Manufacture of cycloalkenylpolyene esters

Details Manufacture of cycloalkenylpolyene esters Manufacture of cycloalkenylpolyene esters

2000-01-18

2001-04-10

Carr, Deborah D. (Department: 1623)

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

Organic compounds

Fatty compounds having an acid moiety which contains the...

C554S129000, C554S154000

Reexamination Certificate

active

06215009

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a novel process for the manufacture of cycloalkenylpolyene esters, in particular retinyl acylates, which are 3,7-dimethyl-9-(2′,6′,6′-trimethylcyclohex-1′-en-1′-yl)-nona-2,4,6,8-tetraenyl acylates. Such compounds are of commercial interest as intermediates for the manufacture of compounds of the vitamin A group, or in certain cases as the compounds themselves.
The process involves an elimination and an isomerization of the corresponding 3,7-dimethyl-6-hydroxy-9-(2′,6′,6′-trimethylcyclohex-1′-en-1′-yl)-nona-2,4,7-trienyl acylate or of a 6-acylated derivative thereof using certain acid anhydrides or complexes thereof previously unknown as agents for this purpose.
SUMMARY OF THE INVENTION
The present invention provides a process for making a retinyl acylate of formula I:
wherein
R
1
is an optionally substituted C
1-23
-alkyl, a C
2-23
-alkenyl having 1 to 5 double bonds, an optionally aromatically substituted phenyl-C
1-6
-alkyl, or an optionally substituted phenyl;
the process comprising reacting, in the presence of dimethylformamide, an agent which is an acid anhydride or a complex of sulfur trioxide with a compound of formula II:
wherein
R
1
is selected from the group consisting of an optionally substituted C
1-23
-alkyl, a C
2-23
-alkenyl having 1 to 5 double bonds, an optionally aromatically substituted phenyl-C
1-6
-alkyl, and an optionally substituted phenyl; and
R
2
is hydrogen or COR
1
.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention provides a process for the manufacture of a retinyl acylate of formula I:
wherein R
1
is an optionally substituted C
1-23
-alkyl; a C
2-23
-alkenyl containing 1 to 5 double bonds; optionally aromatically substituted phenyl-C
1-6
-alkyl; or an optionally substituted phenyl.
In this process, a compound of formula II:
wherein
R
1
is defined above and
R
2
is hydrogen or COR
1
,
is treated with an agent which is an acid anhydride or a complex of sulfur trioxide. Such an agent is selected from trifluoroacetic anhydride; a C
1-6
-alkanesulphonic acid anhydride; trifluoromethanesulphonic acid anhydride; an optionally substituted benzenesulphonic acid anhydride; phosphorus pentoxide; sulfur trioxide; and a complex of sulfur trioxide with a tri(C
1-6
-alkyl)amine, with a nitrogen-containing heteroaromatic compound or with a di(C
1-6
-alkyl)formamide. The treatment is effected in the presence of dimethylformamide which acts simultaneously as a solvent and a weak base.
As used herein, the term “C
1-23
-alkyl” or “C
2-23
-alkenyl containing (or having) 1 to 5 double bonds” with reference to R
1
, depending on the number of carbon atoms, refers to not only straight-chain but also branched alkyl or alkenyl groups. Examples of C
1-23
-alkyl groups include methyl, ethyl, propyl, pentyl, heptyl, undecyl, pentadecyl and heptadecyl. Examples of C
2-23
-alkenyl groups include 8-heptadecenyl and heptadeca-8,11-dienyl. The corresponding alkanoyl and alkenoyl groups (COR
1
) are acetyl, propionyl, butyryl, caproyl, capryl, dodecanoyl, palmitoyl and stearoyl and, respectively, oleoyl and linoleyl. Preferably, R
1
is methyl. In the case where C
1-23
-alkyl is substituted, the substituents may be up to three C
1-4
-alkoxy groups, which may, in each case, be straight-chain or branched. Two or three alkoxy substituents may be the same or different.
As used herein, the term “optionally aromatically substituted phenyl” means that the phenyl group is either unsubstituted or substituted with one or more substituents selected from for example alkyl, alkoxy and nitro groups and halogen atoms. These substituents may be up to three, and selected from 1 to 3 C
1-4
-alkyl groups, 1 to 3 C
1-4
-alkoxy groups, 1 to 2 nitro groups, and 1 to 3 halogen atoms. This applies equally to the “optionally substituted phenyl” group. Any alkyl or alkoxy substituent with 3 or 4 carbon atoms may be straight-chain or branched, and any halogen atom may be fluorine, chlorine, bromine or iodine.
The C
1-6
-alkanesulphonic acid anhydride used in the process of the present invention for promoting the elimination and isomerization reaction involved, may be selected from methane-, ethane-, propane-, butane-, pentane- and hexanesulphonic acid anhydride, of which those featuring an alkane moiety with three to six carbon atoms can have a straight-chain or branched alkane moiety. If the “optionally substituted benzenesulphonic acid anhydride” is substituted, then the substituents may be, for example, one or more alkyl, alkoxy and nitro groups and halogen atoms, wherein each halogen atom may be fluorine, chlorine, bromine or iodine. The substituents may be up to three, and are selected from 1 to 3 C
1-4
-alkyl groups, 1 to 3 C
1-4
-alkoxy groups, 1 to 2 nitro groups, and 1 to 3 halogen atoms. The alkyl or alkoxy group with three or four carbon atoms may be straight-chain or branched.
In the case of a complex of sulfur trioxide with a tri(C
1-6
-alkyl)amine or a di(C
1-6
-alkyl)formamide, the alkyl groups may be straight-chain or branched, and the same or different. Examples of such alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert.butyl, n-pentyl and n-hexyl. Examples of the trialkylamines include trimethylamine, triethylamine and N-ethyldiisopropylamine. An example of the dialkylformamides is dimethylformamide. In complexes of sulfur trioxide with a nitrogen-containing heteroaromatic compound, such compounds are especially heterocycles featuring at least one ring nitrogen atom. Pyridine and pyridine derivatives, such as picoline and quinoline, are examples. Such nitrogen-containing heteroaromatic compounds may also be bonded to a polymeric carrier (“polymer-bound”). Pyridine is the most preferred of these compounds. An example of a pyridine bonded to a polymeric carrier is poly-(4-vinyl-pyridine), the adduct of which with sulfur trioxide is commercially available.
The use of a complex of sulfur trioxide in the process of the present invention is advantageous by virtue of its simple production from the starting materials (educts) sulfur trioxide and the nitrogen containing compound. In addition, such an agent is easier to handle compared to the aggressive sulfur trioxide when used alone. The complexes are in part known and, in some cases, are commercially available. They may be produced readily by introducing sulfur trioxide into the diluted trialkylamine, nitrogen-containing heteroaromatic compound or dialkylformamide, methylene chloride, for example, being used as the diluent.
Preferred agents for use in the process of the present invention are phosphorus pentoxide, sulfur trioxide, and complexes of sulfur trioxide.
The process in accordance with the present invention is effected in the presence of dimethylformamide, which acts simultaneously as a solvent and as a weak base. However, an additional solvent may be present, which is generally an aprotic organic solvent. The solvent may be a polar or an apolar aprotic organic solvent and is suitably an aliphatic hydrocarbon with 5 to 10 carbon atoms, such as pentane, hexane, heptane or octane; an optionally alkyl-substituted alicyclic hydrocarbon with up to 10 carbon atoms, such as cyclohexane, methylcyclohexane or decalin; an aromatic hydrocarbon, such as benzene or toluene; a halogenated aliphatic hydrocarbon, such as methylene chloride, chloroform, carbon tetrachloride or dichloroethane; a nitrated aliphatic hydrocarbon, such as nitro-methane; an aliphatic ether, such as diethyl ether, diisopropyl ether, tert.butyl methyl ether or 1,2-dimethoxyethane; a cyclic ether, such as tetrahydrofuran, methylfuran or 1,4-dioxan; an aliphatic nitrile, such as acetonitrile; an aliphatic amine, such as triethylamine or N-ethyldiisopropylamine; an aliphatic or alicyclic amide (in addition to dimethylformamide itself), such as N,N-dimethylacetamide or 1-methyl-2-pyrrolidone, respectively; dimethyl sulphoxide; tetramethylene sulphone (sulfolane); or a mixture of one or more of the aforementio

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