CA2691065A1 - Process for preparing benzyl pentahydroxyhexylcarbamoylundecanoate - Google Patents
Process for preparing benzyl pentahydroxyhexylcarbamoylundecanoate Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C68/00—Preparation of esters of carbonic or haloformic acids
- C07C68/02—Preparation of esters of carbonic or haloformic acids from phosgene or haloformates
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/34—Esters of acyclic saturated polycarboxylic acids having an esterified carboxyl group bound to an acyclic carbon atom
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/96—Esters of carbonic or haloformic acids
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
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Abstract
The invention relates to an improved process for preparing benzyl pentahydroxyhexylcarbamoylundecanoate.
Benzyl pentahydroxyhexylcarbamoyl-undecanoate has the formula (I).
Benzyl pentahydroxyhexylcarbamoyl-undecanoate has the formula (I).
Description
Process for preparing benzyl pentahydroxyhexylcarbamoylundecanoate The invention relates to an improved process for the preparation of benzyl pentahydroxyhexylcarbamoylundecanoate.
Benzyl pentahydroxyhexylcarbamoylundecanoate has the formula I
O OH OH
~ , O N ~ OH
I
This compound is an intermediate for the preparation of the compound of formula II
HO N - OH
II
which, in turn, is an intermediate in the synthesis of the compound of formula III
OH F N I
0 ~ N = OH
III
which is described in US 7,205,290. The compound of formula III can be used, for example, as an anticholesteremic.
US 7,067,689 describes a process for the preparation of benzyl pentahydroxyhexylcarbamoyl-undecanoate of formula I, where, in a first step, monobenzyl dodecanedioate is prepared from dodecanedioic acid according to a process described in the literature (Prata, et al., J. Am.
Chem. Soc. 126, 12196-12197 (2004)) and this ester is then reacted in a further step by activation with 1-hydroxybenzotriazole (HOBT) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC) with D-glucamine to give the compound of formula I.
The process has the disadvantage that a) the monobenzyl dodecanedioate has to be purified with the help of column chromatography.
b) 1-hydroxybenzotriazole (HOBt) is used as reagent and HOBt is known to be a potentially explosive substance.
c) N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC) is used which is known to be sensitizing and a trigger of allergies.
d) the costs of the individual steps and the availability of the reagents would significantly hinder economic production on an industrial scale.
The object of the present invention was then to provide an improved process for the preparation of the compound of formula I which does not have the aforementioned disadvantages. In particular, the improved process should also permit production of the compound of formula I in an industrial-scale production process. For this, the process should be able to be carried out under the most economical conditions possible, i.e.
cost-effectively.
The object is achieved by preparation process A) 0 O OH + HaI~R1 O tv vi O O Or HYOH
'('~.OH
O OxR1 + HZN OH OH
O
v ~ 0 OHOH
N-yytiOH
Benzyl pentahydroxyhexylcarbamoylundecanoate has the formula I
O OH OH
~ , O N ~ OH
I
This compound is an intermediate for the preparation of the compound of formula II
HO N - OH
II
which, in turn, is an intermediate in the synthesis of the compound of formula III
OH F N I
0 ~ N = OH
III
which is described in US 7,205,290. The compound of formula III can be used, for example, as an anticholesteremic.
US 7,067,689 describes a process for the preparation of benzyl pentahydroxyhexylcarbamoyl-undecanoate of formula I, where, in a first step, monobenzyl dodecanedioate is prepared from dodecanedioic acid according to a process described in the literature (Prata, et al., J. Am.
Chem. Soc. 126, 12196-12197 (2004)) and this ester is then reacted in a further step by activation with 1-hydroxybenzotriazole (HOBT) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC) with D-glucamine to give the compound of formula I.
The process has the disadvantage that a) the monobenzyl dodecanedioate has to be purified with the help of column chromatography.
b) 1-hydroxybenzotriazole (HOBt) is used as reagent and HOBt is known to be a potentially explosive substance.
c) N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC) is used which is known to be sensitizing and a trigger of allergies.
d) the costs of the individual steps and the availability of the reagents would significantly hinder economic production on an industrial scale.
The object of the present invention was then to provide an improved process for the preparation of the compound of formula I which does not have the aforementioned disadvantages. In particular, the improved process should also permit production of the compound of formula I in an industrial-scale production process. For this, the process should be able to be carried out under the most economical conditions possible, i.e.
cost-effectively.
The object is achieved by preparation process A) 0 O OH + HaI~R1 O tv vi O O Or HYOH
'('~.OH
O OxR1 + HZN OH OH
O
v ~ 0 OHOH
N-yytiOH
in which a) the monobenzyl dodecanedioate of formula IV is reacted with the compound of formula VI, in which R1 is an alkyl radical having 1 to 18 carbon atoms, in which one or more CH2 groups of the alkyl radical may be replaced by -0-, -CO-, -CH=CH-, -C=C- or aryl and the alkyl radical may be substituted one or more times by F, Cl, Br or I, to give the compound of formula V and then further b) the compound of formula V is reacted with D-glucamine to give the compound of formula I.
Preferred compounds of formula VI are alkyl acid halides and alkyl esters of haloformic acid, particularly preferably isobutyl chloroformate.
An alkyl radical is understood as meaning a straight-chain or branched hydrocarbon chain having one to eighteen carbon, such as, for example, methyl, ethyl, isopropyl, n-butyl, isobutyl, tert-butyl, hexyl, heptyl, octyl.
Hal is understood as meaning a halogen radical which can have the meaning Br, Cl or I.
An aryl radical is understood as meaning a phenyl, naphthyl or biphenyl radical in which one or more CH groups may be replaced by 0, N or S.
The aryl radicals may be substituted one or more times by suitable groups, such as, for example: F, Cl, Br, I, CF3, NOz, CN, COO(C1-C6)alkyl, CON[(C1-C6)alkyl]2, cycloalkyl, (C1-Clo)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, O-(C1-C6)-alkyl, O-(C2-C6)-alkenyl, O-(C2-C6)-alkynyl, O-CO-(C1-C6)-alkyl, O-CO-(C1-C6)-aryl, O-CO-(C1-C6)-heterocycle, SO2N[(C1-C6)-alkyl]2, S-(Ci-C6)-alkyl, N((Ci-C6)-alkyl)z.
In step a), monobenzyl dodecanedioate is dissolved in a suitable solvent in the presence of a suitable base at -30 C to + 70 C, preferably at -10 C to +40 C, particularly preferably at -5 C
to 0 C and over the course of 30 - 150 minutes, preferably 60-120 minutes, metered into a solution of compound VI, particularly preferably isobutyl chloroformate, chilled to -10 C to 30 C, preferably -10 C to 0 C.
Alternatively, a solution of compound VI, preferably butyl chloroformate, in a suitable solvent, chilled to -10 C to 30 C, preferably -10 C to 0 C, can be initially introduced and then monobenzyl dodecanedioate and a suitable base in a suitable solvent can be metered in at -30 C to + 70 C, preferably at -10 C to +40 C, particularly preferably at -5 C
to 0 C over the course of 30 - 150 minutes, preferably 60-120 minutes.
The reaction mixture is stirred at -10 C to 40 C, preferably at -10 C to 0 C, for 15 to 150 minutes, preferably 30 - 120 minutes. The reaction mixture can now either be used directly in the subsequent reaction, or the formed product is isolated. Preferably, the reaction mixture is used directly. To isolate the compound of formula V, the solvent is evaporated off in vacuo.
Optionally, the reaction mixture is washed with water before the solvent is evaporated off.
Suitable bases are, for example, tertiary amines, such as, for example, triethylamine, ethyldimethylamine, ethyldiisopropylamine, tributylamine, N-ethylmorpholine, tetramethylethylenediamine, guanidine or alkylguanidines, particularly preferably triethylamine or ethyldiisopropylamine.
Suitable solvents are, for example, customary aprotic organic solvents, such as, for example, toluene, chlorobenzene, dichloromethane, ethyl acetate, butyl acetate, diisobutyl ether, diisopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dimethylformamide, N-methylpyrrolidone or methyl ethyl ketone, particularly preferably ethyl acetate or butyl acetate.
In step b), over the course of 5 to 60 minutes, preferably 15-30 minutes, D-glucamine is added in portions to a solution of product V (prepared as described previously;
either reaction solution used directly or the isolated product dissolved in a suitable solvent) and optionally to a suitable base in a suitable solvent at -10 C to 40 C, preferably -5 C to 0 C.
Suitable bases are, for example, tertiary amines, such as, for example, triethylamine, ethyldimethylamine, ethyldiisopropylamine, tributylamine, N-ethylmorpholine (NEM), tetramethylethylenediamine, guanidine or alkylguanidines, particularly preferably triethylamine or ethyldiisopropylamine (Hiinig base).
Suitable solvents are, for example, customary aprotic organic solvents, such as, for example, toluene, chlorobenzene, dichloromethane, ethyl acetate, butyl acetate, diisobutyl ether, diisopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dimethylformamide, N-methylpyrrolidone or methyl ethyl ketone, particularly preferably ethyl acetate or butyl acetate.
The reaction mixture is afterstirredfor 5 to 120 minutes, preferably 30 to 60 minutes, at -10 C
Preferred compounds of formula VI are alkyl acid halides and alkyl esters of haloformic acid, particularly preferably isobutyl chloroformate.
An alkyl radical is understood as meaning a straight-chain or branched hydrocarbon chain having one to eighteen carbon, such as, for example, methyl, ethyl, isopropyl, n-butyl, isobutyl, tert-butyl, hexyl, heptyl, octyl.
Hal is understood as meaning a halogen radical which can have the meaning Br, Cl or I.
An aryl radical is understood as meaning a phenyl, naphthyl or biphenyl radical in which one or more CH groups may be replaced by 0, N or S.
The aryl radicals may be substituted one or more times by suitable groups, such as, for example: F, Cl, Br, I, CF3, NOz, CN, COO(C1-C6)alkyl, CON[(C1-C6)alkyl]2, cycloalkyl, (C1-Clo)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, O-(C1-C6)-alkyl, O-(C2-C6)-alkenyl, O-(C2-C6)-alkynyl, O-CO-(C1-C6)-alkyl, O-CO-(C1-C6)-aryl, O-CO-(C1-C6)-heterocycle, SO2N[(C1-C6)-alkyl]2, S-(Ci-C6)-alkyl, N((Ci-C6)-alkyl)z.
In step a), monobenzyl dodecanedioate is dissolved in a suitable solvent in the presence of a suitable base at -30 C to + 70 C, preferably at -10 C to +40 C, particularly preferably at -5 C
to 0 C and over the course of 30 - 150 minutes, preferably 60-120 minutes, metered into a solution of compound VI, particularly preferably isobutyl chloroformate, chilled to -10 C to 30 C, preferably -10 C to 0 C.
Alternatively, a solution of compound VI, preferably butyl chloroformate, in a suitable solvent, chilled to -10 C to 30 C, preferably -10 C to 0 C, can be initially introduced and then monobenzyl dodecanedioate and a suitable base in a suitable solvent can be metered in at -30 C to + 70 C, preferably at -10 C to +40 C, particularly preferably at -5 C
to 0 C over the course of 30 - 150 minutes, preferably 60-120 minutes.
The reaction mixture is stirred at -10 C to 40 C, preferably at -10 C to 0 C, for 15 to 150 minutes, preferably 30 - 120 minutes. The reaction mixture can now either be used directly in the subsequent reaction, or the formed product is isolated. Preferably, the reaction mixture is used directly. To isolate the compound of formula V, the solvent is evaporated off in vacuo.
Optionally, the reaction mixture is washed with water before the solvent is evaporated off.
Suitable bases are, for example, tertiary amines, such as, for example, triethylamine, ethyldimethylamine, ethyldiisopropylamine, tributylamine, N-ethylmorpholine, tetramethylethylenediamine, guanidine or alkylguanidines, particularly preferably triethylamine or ethyldiisopropylamine.
Suitable solvents are, for example, customary aprotic organic solvents, such as, for example, toluene, chlorobenzene, dichloromethane, ethyl acetate, butyl acetate, diisobutyl ether, diisopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dimethylformamide, N-methylpyrrolidone or methyl ethyl ketone, particularly preferably ethyl acetate or butyl acetate.
In step b), over the course of 5 to 60 minutes, preferably 15-30 minutes, D-glucamine is added in portions to a solution of product V (prepared as described previously;
either reaction solution used directly or the isolated product dissolved in a suitable solvent) and optionally to a suitable base in a suitable solvent at -10 C to 40 C, preferably -5 C to 0 C.
Suitable bases are, for example, tertiary amines, such as, for example, triethylamine, ethyldimethylamine, ethyldiisopropylamine, tributylamine, N-ethylmorpholine (NEM), tetramethylethylenediamine, guanidine or alkylguanidines, particularly preferably triethylamine or ethyldiisopropylamine (Hiinig base).
Suitable solvents are, for example, customary aprotic organic solvents, such as, for example, toluene, chlorobenzene, dichloromethane, ethyl acetate, butyl acetate, diisobutyl ether, diisopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dimethylformamide, N-methylpyrrolidone or methyl ethyl ketone, particularly preferably ethyl acetate or butyl acetate.
The reaction mixture is afterstirredfor 5 to 120 minutes, preferably 30 to 60 minutes, at -10 C
5 to 40 C, preferably at -5 C to 0 C, then for a further 5 to 20 hours, preferably 12 hours, at 0 to 30 C, preferably 15 C to 20 C, and then extracted by washing with water at 10 C - 80 C, preferably at 50 C - 70 C. During subsequent cooling to 20 C, the product of formula I
crystallizes.
A further aspect of this invention is an alternative preparation process B) O
/ O
OH + HaI"Ul, R1 O IV
vi O O O
~ O OxR1 + O OH
0 v 0 n, ~ O O OH OH
+ H2N_,_~OH
~
OH
in which a) the monobenzyl dodecanedioate of formula IV is reacted with the compound of formula VI, in which Rl is an alkyl radical having 1 to 18 carbon atoms, in which one or more CH2 groups of the alkyl radical may be replaced by -0-, -CO-, -CH=CH-, -C=C- or aryl, and the alkyl radical may be substituted one or more times by F, Cl, Br or I, to give the compound of formula V and then further b) the compound of formula V is reacted with further monobenzyl dodecanedioate of formula IV to give the compound of formula VIII, and then c) the compound of formula VIII is reacted with D-glucamine to give the compound of formula I.
In step a), monobenzyl dodecanedioate is dissolved in a suitable solvent in the presence of a suitable base at -30 C to + 70 C, preferably at -10 C to +40 C, particularly preferably at -5 C
to 0 C and, over the course of 30 - 150 minutes, preferably 60-120 minutes, is metered into a solution of compound VI, particularly preferably isobutyl chloroformate, chilled to -10 C to 30 C, preferably -10 C to 0 C.
Alternatively, a solution of compound VI, preferably butyl chloroformate, in a suitable solvent chilled to -10 C to 30 C, preferably -10 C to 0 C, can also be initially introduced and then monobenzyl dodecanedioate and a suitable base in a suitable solvent can be metered in at -30 C to + 70 C, preferably at -10 C to +40 C, particularly preferably at -5 C
to 0 C over the course of 30 - 150 minutes, preferably 60-120 minutes.
The reaction mixture is stirred at -10 C to 40 C, preferably at -10 C to 0 C
for 15 to 150 minutes, preferably 30 - 120 minutes. The reaction mixture can then either be used directly in the subsequent reaction, or the formed product is isolated. Preferably, the reaction mixture is used directly. To isolate the compound of formula V, the solvent is evaporated off in vacuo.
Optionally, the reaction mixture is washed with water before the solvent is evaporated off.
Suitable bases are, for example, tertiary amines, such as, for example, triethylamine, ethyldimethylamine, ethyldiisopropylamine, tributylamine, N-ethylmorpholine, tetramethylethylenediamine, guanidine or alkylguanidines, particularly preferably triethylamine or ethyldiisopropylamine.
Suitable solvents are, for example, customary aprotic organic solvents, such as, for example, toluene, chlorobenzene, dichloromethane, ethyl acetate, butyl acetate, diisobutyl ether, diisopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dimethylformamide, N-methylpyrrolidone or methyl ethyl ketone, particularly preferably ethyl acetate or butyl acetate.
In step b), over the course of 5 to 60 minutes, preferably 15-30 minutes, monobenzyl dodecanedioate of formula IV is metered in portions into a solution of product V(prepared as described previously; either reaction solution used directly or the isolated product dissolved in a suitable solvent) and optionally a suitable base in a suitable solvent at -10 C to 40 C, preferably 0 C to 25 C.
Suitable bases are, for example, tertiary amines, such as, for example, triethylamine, ethyldimethylamine, ethyldiisopropylamine, tributylamine, N-ethylmorpholine, tetramethylethylenediamine, guanidine or alkylguanidines, particularly preferably triethylamine or ethyldiisopropylamine.
Suitable solvents are, for example, customary aprotic organic solvents, such as, for example, toluene, chlorobenzene, dichloromethane, ethyl acetate, butyl acetate, diisobutyl ether, diisopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dimethylformamide, N-methylpyrrolidone or methyl ethyl ketone, particularly preferably ethyl acetate or butyl acetate. The reaction mixture is afterstirred for 5 to 240 minutes, preferably 60 to 150 minutes at -10 C to 40 C, preferably at 0 C to 25 C_ The resulting precipitate is filtered off and dried, giving product of formula VIII.
In step c), over the course of 5 to 60 minutes, preferably 15-30 minutes, D-glucamine is metered in portions into a solution of product VIII and optionally a suitable base in a suitable solvent at -10 C to 40 C, preferably -5 C to 5 C.
Suitable bases are, for example, tertiary amines, such as, for example, triethylamine, ethyldimethylamine, ethyldiisopropylamine, tributylamine, N-ethylmorpholine, tetramethylethylenediamine, guanidine or alkylguanidines, particularly preferably triethylamine or ethyldiisopropylamine.
Suitable solvents are, for example, customary aprotic organic solvents, such as, for example, toluene, chlorobenzene, dichloromethane, ethyl acetate, butyl acetate, diisobutyl ether, diisopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dimethylformamide, N-methylpyrrolidone or methyl ethyl ketone, particularly preferably ethyl acetate or butyl acetate.
The reaction mixture is afterstirred for 1 to 20 hours, preferably 10 to 18 hours at -10 C to 40 C, preferably at 10 C to 25 C and then extracted by washing with water at 10 C - 80 C, preferably at 50 C - 70 C. During subsequent cooling to 20 C, the product of formula I
crystallizes.
The compound of formula I obtained by process A) or B) is further reacted by ~ O OH
I
O
O OH OH OH
HO N-Y~OH +
O H OH OH F -~
II N
0 Ct_NH
ZVH
OH
F I N O OH OH
I / N OH
III
a) converting the compound of formula I to the compound of formula II by cleaving off the benzyl protective group, for example through saponification of the ester under alkaline conditions or through hydrogenation of the ester, and then b) reacting the compound of formula II with the amine of formula VII to give the compound of formula III. This reaction of the compound of formula II with the amine of formula VII in the sense of a peptide coupling is carried out in accordance with customary methods.
Suitable peptide coupling reagents and solvents or solvent mixtures are described, inter alia, in, for example, A. Speicher et al., Journal fur Praktische Chemie/Chemiker-Zeitung (1998), 340, 581-583; Y. S. Klausner and M. Bodansky, Synthesis, (1972), 453 ff; K.
Ishihara et al., J. Org. Chem., 61, 4196 (1996); M. Kunishima et al., Tetrahedron 55, 13159-13170 (1999) and also R.C. Larock: Comprehensive Organic Transformations;
VCH, New York, 1989, page 981 ff.
The reaction of the compound of formula II with the amine of formula VII is described, for example, in WO 02/50027 or US 7,205,290.
crystallizes.
A further aspect of this invention is an alternative preparation process B) O
/ O
OH + HaI"Ul, R1 O IV
vi O O O
~ O OxR1 + O OH
0 v 0 n, ~ O O OH OH
+ H2N_,_~OH
~
OH
in which a) the monobenzyl dodecanedioate of formula IV is reacted with the compound of formula VI, in which Rl is an alkyl radical having 1 to 18 carbon atoms, in which one or more CH2 groups of the alkyl radical may be replaced by -0-, -CO-, -CH=CH-, -C=C- or aryl, and the alkyl radical may be substituted one or more times by F, Cl, Br or I, to give the compound of formula V and then further b) the compound of formula V is reacted with further monobenzyl dodecanedioate of formula IV to give the compound of formula VIII, and then c) the compound of formula VIII is reacted with D-glucamine to give the compound of formula I.
In step a), monobenzyl dodecanedioate is dissolved in a suitable solvent in the presence of a suitable base at -30 C to + 70 C, preferably at -10 C to +40 C, particularly preferably at -5 C
to 0 C and, over the course of 30 - 150 minutes, preferably 60-120 minutes, is metered into a solution of compound VI, particularly preferably isobutyl chloroformate, chilled to -10 C to 30 C, preferably -10 C to 0 C.
Alternatively, a solution of compound VI, preferably butyl chloroformate, in a suitable solvent chilled to -10 C to 30 C, preferably -10 C to 0 C, can also be initially introduced and then monobenzyl dodecanedioate and a suitable base in a suitable solvent can be metered in at -30 C to + 70 C, preferably at -10 C to +40 C, particularly preferably at -5 C
to 0 C over the course of 30 - 150 minutes, preferably 60-120 minutes.
The reaction mixture is stirred at -10 C to 40 C, preferably at -10 C to 0 C
for 15 to 150 minutes, preferably 30 - 120 minutes. The reaction mixture can then either be used directly in the subsequent reaction, or the formed product is isolated. Preferably, the reaction mixture is used directly. To isolate the compound of formula V, the solvent is evaporated off in vacuo.
Optionally, the reaction mixture is washed with water before the solvent is evaporated off.
Suitable bases are, for example, tertiary amines, such as, for example, triethylamine, ethyldimethylamine, ethyldiisopropylamine, tributylamine, N-ethylmorpholine, tetramethylethylenediamine, guanidine or alkylguanidines, particularly preferably triethylamine or ethyldiisopropylamine.
Suitable solvents are, for example, customary aprotic organic solvents, such as, for example, toluene, chlorobenzene, dichloromethane, ethyl acetate, butyl acetate, diisobutyl ether, diisopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dimethylformamide, N-methylpyrrolidone or methyl ethyl ketone, particularly preferably ethyl acetate or butyl acetate.
In step b), over the course of 5 to 60 minutes, preferably 15-30 minutes, monobenzyl dodecanedioate of formula IV is metered in portions into a solution of product V(prepared as described previously; either reaction solution used directly or the isolated product dissolved in a suitable solvent) and optionally a suitable base in a suitable solvent at -10 C to 40 C, preferably 0 C to 25 C.
Suitable bases are, for example, tertiary amines, such as, for example, triethylamine, ethyldimethylamine, ethyldiisopropylamine, tributylamine, N-ethylmorpholine, tetramethylethylenediamine, guanidine or alkylguanidines, particularly preferably triethylamine or ethyldiisopropylamine.
Suitable solvents are, for example, customary aprotic organic solvents, such as, for example, toluene, chlorobenzene, dichloromethane, ethyl acetate, butyl acetate, diisobutyl ether, diisopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dimethylformamide, N-methylpyrrolidone or methyl ethyl ketone, particularly preferably ethyl acetate or butyl acetate. The reaction mixture is afterstirred for 5 to 240 minutes, preferably 60 to 150 minutes at -10 C to 40 C, preferably at 0 C to 25 C_ The resulting precipitate is filtered off and dried, giving product of formula VIII.
In step c), over the course of 5 to 60 minutes, preferably 15-30 minutes, D-glucamine is metered in portions into a solution of product VIII and optionally a suitable base in a suitable solvent at -10 C to 40 C, preferably -5 C to 5 C.
Suitable bases are, for example, tertiary amines, such as, for example, triethylamine, ethyldimethylamine, ethyldiisopropylamine, tributylamine, N-ethylmorpholine, tetramethylethylenediamine, guanidine or alkylguanidines, particularly preferably triethylamine or ethyldiisopropylamine.
Suitable solvents are, for example, customary aprotic organic solvents, such as, for example, toluene, chlorobenzene, dichloromethane, ethyl acetate, butyl acetate, diisobutyl ether, diisopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dimethylformamide, N-methylpyrrolidone or methyl ethyl ketone, particularly preferably ethyl acetate or butyl acetate.
The reaction mixture is afterstirred for 1 to 20 hours, preferably 10 to 18 hours at -10 C to 40 C, preferably at 10 C to 25 C and then extracted by washing with water at 10 C - 80 C, preferably at 50 C - 70 C. During subsequent cooling to 20 C, the product of formula I
crystallizes.
The compound of formula I obtained by process A) or B) is further reacted by ~ O OH
I
O
O OH OH OH
HO N-Y~OH +
O H OH OH F -~
II N
0 Ct_NH
ZVH
OH
F I N O OH OH
I / N OH
III
a) converting the compound of formula I to the compound of formula II by cleaving off the benzyl protective group, for example through saponification of the ester under alkaline conditions or through hydrogenation of the ester, and then b) reacting the compound of formula II with the amine of formula VII to give the compound of formula III. This reaction of the compound of formula II with the amine of formula VII in the sense of a peptide coupling is carried out in accordance with customary methods.
Suitable peptide coupling reagents and solvents or solvent mixtures are described, inter alia, in, for example, A. Speicher et al., Journal fur Praktische Chemie/Chemiker-Zeitung (1998), 340, 581-583; Y. S. Klausner and M. Bodansky, Synthesis, (1972), 453 ff; K.
Ishihara et al., J. Org. Chem., 61, 4196 (1996); M. Kunishima et al., Tetrahedron 55, 13159-13170 (1999) and also R.C. Larock: Comprehensive Organic Transformations;
VCH, New York, 1989, page 981 ff.
The reaction of the compound of formula II with the amine of formula VII is described, for example, in WO 02/50027 or US 7,205,290.
A further aspect of the invention is the novel compound of formula Va.
O O
O O~LO
O
Va A further aspect of the invention is the novel compound of formula VIII.
O O -'I
O O O ~
0 vnI 0 The examples given below serve to illustrate the invention without, however, limiting it.
Experimental section:
1. Preparation of benzyl 12-isobutoxycarbonyloxy-12-oxododecanoate Va 1.5 g (4.7 mmol) of monobenzyl dodecanedioate are initially introduced into 15 ml of ethyl acetate and admixed with 0.8 ml (5.6 mmol) of triethylamine. The mixture is cooled to -5 C, and a solution of 0.7 ml (5.0 mmol) of isobutyl chloroformate is added. After 60 min, the precipitate is drawn off with suction under protective gas, washed twice with ethyl acetate and evaporated to dryness. A colorless oil in a yield of 96.4% is obtained.
1H-NMR (600.13 IvII-Iz, ACN-d3), 6 7.35 (m, 5H), 5.06 (s, 2H), 4.01 (2H, d, J = 6.6 Hz), 2.46 (t, 2H, J = 7.4 Hz), 2.31 (t, 2H, J
7.4 Hz), 1.97 (m, 1 H), 1.57 (m, 2H), 1.60 (m, 2H), 1.32 -1.22 (m, 11 H), 1.31 (m, 1 H), 0.92 (d,6H,J=6.7Hz) 13C-NMR (242.51 MHz, ACN-d3), S
174.22 (C=O), 169.53 (C=O), 150.32 (C=O), 137.76 (C quatemary), 129.48 (CH), 129.00 (CH), 128.97 (CH), 76.15 (CH2), 66.56 (CH2), 34.76 (CH2), 34.66 (CH2), 30.05 (CH2), 30.01 (CHz), 29.89 (CH2), 29.79 (CH2), 29.71 (CH2), 29.38 (CH2), 28.45 (CH), 25.71 (CHZ), 24.94 (CH2), 18.92 (CH3) MW: 420.55; MS: 438.29 (M+NH4) HR-MS: C24H3606+NH¾+ calculated 438.2856 found 438.2860 2. Preparation of benzyl 11-(2S,3R,4R,5R-2,3,4,5,6-pentahydroxyhexylcarbamoyl)-undecanoate I starting from benzyl 12-isobutoxycarbonyloxy-12-oxo-10 dodecanoate Va The benzyl 12-isobutoxycarbonyloxy-12-oxododecanoate prepared as in 1. is dissolved with ml of ethyl acetate and admixed at 0 C with 0.9 g (5.2 mmol) of 2R,3R,4R,5S-6-amino-hexane-1,2,3,4,5-pentanol (D-glucamine). The mixture is stirred for one hour at 0 C, heated 15 to 20 C and left to stand overnight. The resulting white suspension is extracted at 65 C by shaking three times with 20 ml of water at the same temperature. The organic phase is then evaporated to dryness. A colorless solid in a yield of 92.9% is obtained.
Melting point: 129 -132 C
1H-NMR (400.13 MHz, DMSO-d6), 8 7.67 (t, 1H), 7.39 - 7.30 (m, 5H), 5.08 (s, 2H), 4.72 (d, 1H, J = 4.5 Hz), 4.43 (d, IH, J = 5.6 Hz), 4.36 (d, 1 H, J= 5.9 Hz), 4.31 (t, 1 H, 5.7 Hz), 4.24 (d, 1 H, J= 6.3 Hz), 3.61- 3.54 (m, 3H), 3.50 - 3.44 (m, 1H), 3.42 - 3.35 (m, 3H), 3.30 - 3.22 (m, 1H), 3.04 -2.98 (m, 1H), 2.34 (t, 2H, J= 7.4 Hz), 2.06 Hz (t, 2H, J = 7.5 Hz), 1.55 -1.44 (m, 4H), 1.22 (m, 12 H) MW: 483.61; MS: 484.30 (M+I) 3. Preparation of the monobenzyl dodecanedioate anhydride VIII starting from the benzyl 12-isobutoxycarbonyloxy-12-oxododecanoate Va The benzyl 12-isobutoxycarbonyloxy-12-oxododecanoate prepared as in 1. is admixed with 20 ml of ethyl acetate and admixed at 20 C with 1.9 g (4.2 mmol) of monobenzyl dodecanedioate. The niixture is stirred for 2.5 hours, and the resulting precipitate is drawn off with suction and dried. A colorless solid in a yield of 55.0% is obtained.
Melting point: 67 - 70 C
1H-NMR (400.13 MHz, DMSO-d6), b 7.33 - 7.35 (m, 5H), 5.07 (s, 2H), 2.44 (t, 2H, J = 7.4 Hz), 2.32 (t, 2H, J=
7.4 Hz), 1.58 (m, 2H), 1.57 (m, 2H), 1.33 -1.26 (m, 11 H), 1.31 (m, 111) 13C-NMR (161.69 MHz, ACN-d3), b 174.25 (C=O), 170.96 (C=O), 137.75 (C quatemary, 129.48 (CH), 129.00 (CH), 128.97 (CH), 66.57 (CH2), 35.77 (CH2), 34.76 (CH2), 30.06 (CH2), 30.02 (CH2), 29.89 (CH2), 29.83 (CH2), 29.71 (CH2), 29.45 (CH2), 25.71 (CH2), 24.95 (CH2) HR-MS: C38H5407 calculated 623.3948 found 623.3950 4. Preparation of benzyl 11-(2S,3R,4R,5R-2,3,4,5,6-pentahydrogyhezylcarbamoyl)-undecanoate I starting from the monobenzyl dodecanedioate anhydride VIII
0.50 g (0.80 mmol) of monobenzyl dodecanedioate anhydride are initially introduced into 10 ml of ethyl acetate and admixed with 0.14 ml (0.96 mmol) of triethylamine and cooled to 0 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 for 18 h at room temperature. The mixture is heated to 70 C and extracted by shaking three times with 20 ml of water at the same temperature. The organic phase is allowed to cool to room temperature, and the resulting precipitate is filtered off and dried. A colorless solid in a yield of 72% is obtained.
Melting point: 129 -132 C
5. Preparation of benzyl 11-(2S,3R,4R,5R-2,3,4,5,6-pentahydrozyhegylcarbamoyl)-undecanoate I starting from the monobenzyl dodecanedioate IVa without isolation of the intermediates 17 kg of isobutyl chloroformate are initially introduced into 150 1 of ethyl acetate and cooled to -5 C. Over the course of 2 hours, a solution of 37.3 kg of monobenzyl dodecanedioate and 14.2 kg of triethylamine in 100 1 of ethyl acetate, chilled to -5 C, is metered into this solution.
When the metered addition is complete, the mixture is afterstirred for 2 hours at -5 C. Then, at -5 C, over the course of 30 minutes, 23.2 kg of D-glucamine are metered in in portions, and when the metered addition is complete the mixture is afterstirred for a further 1 hour at -5 C
and then for 12 hours at 20 C. The reaction mixture is added to 200 1 of ethyl acetate and 300 1 of water, the mixture is heated to 65 C and the phases are separated from one another.
The organic phase is washed with a further 80 1 of water at 60 C, then the organic phase is cooled to 20 C over the course of 60 minutes. Following afterstirring for 1 hour, the precipitated solid is filtered off and dried. Yield: 44.7 kg (80%).
6. Preparation of benzyl 11-(2S,3R,4R,5R-2,3,4,5,6-pentahydroxyhexylcarbamoyl)-undecanoate I starting from the monobenzyl dodecanedicarboxylate IVa without isolation of the intermediates 2.53 ml (16.8 mmol) of benzyl chloroformate are initially introduced into 20 ml of ethyl acetate and cooled to -5 C. Then, over the course of 15 minutes, 5 g (15.6 mmol) of monobenzyl dodecanedicarboxylate and 2.63 ml (18.7 mmol) of triethylamine in 13.4 ml of ethyl acetate are metered in. The mixture is afterstirred for 2 hours at 0 C, then, over the course of 20 minutes, 3.11 g (17.2 mmol) of 2R,3R,4R,5S-6-aminohexane-1,2,3,4,5-pentanol (D-glucamine) are added in portions and the mixture is further stirred initially for 1 h at 0 C, then for 20 h at room temperature. The mixture is admixed with 40 ml of water, heated to 65 C and stirred for a further 1 h. Following phase separation, extraction is carried out by shaking again with 10 ml of water at the same temperature. The organic phase is allowed to cool to room temperature, and the resulting precipitate is filtered off and dried. A colorless solid in a yield of 2.68 g (36%; purity HPLC 76.7 area%) is obtained.
7. Preparation of benzyl 11-(2S,3R,4R,5R-2,3,4,5,6-pentahydrogyhezylcarbamoyl)-undecanoate I starting from the monobenzyl dodecanedicarboxylate IVa without isolation of the intermediates 2.19 ml (16.9 mmol) of isobutyl chloroformate are initially introduced into 20 ml of butyl acetate and cooled to -5 C. Then, over the course of 20 minutes, 5 g (15.6 mmol) of monobenzyl dodecanedicarboxylate and 2.63 ml (18.7 mmol) of triethylamine in 13.4 ml of butyl acetate are metered in. The resulting thick suspension is diluted with a further 10 ml of butyl acetate. The mixture is afterstirred for 2 hours at 0 C, then, over the course of 20 minutes, 3.11 g (17.2 mmol) of 2R,3R,4R,5S-6-aminohexane-1,2,3,4,5-pentanol (D-glucamine) and a further 10 ml of butyl acetate are added in portions and the mixture is then stirred further firstly for 1 h at -5 C, then for 20 h at room temperature.
The mixture is admixed with 40 ml of water, heated to 80 C and stirred for a further 2 h. The phase mixture is allowed to cool to room temperature, and the resulting precipitate is filtered off, afterwashed with 20 ml of water and dried. A colorless solid in a yield of 6.11 g (81%; purity HPLC 99.4 area%) is obtained.
8. Preparation of benzyl 11-(2S,3R,4R,5R-2,3,4,5,6-pentahydroxyhegylcarbamoyl)-undecanoate I starting from the monobenzyl dodecanedicarboxylate IVa without isolation of the intermediates 2.11 ml (16.8 mmol) of isobutyl chloroformate are initially introduced into 20 ml of butyl acetate and cooled to -5 C. Then, over the course of 15 minutes, 5 g (15.6 mmol) of monobenzyl dodecanedicarboxylate and 2.41 ml (18.7 mmol) of N-ethylmorpholine in 13.4 ml of butyl acetate are metered in. The mixture is afterstirred for 2 hours at 0 C, then, over the course of 20 minutes, a suspension of 3.11 g (17.2 mmol) of 2R,3R,4R,5S-6-amino-hexane-1,2,3,4,5-pentanol (D-glucamine) in 50 ml of butyl acetate is added and the mixture is stirred further firstly for 1 h at -5 C, then for 20 h at room temperature.
The mixture is admixed with 40 ml of water, heated to 65 C and stirred for a further 5 h.
Following phase separation, the organic phase is also washed with 10 ml of water, the organic phase is cooled to room temperature and the precipitate is filtered off and dried. A colorless solid in a yield of 2.53 g (34%; purity HPLC 92.5 area%) is obtained.
9. Preparation of benzy111-(2S,3R,4R,5R-2,3,4,5,6-pentahydrozyhexylcarbamoyl)-undecanoate I starting from the monobenzyl dodecanedicarboxylate IVa without isolation of the intermediates 2.19 ml (16.9 mmol) of isobutyl chloroformate are initially introduced into 20 ml of dichioromethane and cooled to -5 C. Then, over the course of 20 minutes, 5 g (15.6 mmol) of monobenzyl dodecanedicarboxylate and 2.63 ml (18.7 mmol) of triethylamine in 13.4 ml of dichloromethane are metered in. The mixture is afterstirred for 2 hours at 0 C, then, over the course of 20 minutes, 3.11 g (17.2 mmol) of 2R,3R,4R,5S-6-aminohexane-1,2,3,4,5-pentanol (D-glucamine) are added in portions and the mixture is stirred further firstly for 1 h at -5 C, then for 20 h at room temperature. The mixture is admixed with 40 ml of water, heated to 40 C and stirred for a further 2 h. After cooling to room temperature, the precipitate is filtered off, washed with 20 ml of water and dried. A colorless solid in a yield of 6.57 g (87%; purity HPLC 90.5 area%) is obtained.
10. Preparation of benzyl 11-(2S,3R,4R,5R-2,3,4,5,6-pentahydrozyhexylcarbamoyl)-undecanoate I starting from the monobenzyl dodecanedicarboxylate IVa without isolation of the intermediates 3.28 ml (25.3 mmol) of isobutyl chloroformate are initially introduced into 30 ml of toluene and cooled to -5 C. Then, over the course of 15 minutes, 7.5 g (23.4 mmol) of monobenzyl dodecanedicarboxylate and 4.65 ml (28.1 mmol) of ethyldiisopropylamine in 20 ml of toluene are metered in. The mixture is afterstirred for 2 hours at 0 C, then, over the course of 20 minutes, 4.67 g (25.8 mmol) of 2R,3R,4R,5S-6-aminohexane-1,2,3,4,5-pentanol (D-glucamine) are added and the mixture is stirred further firstly for 1 h at -5 C, then is heated to 70 C and afterstirred for 3 hours at this temperature, followed by 20 h at room temperature.
The mixture is admi.xed with 60 ml of water, heated to 70 C and stirred for a further 3 h.
After cooling to room temperature, the precipitate is filtered off. A
colorless solid in a yield of 7.65 g (68%; purity HPLC 86.8 area%) is obtained.
11. Preparation of benzyl I1-(2S,3R,4R,5R-2,3,4,5,6-pentahydrogyhezylcarbamoyl)-undecanoate I starting from the monobenzyl dodecanedicarboxylate IVa without isolation of the intermediates 3.14 m1(25.3 mmol) of pivaloyl chloride are initially introduced into 30 ml of toluene at room temperature and, over the course of 15 minutes, 7.5 g (23.4 mmol) of monobenzyl dodecanedicarboxylate and 3.94 ml (28.1 mmol) of triethylamine in 20 ml of toluene are metered in. The mixture is afterstirred for 2 hours, then, over the course of 20 minutes, 4.67 g (25.8 mmol) of 2R,3R,4R,5S-6-aminohexane-1,2,3,4,5-pentanol (D-glucamine) are added in portions and the mixture is stirred further firstly for 73 h at room temperature. The mixture is admixed with 60 ml of water, heated to 111 C and stirred for a further 4 h. It is filtered hot, the filtrate is cooled to room temperature and the resulting precipitate is diluted with 20 ml of toluene and filtered off. A colorless solid in a yield of 10.9 g (96%; purity HPLC 87.4 area%) is obtained.
O O
O O~LO
O
Va A further aspect of the invention is the novel compound of formula VIII.
O O -'I
O O O ~
0 vnI 0 The examples given below serve to illustrate the invention without, however, limiting it.
Experimental section:
1. Preparation of benzyl 12-isobutoxycarbonyloxy-12-oxododecanoate Va 1.5 g (4.7 mmol) of monobenzyl dodecanedioate are initially introduced into 15 ml of ethyl acetate and admixed with 0.8 ml (5.6 mmol) of triethylamine. The mixture is cooled to -5 C, and a solution of 0.7 ml (5.0 mmol) of isobutyl chloroformate is added. After 60 min, the precipitate is drawn off with suction under protective gas, washed twice with ethyl acetate and evaporated to dryness. A colorless oil in a yield of 96.4% is obtained.
1H-NMR (600.13 IvII-Iz, ACN-d3), 6 7.35 (m, 5H), 5.06 (s, 2H), 4.01 (2H, d, J = 6.6 Hz), 2.46 (t, 2H, J = 7.4 Hz), 2.31 (t, 2H, J
7.4 Hz), 1.97 (m, 1 H), 1.57 (m, 2H), 1.60 (m, 2H), 1.32 -1.22 (m, 11 H), 1.31 (m, 1 H), 0.92 (d,6H,J=6.7Hz) 13C-NMR (242.51 MHz, ACN-d3), S
174.22 (C=O), 169.53 (C=O), 150.32 (C=O), 137.76 (C quatemary), 129.48 (CH), 129.00 (CH), 128.97 (CH), 76.15 (CH2), 66.56 (CH2), 34.76 (CH2), 34.66 (CH2), 30.05 (CH2), 30.01 (CHz), 29.89 (CH2), 29.79 (CH2), 29.71 (CH2), 29.38 (CH2), 28.45 (CH), 25.71 (CHZ), 24.94 (CH2), 18.92 (CH3) MW: 420.55; MS: 438.29 (M+NH4) HR-MS: C24H3606+NH¾+ calculated 438.2856 found 438.2860 2. Preparation of benzyl 11-(2S,3R,4R,5R-2,3,4,5,6-pentahydroxyhexylcarbamoyl)-undecanoate I starting from benzyl 12-isobutoxycarbonyloxy-12-oxo-10 dodecanoate Va The benzyl 12-isobutoxycarbonyloxy-12-oxododecanoate prepared as in 1. is dissolved with ml of ethyl acetate and admixed at 0 C with 0.9 g (5.2 mmol) of 2R,3R,4R,5S-6-amino-hexane-1,2,3,4,5-pentanol (D-glucamine). The mixture is stirred for one hour at 0 C, heated 15 to 20 C and left to stand overnight. The resulting white suspension is extracted at 65 C by shaking three times with 20 ml of water at the same temperature. The organic phase is then evaporated to dryness. A colorless solid in a yield of 92.9% is obtained.
Melting point: 129 -132 C
1H-NMR (400.13 MHz, DMSO-d6), 8 7.67 (t, 1H), 7.39 - 7.30 (m, 5H), 5.08 (s, 2H), 4.72 (d, 1H, J = 4.5 Hz), 4.43 (d, IH, J = 5.6 Hz), 4.36 (d, 1 H, J= 5.9 Hz), 4.31 (t, 1 H, 5.7 Hz), 4.24 (d, 1 H, J= 6.3 Hz), 3.61- 3.54 (m, 3H), 3.50 - 3.44 (m, 1H), 3.42 - 3.35 (m, 3H), 3.30 - 3.22 (m, 1H), 3.04 -2.98 (m, 1H), 2.34 (t, 2H, J= 7.4 Hz), 2.06 Hz (t, 2H, J = 7.5 Hz), 1.55 -1.44 (m, 4H), 1.22 (m, 12 H) MW: 483.61; MS: 484.30 (M+I) 3. Preparation of the monobenzyl dodecanedioate anhydride VIII starting from the benzyl 12-isobutoxycarbonyloxy-12-oxododecanoate Va The benzyl 12-isobutoxycarbonyloxy-12-oxododecanoate prepared as in 1. is admixed with 20 ml of ethyl acetate and admixed at 20 C with 1.9 g (4.2 mmol) of monobenzyl dodecanedioate. The niixture is stirred for 2.5 hours, and the resulting precipitate is drawn off with suction and dried. A colorless solid in a yield of 55.0% is obtained.
Melting point: 67 - 70 C
1H-NMR (400.13 MHz, DMSO-d6), b 7.33 - 7.35 (m, 5H), 5.07 (s, 2H), 2.44 (t, 2H, J = 7.4 Hz), 2.32 (t, 2H, J=
7.4 Hz), 1.58 (m, 2H), 1.57 (m, 2H), 1.33 -1.26 (m, 11 H), 1.31 (m, 111) 13C-NMR (161.69 MHz, ACN-d3), b 174.25 (C=O), 170.96 (C=O), 137.75 (C quatemary, 129.48 (CH), 129.00 (CH), 128.97 (CH), 66.57 (CH2), 35.77 (CH2), 34.76 (CH2), 30.06 (CH2), 30.02 (CH2), 29.89 (CH2), 29.83 (CH2), 29.71 (CH2), 29.45 (CH2), 25.71 (CH2), 24.95 (CH2) HR-MS: C38H5407 calculated 623.3948 found 623.3950 4. Preparation of benzyl 11-(2S,3R,4R,5R-2,3,4,5,6-pentahydrogyhezylcarbamoyl)-undecanoate I starting from the monobenzyl dodecanedioate anhydride VIII
0.50 g (0.80 mmol) of monobenzyl dodecanedioate anhydride are initially introduced into 10 ml of ethyl acetate and admixed with 0.14 ml (0.96 mmol) of triethylamine and cooled to 0 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 for 18 h at room temperature. The mixture is heated to 70 C and extracted by shaking three times with 20 ml of water at the same temperature. The organic phase is allowed to cool to room temperature, and the resulting precipitate is filtered off and dried. A colorless solid in a yield of 72% is obtained.
Melting point: 129 -132 C
5. Preparation of benzyl 11-(2S,3R,4R,5R-2,3,4,5,6-pentahydrozyhegylcarbamoyl)-undecanoate I starting from the monobenzyl dodecanedioate IVa without isolation of the intermediates 17 kg of isobutyl chloroformate are initially introduced into 150 1 of ethyl acetate and cooled to -5 C. Over the course of 2 hours, a solution of 37.3 kg of monobenzyl dodecanedioate and 14.2 kg of triethylamine in 100 1 of ethyl acetate, chilled to -5 C, is metered into this solution.
When the metered addition is complete, the mixture is afterstirred for 2 hours at -5 C. Then, at -5 C, over the course of 30 minutes, 23.2 kg of D-glucamine are metered in in portions, and when the metered addition is complete the mixture is afterstirred for a further 1 hour at -5 C
and then for 12 hours at 20 C. The reaction mixture is added to 200 1 of ethyl acetate and 300 1 of water, the mixture is heated to 65 C and the phases are separated from one another.
The organic phase is washed with a further 80 1 of water at 60 C, then the organic phase is cooled to 20 C over the course of 60 minutes. Following afterstirring for 1 hour, the precipitated solid is filtered off and dried. Yield: 44.7 kg (80%).
6. Preparation of benzyl 11-(2S,3R,4R,5R-2,3,4,5,6-pentahydroxyhexylcarbamoyl)-undecanoate I starting from the monobenzyl dodecanedicarboxylate IVa without isolation of the intermediates 2.53 ml (16.8 mmol) of benzyl chloroformate are initially introduced into 20 ml of ethyl acetate and cooled to -5 C. Then, over the course of 15 minutes, 5 g (15.6 mmol) of monobenzyl dodecanedicarboxylate and 2.63 ml (18.7 mmol) of triethylamine in 13.4 ml of ethyl acetate are metered in. The mixture is afterstirred for 2 hours at 0 C, then, over the course of 20 minutes, 3.11 g (17.2 mmol) of 2R,3R,4R,5S-6-aminohexane-1,2,3,4,5-pentanol (D-glucamine) are added in portions and the mixture is further stirred initially for 1 h at 0 C, then for 20 h at room temperature. The mixture is admixed with 40 ml of water, heated to 65 C and stirred for a further 1 h. Following phase separation, extraction is carried out by shaking again with 10 ml of water at the same temperature. The organic phase is allowed to cool to room temperature, and the resulting precipitate is filtered off and dried. A colorless solid in a yield of 2.68 g (36%; purity HPLC 76.7 area%) is obtained.
7. Preparation of benzyl 11-(2S,3R,4R,5R-2,3,4,5,6-pentahydrogyhezylcarbamoyl)-undecanoate I starting from the monobenzyl dodecanedicarboxylate IVa without isolation of the intermediates 2.19 ml (16.9 mmol) of isobutyl chloroformate are initially introduced into 20 ml of butyl acetate and cooled to -5 C. Then, over the course of 20 minutes, 5 g (15.6 mmol) of monobenzyl dodecanedicarboxylate and 2.63 ml (18.7 mmol) of triethylamine in 13.4 ml of butyl acetate are metered in. The resulting thick suspension is diluted with a further 10 ml of butyl acetate. The mixture is afterstirred for 2 hours at 0 C, then, over the course of 20 minutes, 3.11 g (17.2 mmol) of 2R,3R,4R,5S-6-aminohexane-1,2,3,4,5-pentanol (D-glucamine) and a further 10 ml of butyl acetate are added in portions and the mixture is then stirred further firstly for 1 h at -5 C, then for 20 h at room temperature.
The mixture is admixed with 40 ml of water, heated to 80 C and stirred for a further 2 h. The phase mixture is allowed to cool to room temperature, and the resulting precipitate is filtered off, afterwashed with 20 ml of water and dried. A colorless solid in a yield of 6.11 g (81%; purity HPLC 99.4 area%) is obtained.
8. Preparation of benzyl 11-(2S,3R,4R,5R-2,3,4,5,6-pentahydroxyhegylcarbamoyl)-undecanoate I starting from the monobenzyl dodecanedicarboxylate IVa without isolation of the intermediates 2.11 ml (16.8 mmol) of isobutyl chloroformate are initially introduced into 20 ml of butyl acetate and cooled to -5 C. Then, over the course of 15 minutes, 5 g (15.6 mmol) of monobenzyl dodecanedicarboxylate and 2.41 ml (18.7 mmol) of N-ethylmorpholine in 13.4 ml of butyl acetate are metered in. The mixture is afterstirred for 2 hours at 0 C, then, over the course of 20 minutes, a suspension of 3.11 g (17.2 mmol) of 2R,3R,4R,5S-6-amino-hexane-1,2,3,4,5-pentanol (D-glucamine) in 50 ml of butyl acetate is added and the mixture is stirred further firstly for 1 h at -5 C, then for 20 h at room temperature.
The mixture is admixed with 40 ml of water, heated to 65 C and stirred for a further 5 h.
Following phase separation, the organic phase is also washed with 10 ml of water, the organic phase is cooled to room temperature and the precipitate is filtered off and dried. A colorless solid in a yield of 2.53 g (34%; purity HPLC 92.5 area%) is obtained.
9. Preparation of benzy111-(2S,3R,4R,5R-2,3,4,5,6-pentahydrozyhexylcarbamoyl)-undecanoate I starting from the monobenzyl dodecanedicarboxylate IVa without isolation of the intermediates 2.19 ml (16.9 mmol) of isobutyl chloroformate are initially introduced into 20 ml of dichioromethane and cooled to -5 C. Then, over the course of 20 minutes, 5 g (15.6 mmol) of monobenzyl dodecanedicarboxylate and 2.63 ml (18.7 mmol) of triethylamine in 13.4 ml of dichloromethane are metered in. The mixture is afterstirred for 2 hours at 0 C, then, over the course of 20 minutes, 3.11 g (17.2 mmol) of 2R,3R,4R,5S-6-aminohexane-1,2,3,4,5-pentanol (D-glucamine) are added in portions and the mixture is stirred further firstly for 1 h at -5 C, then for 20 h at room temperature. The mixture is admixed with 40 ml of water, heated to 40 C and stirred for a further 2 h. After cooling to room temperature, the precipitate is filtered off, washed with 20 ml of water and dried. A colorless solid in a yield of 6.57 g (87%; purity HPLC 90.5 area%) is obtained.
10. Preparation of benzyl 11-(2S,3R,4R,5R-2,3,4,5,6-pentahydrozyhexylcarbamoyl)-undecanoate I starting from the monobenzyl dodecanedicarboxylate IVa without isolation of the intermediates 3.28 ml (25.3 mmol) of isobutyl chloroformate are initially introduced into 30 ml of toluene and cooled to -5 C. Then, over the course of 15 minutes, 7.5 g (23.4 mmol) of monobenzyl dodecanedicarboxylate and 4.65 ml (28.1 mmol) of ethyldiisopropylamine in 20 ml of toluene are metered in. The mixture is afterstirred for 2 hours at 0 C, then, over the course of 20 minutes, 4.67 g (25.8 mmol) of 2R,3R,4R,5S-6-aminohexane-1,2,3,4,5-pentanol (D-glucamine) are added and the mixture is stirred further firstly for 1 h at -5 C, then is heated to 70 C and afterstirred for 3 hours at this temperature, followed by 20 h at room temperature.
The mixture is admi.xed with 60 ml of water, heated to 70 C and stirred for a further 3 h.
After cooling to room temperature, the precipitate is filtered off. A
colorless solid in a yield of 7.65 g (68%; purity HPLC 86.8 area%) is obtained.
11. Preparation of benzyl I1-(2S,3R,4R,5R-2,3,4,5,6-pentahydrogyhezylcarbamoyl)-undecanoate I starting from the monobenzyl dodecanedicarboxylate IVa without isolation of the intermediates 3.14 m1(25.3 mmol) of pivaloyl chloride are initially introduced into 30 ml of toluene at room temperature and, over the course of 15 minutes, 7.5 g (23.4 mmol) of monobenzyl dodecanedicarboxylate and 3.94 ml (28.1 mmol) of triethylamine in 20 ml of toluene are metered in. The mixture is afterstirred for 2 hours, then, over the course of 20 minutes, 4.67 g (25.8 mmol) of 2R,3R,4R,5S-6-aminohexane-1,2,3,4,5-pentanol (D-glucamine) are added in portions and the mixture is stirred further firstly for 73 h at room temperature. The mixture is admixed with 60 ml of water, heated to 111 C and stirred for a further 4 h. It is filtered hot, the filtrate is cooled to room temperature and the resulting precipitate is diluted with 20 ml of toluene and filtered off. A colorless solid in a yield of 10.9 g (96%; purity HPLC 87.4 area%) is obtained.
Claims (24)
1. A process for the preparation of the compound of formula I
which comprises reacting a) the compound of formula IV
with a compound of formula VI
in which Hal can have the meaning Br, Cl or I and in which R1 is an alkyl radical having 1 to 18 carbon atoms, in which one or more CH2 groups of the alkyl radical may be replaced by -O-, -CO-, -CH-CH-, -C.ident.C- or aryl and the alkyl radical may be substituted one or more times by F, Cl, Br or I, to give the compound of formula V
and then, in a second step, b) reacting the compound of formula V with D-glucamine to give the compound of formula I.
which comprises reacting a) the compound of formula IV
with a compound of formula VI
in which Hal can have the meaning Br, Cl or I and in which R1 is an alkyl radical having 1 to 18 carbon atoms, in which one or more CH2 groups of the alkyl radical may be replaced by -O-, -CO-, -CH-CH-, -C.ident.C- or aryl and the alkyl radical may be substituted one or more times by F, Cl, Br or I, to give the compound of formula V
and then, in a second step, b) reacting the compound of formula V with D-glucamine to give the compound of formula I.
2. The process as claimed in claim 1, wherein Hal in the compound of formula VI has the meaning Cl.
3. The process as claimed in claim 1 or 2, wherein R1 in the compound of formula VI
has the meaning methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, tert-butyloxy or benzyloxy.
has the meaning methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, tert-butyloxy or benzyloxy.
4. The process as claimed in claim 1, 2 or 3, wherein R1 in the compound of formula VI
has the meaning isobutyloxy.
has the meaning isobutyloxy.
5. A process for the preparation of the compound of formula I
which comprises reacting a) the compound of formula IV
with a compound of formula VI
in which Hal can have the meaning Br, Cl or I and in which R1 is an alkyl radical having 1 to 18 carbon atoms, in which one or more CH2 groups of the alkyl radical may be replaced by -O-, -CO-, -CH=CH-, -C.ident.C- or aryl and the alkyl radical may be substituted one or more times by F, Cl, Br or I, to give the compound of formula V
and then, in a second step, b) reacting the compound of formula V with further monobenzyl dodecanedioate of formula IV to give the compound of formula VIII
and then, in a third step, c) reacting the compound of formula VIII with D-glucamine to give the compound of formula I.
which comprises reacting a) the compound of formula IV
with a compound of formula VI
in which Hal can have the meaning Br, Cl or I and in which R1 is an alkyl radical having 1 to 18 carbon atoms, in which one or more CH2 groups of the alkyl radical may be replaced by -O-, -CO-, -CH=CH-, -C.ident.C- or aryl and the alkyl radical may be substituted one or more times by F, Cl, Br or I, to give the compound of formula V
and then, in a second step, b) reacting the compound of formula V with further monobenzyl dodecanedioate of formula IV to give the compound of formula VIII
and then, in a third step, c) reacting the compound of formula VIII with D-glucamine to give the compound of formula I.
6. The process as claimed in claim 5, wherein Hal in the compound of formula VI has the meaning Cl.
7. The process as claimed in claim 5 or 6, wherein R1 in the compound of formula VI
has the meaning methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, tert-butyloxy or benzyloxy.
has the meaning methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, tert-butyloxy or benzyloxy.
8. The process as claimed in claim 5, 6 or 7, wherein R1 in the compound of formula VI
has the meaning isobutyloxy.
has the meaning isobutyloxy.
9. The process as claimed in any one of claims 1 to 8, wherein the compound of formula I is converted in a further step to the compound of formula II
10. The process as claimed in claim 9, wherein the compound of formula II is converted in a further step through reaction with the compound of formula VII
to the compound of formula III
to the compound of formula III
11. A compound of formula Va
12. A process for the preparation of the compound of formula Va which comprises reacting the compound of formula IV
with a compound of formula VIa in which Hal can have the meaning Br, Cl or I.
with a compound of formula VIa in which Hal can have the meaning Br, Cl or I.
13. A process for the preparation of the compound of formula which comprises reacting the compound of formula Va with D-glucamine to give the compound of formula I.
14. A compound of formula VIII
15. A process for the preparation of the compound of formula VIII
which comprises reacting a) the compound of formula IV
with a compound of formula VIa in which Hal can have the meaning Br, Cl or I
to give the compound of formula Va and then, in a second step, b) reacting the compound of formula Va with the compound of formula IV to give the compound of formula VIII.
which comprises reacting a) the compound of formula IV
with a compound of formula VIa in which Hal can have the meaning Br, Cl or I
to give the compound of formula Va and then, in a second step, b) reacting the compound of formula Va with the compound of formula IV to give the compound of formula VIII.
16. A process for the preparation of the compound of formula I
which comprises reacting the compound of formula VIII
with D-glucamine to give the compound of formula I.
which comprises reacting the compound of formula VIII
with D-glucamine to give the compound of formula I.
17. A process for the preparation of the compound of formula I
which comprises reacting a) the compound of formula IV
with a compound of formula VI
in which Hal can have the meaning Br, Cl or I and in which R1 is an alkyl radical having 1 to 18 carbon atoms, in which one or more carbon atoms of the alkyl radical may be replaced by -O-, -CO-, -CH=CH-, -C.ident.C- or aryl and the alkyl radical may be substituted one or more times by F, Cl, Br or I, to give the compound of formula V
and then, in a second step, b) reacting the compound of formula V with D-glucamine to give the compound of formula I.
which comprises reacting a) the compound of formula IV
with a compound of formula VI
in which Hal can have the meaning Br, Cl or I and in which R1 is an alkyl radical having 1 to 18 carbon atoms, in which one or more carbon atoms of the alkyl radical may be replaced by -O-, -CO-, -CH=CH-, -C.ident.C- or aryl and the alkyl radical may be substituted one or more times by F, Cl, Br or I, to give the compound of formula V
and then, in a second step, b) reacting the compound of formula V with D-glucamine to give the compound of formula I.
18. The process as claimed in claim 17, wherein Hal in the compound of formula VI has the meaning Cl.
19. The process as claimed in claim 17 or 18, wherein R1 in the compound of formula VI
has the meaning methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, tert-butyloxy or benzyloxy.
tert-butyl, methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, tert-butyloxy or benzyloxy.
has the meaning methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, tert-butyloxy or benzyloxy.
tert-butyl, methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, tert-butyloxy or benzyloxy.
20. The process as claimed in claim 17, 18 or 19, wherein R1 in the compound of formula VI has the meaning isobutyloxy.
21. The process as claimed in claim 17, 18 or 19, wherein R1 in the compound of formula VI has the meaning benzyloxy.
22. The process as claimed in claim 17, 18 or 19, wherein R1 in the compound of formula VI has the meaning tert-butyloxy.
23. The process as claimed in any one of claims 17 to 22, wherein the compound of formula I is converted in a further step to the compound of formula II
24. The process as claimed in claim 23, wherein the compound of formula II is converted in a further step through reaction with the compound of formula VII
to the compound of formula III
to the compound of formula III
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US11/767,298 | 2007-06-22 | ||
| US11/767,284 US20080319218A1 (en) | 2007-06-22 | 2007-06-22 | Processes for Making and Using Benzyl Pentahydroxyhexylcarbamoylundecanoate |
| US11/767,284 | 2007-06-22 | ||
| US11/767,298 US20080319221A1 (en) | 2007-06-22 | 2007-06-22 | Esters of Pentahydroxyhexylcarbamoyl Alkanoic Acids |
| DE102007029612.8 | 2007-06-27 | ||
| DE102007029612A DE102007029612A1 (en) | 2007-06-27 | 2007-06-27 | Preparing pentahydroxy-pentylcarbamoyl-undecanoic acid benzyl ester, useful to prepare tetrahydroxy-hexylcarbamoyl-undecanoic acid, comprises reacting dodecanedioic acid monobenzyl ester with halo-carbonyl compound and then with glucamine |
| PCT/EP2008/004552 WO2009000397A1 (en) | 2007-06-22 | 2008-06-07 | Process for preparing benzyl pentahydroxyhexylcarbamoylundecanoate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2691065A1 true CA2691065A1 (en) | 2008-12-31 |
Family
ID=39695874
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2691065A Abandoned CA2691065A1 (en) | 2007-06-22 | 2008-06-07 | Process for preparing benzyl pentahydroxyhexylcarbamoylundecanoate |
Country Status (12)
| Country | Link |
|---|---|
| KR (1) | KR20100023886A (en) |
| CN (1) | CN101687769A (en) |
| AR (1) | AR068977A1 (en) |
| AU (1) | AU2008267515A1 (en) |
| BR (1) | BRPI0813120A2 (en) |
| CA (1) | CA2691065A1 (en) |
| CL (1) | CL2008001857A1 (en) |
| IL (1) | IL202824A0 (en) |
| MX (1) | MX2009012727A (en) |
| TW (1) | TW200914406A (en) |
| UY (1) | UY31165A1 (en) |
| WO (1) | WO2009000397A1 (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP3857338B2 (en) * | 1995-10-25 | 2006-12-13 | 株式会社Ｌｔｔバイオファーマ | Lecithinized superoxide dismutase and medicine containing the same as an active ingredient |
| US7067689B1 (en) * | 2005-07-08 | 2006-06-27 | Microbia, Inc. | Process for production of pentahydroxyhexylcarbamoyl alkanoic acids |
-
2008
- 2008-06-07 BR BRPI0813120A patent/BRPI0813120A2/en not_active Application Discontinuation
- 2008-06-07 CN CN200880021496A patent/CN101687769A/en active Pending
- 2008-06-07 AU AU2008267515A patent/AU2008267515A1/en not_active Abandoned
- 2008-06-07 KR KR1020097026689A patent/KR20100023886A/en not_active Application Discontinuation
- 2008-06-07 MX MX2009012727A patent/MX2009012727A/en not_active Application Discontinuation
- 2008-06-07 WO PCT/EP2008/004552 patent/WO2009000397A1/en active Application Filing
- 2008-06-07 CA CA2691065A patent/CA2691065A1/en not_active Abandoned
- 2008-06-19 AR ARP080102606A patent/AR068977A1/en unknown
- 2008-06-19 TW TW097122784A patent/TW200914406A/en unknown
- 2008-06-20 CL CL200801857A patent/CL2008001857A1/en unknown
- 2008-06-20 UY UY31165A patent/UY31165A1/en unknown
-
2009
- 2009-12-17 IL IL202824A patent/IL202824A0/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| KR20100023886A (en) | 2010-03-04 |
| BRPI0813120A2 (en) | 2019-09-10 |
| WO2009000397A1 (en) | 2008-12-31 |
| CN101687769A (en) | 2010-03-31 |
| CL2008001857A1 (en) | 2008-10-10 |
| AR068977A1 (en) | 2009-12-23 |
| MX2009012727A (en) | 2009-12-08 |
| AU2008267515A1 (en) | 2008-12-31 |
| UY31165A1 (en) | 2009-01-30 |
| IL202824A0 (en) | 2010-06-30 |
| TW200914406A (en) | 2009-04-01 |
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