH.sub.2-- group of the alkyl
radical is optionally replaced by at least one group chosen from
--O--, --CO--, --CH.dbd.CH--, --C.ident.C--, and aryl groups, and
[0070] the alkyl radical is optionally substituted by at least one
halogen chosen from F, Cl, Br, and l, to form a compound of formula
V
##STR00048##
[0071] b) reacting the compound of formula V with the compound of
formula IV to form a compound of formula VIII
##STR00049##
[0072] c) reacting the compound of formula VIII with D-glucamine to
form the compound of formula I.
[0073] In some exemplary embodiments, the compound of formula VI is
chosen from alkylcarboxylic halides and alkyl haloformates. In some
exemplary embodiments, the compound of formula VI is isobutyl
chloroformate.
[0074] In some exemplary embodiments, Hal is Cl.
[0075] In some exemplary embodiments, R1 is chosen from methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methyloxy,
ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy,
tert-butyloxy, and benzyloxy. In some exemplary embodiments, R1 is
isobutyloxy.
[0076] In some exemplary embodiments, in step a), the compound of
formula IV is dissolved in a suitable solvent or solvent mixture in
the presence of at least one base at from -30.degree. C. to
70.degree. C., such as from -10.degree. C. to 40.degree. C.,
further such as from -5.degree. C. to 0.degree. C., and added over
a period of 30-150 minutes, such as 60-120 minutes, to a solution
of compound of formula VI which is cooled to from -10.degree. C. to
30.degree. C., such as from -10 to 0.degree. C.
[0077] In some exemplary embodiments, in step a), a solution of a
compound of formula VI in a suitable solvent or solvent mixture is
cooled to from -10.degree. C. to 30.degree. C., such as from
-10.degree. C. to 0.degree. C., in a reaction vessel and then is
added to a compound of formula IV and a suitable base in a suitable
solvent or solvent mixture at from -30.degree. C. to 70.degree. C.,
such as from -10.degree. C. to 40.degree. C., further such as from
-5.degree. C. to 0.degree. C., over a period of 30-150 minutes,
such as 60-120 minutes.
[0078] In some exemplary embodiments, the reaction mixture in step
a) is stirred at from -10.degree. C. to 40.degree. C., such as from
-10.degree. C. to 0.degree. C., for from 15-150 minutes, such as
30-120 minutes. The reaction mixture can then either be used
directly in the subsequent reaction or the product formed is
isolated. In some exemplary embodiments, the reaction mixture is
used directly. In some exemplary embodiments, the compound of
formula V is isolated by evaporation under reduced pressure. In
some exemplary embodiments, the reaction mixture is washed with
water before the evaporation.
[0079] In some exemplary embodiments, the suitable base used in
step a) is chosen from tertiary amines such as triethylamine,
ethyldimethylamine, ethyldiisopropylamine, tributylamine,
N-ethylmorpholine, tetramethylethylenediamine, guanidine, and alkyl
guanidines. In some exemplary embodiments, the suitable base is
chosen from triethylamine and ethyidiisopropylamine.
[0080] In some exemplary embodiments, the suitable solvent used in
step a) is chosen from customary organic solvents such as toluene,
chlorobenzene, dichloromethane, ethyl acetate, butyl acetate,
diisobutyl ether, diisopropyl ether, tetrahydrofuran,
2-methyltetrahydrofuran, dimethylformamide, N-methylpyrrolidone, or
methyl ethyl ketone. In some exemplary embodiments, the suitable
solvent is ethyl acetate or butyl acetate. In some exemplary
embodiments, a mixture of solvents is used.
[0081] In some exemplary embodiments, in step b), the compound of
formula IV is added a little at a time to a solution of product V
and optionally a suitable base in a suitable solvent or solvent
mixture at from -10.degree. C. to 40.degree. C., such as from
0.degree. C. to 25.degree. C., over a period of 5-60 minutes, such
as 15-30 minutes.
[0082] In some exemplary embodiments, the suitable base used in
step b) is chosen from tertiary amines such as triethylamine,
ethyldimethylamine, ethyldiisopropylamine, tributylamine,
N-ethylmorpholine, tetramethylethylenediamine, guanidine, and alkyl
guanidines. In some exemplary embodiments, the suitable base is
chosen from triethylamine and ethyidiisopropylamine.
[0083] In some exemplary embodiments, the suitable solvent used in
step b) is chosen from aprotic organic solvents such as toluene,
chlorobenzene, dichloromethane, ethyl acetate, butyl acetate,
diisobutyl ether, diisopropyl ether, tetrahydrofuran,
2-methyltetrahydrofuran, dimethylformamide, N-methylpyrrolidone,
and methyl ethyl ketone. In some exemplary embodiments, the
suitable solvent is chosen from ethyl acetate and butyl acetate. In
some exemplary embodiments, a mixture of solvents is used.
[0084] In some exemplary embodiments, the reaction mixture of step
b) is stirred at from -10.degree. C. to 40.degree. C., such as from
0.degree. C. to 25.degree. C., for another 5-240 minutes, such as
60-150 minutes. In some exemplary embodiments, the precipitate
formed is filtered and dried, giving a compound of formula
VIII.
[0085] In some exemplary embodiments, in step c), D-glucamine is
added a little at a time to a solution of product VIII and
optionally a suitable base in a suitable solvent or solvent mixture
at from -10.degree. C. to 40.degree. C., such as from -5.degree. C.
to 5.degree. C., over a period of from 5-60 minutes, such as 15-30
minutes.
[0086] In some exemplary embodiments, the suitable base used in
step c) is chosen from tertiary amines such as triethylamine,
ethyldimethylamine, ethyldiisopropylamine, tributylamine,
N-ethylmorpholine, tetramethylethylenediamine, guanidine, and alkyl
guanidines. In some exemplary embodiments, the suitable base is
chosen from triethylamine and ethyidiisopropylamine.
[0087] In some exemplary embodiments, the suitable solvent used in
step c) is chosen from aprotic organic solvents such as toluene,
chlorobenzene, dichloromethane, ethyl acetate, butyl acetate,
diisobutyl ether, diisopropyl ether, tetrahydrofuran,
2-methyltetrahydrofuran, dimethylformamide, N-methylpyrrolidone,
and methyl ethyl ketone. In some exemplary embodiments, the
suitable solvent is chosen from ethyl acetate and butyl acetate. In
some exemplary embodiments, a mixture of solvents is used.
[0088] In some exemplary embodiments, the reaction mixture in step
c) is stirred at from -10.degree. C. to 40.degree. C., such as from
10.degree. C. to 25.degree. C., for another 1-20 hours, such as
10-18 hours, and subsequently washed with water at 10.degree. C. to
80.degree. C., such as 50.degree. C. to 70.degree. C. The mixture
is subsequently cooled to a temperature sufficient to induce
crystallization of the compound of formula I, such as 20.degree. C.
In some exemplary embodiments, the compound of formula I is
purified by recrystallization.
[0089] In some exemplary embodiments, the compound of formula I,
which may be obtained as described herein, is converted into a
compound of formula II
##STR00050##
[0090] In some exemplary embodiments, converting the compound of
formula I into a compound of formula II comprises reacting the
compound of formula I under alkaline conditions, using, for
example, aqueous sodium hydroxide or aqueous potassium
hydroxide.
[0091] In some embodiments, converting the compound of formula I
into a compound of formula II comprises reacting the compound of
formula I under enzymatic conditions to form formula II.
Non-limiting examples of suitable enzymes include lipases, for
example Candida.
[0092] In some exemplary embodiments, converting the compound of
formula I into a compound of formula II comprises hydrogenating the
compound of formula I under suitable conditions.
[0093] In some exemplary embodiments, hydrogenating the compound of
formula I comprises reacting the compound of formula I with a
hydrogen source in the presence of a hydrogenation catalyst. In
some exemplary embodiments, a hydrogenation catalyst, such as
palladium on carbon (Pd/C), Raney-Nickel, platinum, platinum oxide,
or zinc oxide is used. In some exemplary embodiments, the hydrogen
source is chosen from hydrogen gas and ammonium formate.
[0094] Also provided is a process for preparing a compound of
formula III
##STR00051##
comprising
[0095] a) reacting a compound of formula IV
##STR00052##
with a compound of formula VI
##STR00053##
wherein Hal is chosen from Br, Cl, and l, and
[0096] R1 is an alkyl radical which has from 1 to 18 carbon atoms
and in which [0097] at least one --CH.sub.2-- group of the alkyl
radical is optionally replaced by at least one group chosen from
--O--, --CO--, --CH.dbd.CH--, --C.ident.C--, and aryl groups, and
[0098] the alkyl radical is optionally substituted by at least one
halogen chosen from F, Cl, Br, and l, to form a compound of formula
V
##STR00054##
[0099] b) reacting the compound of formula V with D-glucamine to
form the compound of formula I
##STR00055##
[0100] c) converting the compound of formula I into a compound of
formula II
##STR00056##
[0101] d) reacting the compound of formula II with a compound of
formula VII
##STR00057##
to form a compound of formula III.
[0102] In some exemplary embodiments, the reaction conditions for
the preparation of a compound of formula V, a compound of formula
I, and a compound of formula II are as described herein.
[0103] In some exemplary embodiments, reacting the compound of
formula II with a compound of formula VII comprises reacting the
compound of formula II with suitable peptide coupling reagents in a
suitable solvent or solvent mixture, and then further reacting with
a compound of formula VII. Suitable peptide coupling reagents and
solvents or solvent mixtures are described, inter alia, in, for
example, A. Speicher et al. In Journal fur Praktische
Chemie/Chemiker-Zeitung (1998), 340, 581-583; Y. S. Klausner and M.
Bodansky, Synthesis, (1972), 453 et seq.; K. Ishihara et al., J.
Org. Chem., 61, 4196 (1996); M. Kunishima et al., Tetrahedron
55,13159-13170 (1999), or R. C. Larock: Comprehensive Organic
Transformations; VCH, New York, 1989, page 981 et. seq.
[0104] The reaction of the compound of formula II with the amine of
formula VII is described, for example, in WO 02/50027 or U.S. Pat.
No. 7,205,290.
[0105] Also provided herein is a process for preparing a compound
of formula III
##STR00058##
comprising
[0106] a) reacting a compound of formula IV
##STR00059##
with a compound of formula VI
##STR00060##
wherein Hal is chosen from Br, Cl, and l, and
[0107] R1 is an alkyl radical which has from 1 to 18 carbon atoms
and in which [0108] at least one --CH.sub.2-- group of the alkyl
radical is optionally replaced by at least one group chosen from
--O--, --CO--, --CH.dbd.CH--, --C.ident.C--, and aryl groups, and
[0109] the alkyl radical is optionally substituted by at least one
halogen chosen from F, Cl, Br, and l, to form a compound of formula
V
##STR00061##
[0110] b) reacting the compound of formula V with monobenzyl ester
of dodecanedioic acid of formula IV to form a compound of formula
VIII
##STR00062##
[0111] c) reacting the compound of formula VIII with D-glucamine to
form the compound of formula I
##STR00063##
[0112] d) converting the compound of formula I into a compound of
formula II
##STR00064##
[0113] e) reacting the compound of formula II with a compound of
formula VII
##STR00065##
to form a compound of formula III.
[0114] In some exemplary embodiments, the reaction conditions for
the preparation of a compound of formula V, a compound of formula
VIII, a compound of formula I, a compound of formula II, and a
compound of formula III are as described herein.
[0115] Also provided is a process of preparing a compound of
formula I
##STR00066##
comprising converting a compound of formula V
##STR00067##
to the compound of formula I.
[0116] In some exemplary embodiments, the reaction conditions for
the preparation of a compound of formula I from a compound of
formula V are as described herein.
[0117] Also provided is a process of preparing a compound of
formula I
##STR00068##
comprising converting a compound of formula Va
##STR00069##
to the compound of formula I.
[0118] In some exemplary embodiments, the reaction conditions for
the preparation of a compound of formula I from a compound of
formula Va are as described herein.
[0119] Also provided is a process for preparing a compound of
formula Va
##STR00070##
comprising reacting a compound of formula IV
##STR00071##
with a compound of formula Via
##STR00072##
wherein Hal is chosen from Br, Cl, and l to form a compound of
formula Va.
[0120] In some exemplary embodiments, the processes for the
preparation of a compound of formula Va from a compound of formula
IV are as described herein.
[0121] Also provided is a process for preparing a compound of
formula I
##STR00073##
comprising reacting a compound of formula Va
##STR00074##
with D-glucamine to form the compound of formula I.
[0122] In some exemplary embodiments, the reaction conditions for
the preparation of a compound of formula I from a compound of
formula Va are as described herein.
[0123] Also provided is a process for preparing a compound of
formula VIII
##STR00075##
comprising
[0124] a) reacting a compound of formula IV
##STR00076##
with a compound of formula Via
##STR00077##
wherein Hal is chosen from Br, Cl, and l, to form a compound of
formula Va
##STR00078##
and,
[0125] b) reacting the compound of formula Va with the compound of
formula IV to form the compound of formula VII.
[0126] In some exemplary embodiments, the reaction conditions for
the preparation of a compound of formula Va from a compound of
formula IV and for the preparation of a compound of formula VIII
from a compound of formula Va are as described herein.
[0127] Also provided is a process for preparing a compound of
formula I
##STR00079##
comprising reacting a compound of formula VIII
##STR00080##
with D-glucamine to form the compound of formula I.
[0128] In some exemplary embodiments, the reaction conditions for
the preparation of a compound of formula I from a compound of
formula VIII are as described herein.
[0129] Also provided is a compound of formula Va.
##STR00081##
[0130] Also provided is a compound of formula VIII.
##STR00082##
EXAMPLES
[0131] The following examples serve to more fully describe the
manner of using the invention. These examples are presented for
illustrative purposes and should not serve to limit the true scope
of the invention.
1. Preparation of Benzyl 12-isobutoxycarbonyloxy-12-oxododecanoate
(Va)
[0132] 1.5 g (4.7 mmol) of the monobenzyl ester of dodecanedioic
acid together with 15 ml of ethyl acetate are placed in a reaction
vessel and admixed with 0.8 ml (5.6 mmol) of triethylamine. The
mixture is cooled to -5.degree. C. and a solution of 0.7 ml (5.0
mmol) of isobutyl chloroformate is added. After 60 minutes, the
precipitate is filtered off with suction under protective gas,
washed twice with ethyl acetate, and the filtrate is evaporated to
dryness to obtain benzyl 12-isobutoxycarbonyloxy-12-oxododecanoate
(Va).
2. Preparation of Benzyl
11-(2S,3R,4R,5R-2,3,4,5,6-pentahydroxyhexylcarbamoyl)undecanoate I
from Benzyl 12-isobutoxycarbonyloxy-12-oxododecanoate (Va)
[0133] Benzyl 12-isobutoxycarbonyloxy-12-oxododecanoate is
dissolved in 15 ml of ethyl acetate and admixed at 0.degree. C.
with 0.9 g (5.2 mmol) of
2R,3R,4R,5S-6-aminohexane-1,2,3,4,5-pentanol (D-glucamine). The
mixture is stirred at 0.degree. C. for one hour, warmed to
20.degree. C. and allowed to stand overnight. The white suspension
formed is shaken three times at 65.degree. C. with 20 ml of water
at the same temperature. The organic phase is subsequently
evaporated to dryness to obtain benzyl
11-(2S,3R,4R,5R-2,3,4,5,6-pentahydroxyhexylcarbamoyl)undecanoate
(I).
3. Preparation of the Anhydride of Dodecanedicarboxylic Monobenzyl
Ester (VIII) from benzyl 12-isobutoxycarbonyloxy-12-oxododecanoate
(Va)
[0134] Benzyl 12-isobutoxycarbonyloxy-12-oxododecanoate is admixed
with 20 ml of ethyl acetate and admixed at 20.degree. C. with 1.9 g
(4.2 mmol) of the monobenzyl ester of dodecanedioic acid. The
mixture is stirred for 2.5 hours, and the precipitate formed is
filtered off and dried to obtain anhydride of dodecanedicarboxylic
monobenzyl ester (VIII).
4. Preparation of Benzyl
11-(2S,3R,4R,5R-2,3,4,5,6-pentahydroxyhexylcarbamoyl)undecanoate
(I) from the Anhydride of Dodecanedioic Acid Monobenzyl Ester
(VIII)
[0135] 0.50 g (0.80 mmol) of the anhydride of dodecanedioic acid
monobenzyl ester (VIII) together with 10 ml of ethyl acetate are
placed in a reaction vessel and admixed with 0.14 ml (0.96 mmol) of
triethylamine and the mixture is cooled to 0.degree. C. A
suspension of 0.16 g (0.88 mmol) of
2R,3R,4R,5S-6-aminohexane-1,2,3,4,5-pentanol (D-glucamine) in 6 ml
of ethyl acetate is added and the mixture is stirred at room
temperature for 18 hours. The mixture is heated to 70.degree. C.
and shaken three times with 20 ml of water at the same temperature.
The organic phase is allowed to cool to room temperature, and the
precipitate formed is filtered off and dried to obtain benzyl
11-(2S,3R,4R,5R-2,3,4,5,6-pentahydroxyhexylcarbamoyl)undecanoate
(I).
5. Preparation of Benzyl
11-(2S,3R,4R,5R-2,3,4,5,6-pentahydroxyhexylcarbamoyl)undecanoate
(I) from the Monobenzyl Ester of Dodecanedioic Acid (IVa) without
Isolation of the Intermediates
[0136] 17 kg of isobutyl chloroformate together with 150 L of ethyl
acetate are placed in a reaction vessel and cooled to -5.degree. C.
A solution of 37.3 kg of the monobenzyl ester of dodecanedioic acid
and 14.2 kg of triethylamine in 100 L of ethyl acetate which has
been cooled to -5.degree. C. is added to the above solution over a
period of 2 hours. After the addition is complete to form a
compound of formula Va, the mixture is stirred at -5.degree. C. for
another 2 hours. 23.2 kg of D-glucamine are then added a little at
a time at -5.degree. C. over a period 30 minutes and, after the
addition is complete, the mixture is stirred at -5.degree. C. for
another 1 hour and subsequently at 20.degree. C. for 12 hours. The
reaction mixture is poured into 200 L of ethyl acetate and 300 L of
water, the mixture is heated to 65.degree. C., and the phases are
separated. The organic phase is washed at 60.degree. C. with a
further 80 L of water and the organic phase is subsequently cooled
to 20.degree. C. over a period of 60 minutes. After stirring for
another 1 hour, the precipitated solid is filtered off and dried to
obtain benzyl
11-(2S,3R,4R,5R-2,3,4,5,6-pentahydroxyhexylcarbamoyl)undecanoate
(I).
[0137] Subsequent experiments produced a compound of formula (II)
from a compound of formula (I) under various conditions, including
basic reaction conditions, enzymatic reaction conditions, and
hydrogenation reaction conditions, utilizing Pd/C and hydrogen, and
experiments were also performed to further produce from a compound
of formula (II) a compound of formula (III), which has use for
treating hyperlipidemia and arteriosclerosis and
hypercholesterolemia as described in U.S. Pat. No. 7,205,290.
[0138] While the present invention has been described with
reference to the specific embodiments thereof, it should be
understood by those skilled in the art that various changes may be
made and equivalents may be substituted without departing from the
true spirit and scope of the invention. In addition, many
modifications may be made to adapt a particular situation,
material, composition of matter, process, process step, or steps,
and all such modifications are intended to be within the scope of
the claims appended hereto.
* * * * *