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(11) | EP 1 461 331 B9 |
| (12) | CORRECTED EUROPEAN PATENT SPECIFICATION |
| Note: Bibliography reflects the latest situation |
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PROCESS FOR THE PREPARATION OF 2-(6-SUBSTITUTED-1,3-DIOXANE-4-YL) ACETIC ACID DERIVATIVES PROZESS FÜR DIE HERSTELLUNG VON 2-(6-SUBSTITUIERTEN-1,3-DIOXAN-4-YL) ESSIGSÄURE DERIVATEN PROCEDE DE PREPARATION DE DERIVES D'ACIDE 2-(6-SUBSTITUE-1,3-DIOXANE-4-YL) ACETIQUE |
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| Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). |
[0001] The invention relates to a process for the preparation of a 2-(6-substituted-1,3-dioxane-4-yl) acetic acid derivative according to formula 1,
wherein R1, R2 and R3 are each independently a C1-4 alkylgroup or wherein R1 and R2 together with the C-atom to which they are bound form a 5- or 6-membered cycloalkyl and wherein Y stands for RA-CO- or for RB-SO2- with RA, RB are chosen from the group of alkyl or aryl with 1-12 C-atoms, from its corresponding 2-(6-substituted-1,3-dioxane-4-yl) acetic acid derivative according to formula 2,
wherein R1, R2 and R3 are as defined above and wherein X stands for a halogen, in the presence of a phase transfer catalyst and an oxylating agent.
[0002] Such a process is known from EP 1 024 139, wherein the preparation of a compound according to formula 1 from a compound according to formula 2 is achieved in the presence of a quaternary ammonium salt (phase transfer catalyst) and a carboxylic acid salt (acyloxylating agent).
[0003] It is the object of the invention to provide an alternative process for the preparation of a 2-(6-substituted-1,3-dioxane-4-yl) acetic acid derivative according to formula 1 from its corresponding 2-(6-substituted-1,3-dioxane-4-yl) acetic acid derivative according to formula 2.
[0004] This is achieved according to the invention by using a quarternary phosphonium ion according to formula 3 as a phase transfer catalyst,
wherein R4, R5, R6, R7 each independently stand for an alkyl, cycloalkyl, aralkyl or aryl with 1 to 12 C-atoms, and an ion according to formula 4,
OY- (4)
wherein Y is as defined above, as an oxylating agent. The reaction has a high yield.
[0005] The quarternary phosphonium ion according to formula 3 used as a phase transfer catalyst and the ion according to formula 4 used as an oxylating agent may be present in a quarternary phosphonium salt according to formula 5,
wherein Y, R4, R5, R6 and R7 are as defined above. The phosphonium salt according to formula 5 can be used as both a phase transfer catalyst and as an oxylating agent. The quarternary phosphonium salt according to formula 5 can be prepared according to methods known to the person skilled in the art (e.g. analogous to the preparation of tetra-n-butylammoniumacetate as described in US 5 278 313).
[0006] In a preferred embodiment of the invention, the phase transfer catalyst and the oxylating agent are not present in the same molecule. In this embodiment, a quarternary phosphonium salt according to formula 3a,
wherein R4, R5, R6 and R7 are as defined above and wherein A stands for the anion of the quarternary phopshoniumsalt and is selected from the group of halogens, for example Cl, Br, I is used as a phase transfer catalyst and the acid salt according to formula 4a,
(OY-)n Mn+ (4a)
wherein Y is as defined above, wherein M stands for alkali metal or an alkaline metal, for example Li, K, Na, Mg, Ca, Ba and wherein n represents an integer of 1 or 2, depending on the valence of M is used as an oxylating agent. Preferred is M is K or Na.
[0007] In the process according to the invention, halogens X are preferably Cl, Br or I, more preferably Cl.
[0008] In the process according to the invention, R1, R2 and R3 are preferably a C1-4 alkyl group, more preferably R1 and R2 are a methyl or an ethyl group, more preferably a methyl group. R3 is preferably a methyl or a butyl, most preferably a t-butyl.
[0009] In the process according to the invention Y groups are preferably represented by RA-CO- or RB-SO2-, wherein RA, RB are chosen from the group of C1-C4 alkyl or aryl with 6-10 C-atoms. In a preferred embodiment, Y is chosen from the group of acyl, more preferably acetyl (with RA is CH3), benzenesulphonyl (with RB is benzene), more preferably nitro substituted benzenesulphonyl (with RB is p-nitrobenzene), tosyl (with RB is p-methyl-benzene) or mesyl (with RB is methyl).
[0010] In the process according to the invention, preferably a phosphonium salt according to formula 3a or according to formula 5, with at least three out of four R groups are the same (e.g. R4, R5, R6 are butyl and R7 is methyl or R4, R5, R6 are phenyl and R7 is butyl), more preferably a phosphonium salt with all four R groups are the same, is used.
[0011] RA and RB and R4, R5, R6, R7, -in case R4, R5, R6, R7 are aryl or aralkyl-, may be substituted for example with substituents chosen from the group of halogens, alkoxy (e.g. methoxy or ethoxy) with 1-6 C-atoms, alkyl with 1-6 C atoms, (e.g. methyl if RB is toluene) or nitro, preferably only RA or RB are substituted.
[0012] The quarternary phosphonium salt according to formula 3a is preferably used in a molar equivalent amount of 0.01 to 1.0, more preferably 0.05 to 0.7, most preferably 0.1 to 0.5 relative to the amount of compound according to formula 2.
[0013] The quarternary phosphonium salt according to formula 5 is preferably used in a molar equivalent amount of 0.8 to 5, preferably 1 to 3, most preferably 1 to 1.5.
[0014] The acid salt according to formula 4a is preferably used in a molar equivalent amount of 1 to 5 relative to the amount of compound according to formula 2 present. More preferably, a molar equivalent amount of acid salt according to formula 4a of 1 to 4, most preferably 2 to 3, is used.
[0015] The solvents suitable for use in the present invention are a various number of organic solvents, which are known to the person skilled in the art. Organic solvents, which may be used are hydrocarbon series solvents, for example benzene, toluene, cyclohexane, etc; ether series solvents, for example diethyl ether tetrahydrofuran, 1,4-dioxane, methyl-t-butyl ether, dimethoxyethane, etc.; ester series solvents, for example ethyl acetate, butyl acetate, etc.; halogen containing solvents, for example methylene chloride, chloroform, 1,1,1-trichloroethane, etc.; nitrogen-containing solvents, for example acetamide, formamide, acetonitrile etc.; and aprotic polar solvents, for example dimethyl sulfoxide, N,N-dimethylformamide, N-methylpyrrolidone, hexamethylphosphoric triamide etc. Preferably, the solvent used is an aprotic polar solvent, more preferably the solvent used is N-methylpyrrolidone or N.N-dimethylformamide. The solvent can be used alone or in combination with one or more other solvent species, for example N-methylpyrrolidone in combination with toluene.
[0016] The temperature, by which the process of the invention is preferably carried out, is between 80 and 200°C, more preferably between 100 and 160°C, most preferably between 110 and 150°C.
[0017] The reaction product can be isolated from the reaction medium, if desired, according to methods known to the person skilled in the art (e.g. the method as described in US 5 278 313).
[0018] The invention will be illustrated by way of the following examples. However, these examples are not meant to restrict the invention.
Examples
Example 1
[0019] 0.5 molar equivalents tetrabutylphosphoniumbromide (TBPB) and 2.5 molar equivalents potassiumacetate were added to a solution of I (tert-butyl 2-[(4R,6S)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetate) in the solvent N-methylpyrrolidone (1g/3ml) at 100°C. The conversion of I in the presence of TBPB was 87.6% after 20 hours reaction time, the conversion af I into II (tert-butyl 2-{(4R,6S)-2,2-dimethyl-6-[(methyl-carbonyloxy)methyl]-1,3-dioxan-4-yl}acetate) thereof being 90.3%.
Example 2
[0020] Example I was repeated whereby the reaction temperature for the conversion of I into II was kept at 115°C. The conversion of I in the presence of TBPB was 95.1% after 3 hours reaction time, the conversion of I into II thereof being 91%.
Example 3
[0021] 0.1 molar equivalents tetraphenylphosphoniumbromide (TTB) and 2.5 molar equivalents potassiumacetate were added to a solution of I (tert-butyl 2-[(4R,6S)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetate) in the solvent N-methylpyrrolidone (1g/3ml) at 140°C. After 20 hours, the conversion of I was 97%, the conversion of I into II thereof being 77.2%.
1. Process for the preparation of a 2-(6-substituted-1,3-dioxane-4-yl) acetic acid derivative
according to formula 1,
wherein R1, R2 and R3 are each independently a C1-4 alkylgroup or wherein R1 and R2 together with the C-atom to which they are bound form a 5- or 6-membered cycloalkyl and wherein Y stands for RA-CO- or for RB-SO2- with RA,RB are chosen from the group of alkyl or aryl with 1-12 C-atoms, from its corresponding 2-(6-substituted-1,3-dioxane-4-yl) acetic acid derivative according to formula 2,
wherein R1, R2 and R3 are as defined above and wherein X stands for a halogen, in the presence of a phase transfer catalyst and an oxylating agent, characterized in that a quarternary phosphonium ion according to formula 3,
wherein R4, R5, R6, R7 each independently stand for an alkyl, cycloalkyl, aralkyl or aryl with 1 to 12 C-atoms, is used as a phase transfer catalyst and an ion according to formula 4,
OY- (4)
wherein Y is as defined above, is used as an oxylating agent;
wherein RA and RB and R4, R5, R6, R7, -in case R4, R5, R6. R7 are aryl or aralky-, may be substituted with substituents chosen from the group of halogens, alkoxy with 1-6 C-atoms, alkyl with 1-6 C atoms, or nitro.
wherein R1, R2 and R3 are each independently a C1-4 alkylgroup or wherein R1 and R2 together with the C-atom to which they are bound form a 5- or 6-membered cycloalkyl and wherein Y stands for RA-CO- or for RB-SO2- with RA,RB are chosen from the group of alkyl or aryl with 1-12 C-atoms, from its corresponding 2-(6-substituted-1,3-dioxane-4-yl) acetic acid derivative according to formula 2,
wherein R1, R2 and R3 are as defined above and wherein X stands for a halogen, in the presence of a phase transfer catalyst and an oxylating agent, characterized in that a quarternary phosphonium ion according to formula 3,
wherein R4, R5, R6, R7 each independently stand for an alkyl, cycloalkyl, aralkyl or aryl with 1 to 12 C-atoms, is used as a phase transfer catalyst and an ion according to formula 4,
OY- (4)
wherein Y is as defined above, is used as an oxylating agent;
wherein RA and RB and R4, R5, R6, R7, -in case R4, R5, R6. R7 are aryl or aralky-, may be substituted with substituents chosen from the group of halogens, alkoxy with 1-6 C-atoms, alkyl with 1-6 C atoms, or nitro.
2. Process according to claim 1, characterized in that RA, RB are chosen from the group of C1-C4 alkyl or aryl with 6-10 C-atoms.
3. Process according to any of claims 1-2, characterized in that as a phase transfer catalyst a quarternary phosphonium salt according to formula
3a,
wherein R4, R5, R6 and R7 are as defined above and wherein A stands for a halogen, is used and in that an acid salt according to formula 4a,
(OY-) n Mn+ (4a)
wherein Y is as defined above, wherein M stands for alkali metal or an alkaline metal, is used as an oxylating agent.
wherein R4, R5, R6 and R7 are as defined above and wherein A stands for a halogen, is used and in that an acid salt according to formula 4a,
(OY-) n Mn+ (4a)
wherein Y is as defined above, wherein M stands for alkali metal or an alkaline metal, is used as an oxylating agent.
4. Process according to claim 3, characterized in that the quarternary phosphonium salt according to formula 3a is used in a molar equivalent
amount of 0.05 to 0.7 relative to the amount of compound according to formula 2.
5. Process according to claim 4, characterized in that the quarternary phosphonium salt according to formula 3a is used in a molar equivalent
amount of 0.1 to 0.5 relative to the amount of compound according to formula 2.
6. Process according to any of claims 1-5, characterized in that the process is carried out at a temperature between 100 and 160°C.
7. Process according to any of claims 1-6, characterized in that the process is carried out at a temperature between 110 and 150°C.
8. Process according to any of claims 1-7, characterized in that the compound according to formula 1 is tert-butyl 2-{(4R,6S)-2,2 dimethyl-6-[(methylcarbonyloxy)methyl]-1,3-dioxan-4-yl}acetate
and in that the compound according to formula 2 is tert-butyl 2-[(4R,6S)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetate.
1. Verfahren zur Herstellung eines 2-(1,3-Dioxan-4-yl)essigsäurederivats mit 6-substituierter
Dioxanylgruppe gemäß Formel 1
worin R1, R2 und R3 jeweils unabhängig voneinander für eine C1-4-Alkylgruppe stehen oder R1 und R2 gemeinsam mit dem C-Atom, an das sie gebunden sind, 5- oder 6-gliedriges Cycloalkyl bilden und Y für RA-CO- oder RB-SO2- steht, wobei RA und RB aus der Gruppe bestehend aus Alkyl oder Aryl mit 1-12 C-Atomen ausgewählt sind, aus dem entsprechenden 2-(1,3-Dioxan-4-yl)essigsäurederivat mit 6-substituierter Dioxanylgruppe gemäß Formel 2
worin R1, R2 und R3 die oben angegebene Bedeutung besitzen und X für Halogen steht, in Gegenwart eines Phasentransferkatalysators und eines Oxylierungsmittels, dadurch gekennzeichnet, daß man als Phasentransferkatalysator ein quaternäres Phosphoniumion gemäß Formel 3
worin R4, R5, R6 und R7 jeweils unabhängig voneinander für Alkyl, Cycloalkyl, Aralkyl oder Aryl mit 1 bis 12 C-Atomen stehen, und als Oxylierungsmittel ein Ion gemäß Formel 4
OY- (4)
worin Y die oben angegebene Bedeutung besitzt, verwendet;
wobei RA und RB und R4, R5, R6 und R7- in dem Fall, daß R4, R5, R6 und R7 für Aryl oder Aralkyl stehen - durch Substituenten aus der Gruppe bestehend aus Halogenen, Alkoxy mit 1-6 C-Atomen, Alkyl mit 1-6 C-Atomen oder Nitro substituiert sind.
worin R1, R2 und R3 jeweils unabhängig voneinander für eine C1-4-Alkylgruppe stehen oder R1 und R2 gemeinsam mit dem C-Atom, an das sie gebunden sind, 5- oder 6-gliedriges Cycloalkyl bilden und Y für RA-CO- oder RB-SO2- steht, wobei RA und RB aus der Gruppe bestehend aus Alkyl oder Aryl mit 1-12 C-Atomen ausgewählt sind, aus dem entsprechenden 2-(1,3-Dioxan-4-yl)essigsäurederivat mit 6-substituierter Dioxanylgruppe gemäß Formel 2
worin R1, R2 und R3 die oben angegebene Bedeutung besitzen und X für Halogen steht, in Gegenwart eines Phasentransferkatalysators und eines Oxylierungsmittels, dadurch gekennzeichnet, daß man als Phasentransferkatalysator ein quaternäres Phosphoniumion gemäß Formel 3
worin R4, R5, R6 und R7 jeweils unabhängig voneinander für Alkyl, Cycloalkyl, Aralkyl oder Aryl mit 1 bis 12 C-Atomen stehen, und als Oxylierungsmittel ein Ion gemäß Formel 4
OY- (4)
worin Y die oben angegebene Bedeutung besitzt, verwendet;
wobei RA und RB und R4, R5, R6 und R7- in dem Fall, daß R4, R5, R6 und R7 für Aryl oder Aralkyl stehen - durch Substituenten aus der Gruppe bestehend aus Halogenen, Alkoxy mit 1-6 C-Atomen, Alkyl mit 1-6 C-Atomen oder Nitro substituiert sind.
2. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß man RA und RB aus der Gruppe bestehend aus C1-C4-Alkyl oder Aryl mit 6-10 C-Atomen auswählt.
3. Verfahren nach einem der Ansprüche 1-2, dadurch gekennzeichnet, daß man als Phasentransferkatalysator ein quaternäres Phosphoniumsalz gemäß Formel 3a
worin R4, R5 , R6 und R7 die oben angegebene Bedeutung besitzen und A für Halogen steht, und als Oxylierungsmittel ein Säuresalz gemäß Formel 4a
(OY-)n Mn+ (4a)
worin Y die oben angegebene Bedeutung besitzt und M für Alkalimetall oder ein alkalisches Metall steht, verwendet.
worin R4, R5 , R6 und R7 die oben angegebene Bedeutung besitzen und A für Halogen steht, und als Oxylierungsmittel ein Säuresalz gemäß Formel 4a
(OY-)n Mn+ (4a)
worin Y die oben angegebene Bedeutung besitzt und M für Alkalimetall oder ein alkalisches Metall steht, verwendet.
4. Verfahren nach Anspruch 3, dadurch gekennzeichnet, daß man das quaternäre Phosphoniumsalz gemäß Formel 3a in einer Moläquivalentmenge von
0,05 bis 0,7, bezogen auf die Menge an Verbindung der Formel 2, verwendet.
5. Verfahren nach Anspruch 4, dadurch gekennzeichnet, daß man das quaternäre Phosphoniumsalz gemäß Formel 3a in einer Moläquivalentmenge von
0,1 bis 0,5, bezogen auf die Menge an Verbindung der Formel 2, verwendet.
6. Verfahren nach einem der Ansprüche 1-5, dadurch gekennzeichnet, daß man es bei einer Temperatur zwischen 100 und 160°C durchführt.
7. Verfahren nach einem der Ansprüche 1-6, dadurch gekennzeichnet, daß man es bei einer Temperatur zwischen 110 und 150°C durchführt.
8. Verfahren nach einem der Ansprüche 1-7, dadurch gekennzeichnet, daß es sich bei der Verbindung gemäß Formel 1 um 2-{(4R,6S)-2,2-Dimethyl-6-[(methylcarbonyloxy)methyl]-1,3-dioxan-4-yl}essigsäure-tert.-butylester
und bei der Verbindung gemäß Formel 2 um 2-[(4R,6S)-6-(Chlormethyl)-2,2-dimethyl-1,3-dioxan-4-yl]essigsäure-tert.-butylester
handelt.
1. Procédé pour la préparation d'un dérivé d'acide 2-((6-substituant)-1,3-dioxane-4-yl)acétique
selon la formule 1,
dans laquelle R1, R2 et R3 sont chacun indépendamment un groupe alkyle en C1-4 ou dans laquelle R1 et R2 avec l'atome C auquel ils sont liés forment un cycloalkyle à 5 ou 6 éléments et dans laquelle Y représente RA-CO- ou RB-SO2-, RA et RB étant choisis entre un alkyle ou un aryle ayant 1-12 atomes de C, à partir de son dérivé d'acide 2-( (6-substituant)-1,3-dioxane-4-yl)acétique correspondant selon la formule 2,
dans laquelle R1, R2 et R3 sont tels que définis ci-dessus et dans laquelle X représente un halogène, en présence d'un catalyseur de transfert de phase et d'un agent oxylant, caractérisé en ce que qu'on utilise comme catalyseur de transfert de phase un ion phosphonium quaternaire selon la formule 3,
dans laquelle R4, R5, R6, R7 représentent chacun indépendamment un alkyle, un cycloalkyle, un aralkyle ou un aryle ayant 1 à 12 atomes de C et en ce qu'on utilise comme agent oxylant un ion selon la formule 4,
OY- (4)
dans laquelle Y est tel que défini ci-dessus ;
dans lequel RA et RB et R4, R5, R6, R7, -dans le cas où R4, R5, R6, R7 sont un aryle ou un aralkyle-, peuvent être substitués par des substituants choisis entre des halogènes, un alcoxy ayant 1-6 atomes de C, un alkyle ayant 1-6 atomes de C ou un nitro.
dans laquelle R1, R2 et R3 sont chacun indépendamment un groupe alkyle en C1-4 ou dans laquelle R1 et R2 avec l'atome C auquel ils sont liés forment un cycloalkyle à 5 ou 6 éléments et dans laquelle Y représente RA-CO- ou RB-SO2-, RA et RB étant choisis entre un alkyle ou un aryle ayant 1-12 atomes de C, à partir de son dérivé d'acide 2-( (6-substituant)-1,3-dioxane-4-yl)acétique correspondant selon la formule 2,
dans laquelle R1, R2 et R3 sont tels que définis ci-dessus et dans laquelle X représente un halogène, en présence d'un catalyseur de transfert de phase et d'un agent oxylant, caractérisé en ce que qu'on utilise comme catalyseur de transfert de phase un ion phosphonium quaternaire selon la formule 3,
dans laquelle R4, R5, R6, R7 représentent chacun indépendamment un alkyle, un cycloalkyle, un aralkyle ou un aryle ayant 1 à 12 atomes de C et en ce qu'on utilise comme agent oxylant un ion selon la formule 4,
OY- (4)
dans laquelle Y est tel que défini ci-dessus ;
dans lequel RA et RB et R4, R5, R6, R7, -dans le cas où R4, R5, R6, R7 sont un aryle ou un aralkyle-, peuvent être substitués par des substituants choisis entre des halogènes, un alcoxy ayant 1-6 atomes de C, un alkyle ayant 1-6 atomes de C ou un nitro.
2. Procédé selon la revendication 1, caractérisé en ce que RA, RB sont choisis entre un alkyle en C1-C4 ou un aryle ayant 6-10 atomes de C.
3. Procédé selon l'une quelconque des revendications 1-2, caractérisé en ce qu'on utilise comme catalyseur de transfert de phase un sel de phosphonium quaternaire
selon la formule 3a,
dans laquelle R4, R5, R6 et R7 sont tels que définis ci-dessus et dans laquelle A représente un halogène et en ce qu'on utilise comme agent oxylant un sel d'acide selon la formule 4a,
(OY-)n Mn+ (4a)
dans laquelle Y est tel que défini ci-dessus, dans laquelle M représente un métal d'un alcali ou un métal alcalin.
dans laquelle R4, R5, R6 et R7 sont tels que définis ci-dessus et dans laquelle A représente un halogène et en ce qu'on utilise comme agent oxylant un sel d'acide selon la formule 4a,
(OY-)n Mn+ (4a)
dans laquelle Y est tel que défini ci-dessus, dans laquelle M représente un métal d'un alcali ou un métal alcalin.
4. Procédé selon la revendication 3, caractérisé en ce que le sel de phosphonium quaternaire selon la formule 3a est utilisé en quantité en
équivalent molaire de 0,05 à 0,7 par rapport à la quantité de composé selon la formule
2.
5. Procédé selon la revendication 4, caractérisé en ce qu'on utilise le sel de phosphonium quaternaire selon la formule 3a en quantité en équivalent
molaire de 0,1 à 0,5 par rapport à la quantité de composé selon la formule 2.
6. Procédé selon l'une quelconque des revendications 1-5, caractérisé en ce qu'on effectue le procédé à une température comprise entre 100 et 160'C.
7. Procédé selon l'une quelconque des revendications 1-6, caractérisé en ce qu'on effectue le procédé à une température comprise entre 110 et 150°C.
8. Procédé selon l'une quelconque des revendications 1-7, caractérisé en ce que le composé selon la formule 1 est le 2-{(4R,6S)-2,2-diméthyl-6-[(méthylcarbonyloxy)méthyl]-1,3-dioxan-4-yl}acétate
de tert-butyle et en ce que le composé selon la formule 2 est le 2-[(4R,6S)-6-(chlorométhyl)-2,2-diméthyl-1,3-dioxan-4-yl]acétate
de tert-butyle.