Catalytic reduction of alkyne compounds

Details Catalytic reduction of alkyne compounds Catalytic reduction of alkyne compounds

2001-09-18

2004-03-02

Ford, John M. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ketone doai

C514S464000, C514S725000, C514S728000, C549S437000, C549S434000, C568S338000, C568S347000, C568S361000

Reexamination Certificate

active

06699911

ABSTRACT:

The present invention relates to a novel process for the reduction of alkyne compounds; in particular, the invention relates to a process for the preparation of cyclohexene derivatives which are suitable as intermediates for the preparation of carotinoids.
A large number of the industrial carotinoid syntheses described in the literature, including the preparation of astaxanthine, proceed via cyclohexene intermediates which, in additon to one or more C═C double bonds, also contain a C═C triple bond. To form a conjugated double bond system, this triple bond has to be partially reduced in a separate process step.
In the case of the alkynediol IVa involved in the astaxanthine synthesis described in DE-A-43 22 277, this can be done with zinc/acetic acid in methylene chloride.
EP-A-0 005 748 relates to another process for the preparation of astaxanthine, in which the partial reduction of the alkynediol of formula IIIa is likewise carried out with zinc/acetic acid in methylene chloride.
The disadvantage of the zinc/acetic acid reduction described is the inadequate selectivity of the method. Unwanted by-products, e.g. the formation of spiro compounds which cannot be converted to the desired secondary products later in the synthesis, can lead to significant losses of yield.
Other methods of reduction are described inter alia in J. Amer. Oil Chem. Soc. 49 (1972) 72, where the reduction of triple bonds to cis double bonds in long-chain conjugated fatty acids is carried out with zinc in boiling protic solvents.
The drastic reduction conditions mentioned here are unsuitable for thermally labile compounds.
Helv. Chim. Acta 58 (1975) 1016 describes the reduction of conjugated alkynes in protic solvents. The reducing agent used by the authors is zinc dust which has been activated by the addition of potassium cyanide.
On the one hand, the abovementioned methods give only moderate yields; on the other hand, the activation with potassium cyanide carries an appreciable health risk.
The paper published in Journal für praktische Chemie 336 (1994) 714-715 contains a method for the (Z)-selective reduction of conjugated triple bonds with a combination of Zn (Cu/Ag) in polar protic solvents, e.g. methanol/water.
This process has the disadvantage that the reagent is very expensive to prepare and moreover must always be freshly prepared.
It is therefore an object of the present invention to provide a process for the partial reduction of alkyne compounds which avoids the abovementioned disadvantages of the prior art.
We have found that this object is achieved by a process for the preparation of cyclohexene derivatives of general formulae I or II:
in which the substituents R
1
and R
2
independently of one another are defined as follows:
R
1
is
R
2
is OH or a protective group convertible to a hydroxyl group by hydrolysis;
R
3
and R
4
are hydrogen or C
1
-C
4
-alkyl; and
R
5
is hydrogen or C
1
-C
4
-acyl,
by the reduction of alkyne compounds of general formulae III or IV:
in which the substituents R
1
and R
2
are as defined above, wherein the reducing agent used is a mixture of zinc and at least one compound B selected from the group consisting of ammonium salts, copper salts and alkali metal and alkaline earth metal salts.
Alkyl radicals R
3
and R
4
which may be mentioned are linear or branched C
1
-C
4
-alkyl chains, e.g. methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl and 1,1-dimethylethyl. Preferred alkyl radicals are methyl and ethyl.
The radicals R
3
and R
4
can also form a cycloheptyl or cyclohexyl ring together with the carbon atom to which they are bonded.
Substituents R
5
which may be mentioned are linear or branched C
1
-C
4
-acyl chains, e.g. formyl, acetyl, propionyl and isopropionyl. The preferred acyl radical is acetyl.
Suitable protective groups R
2
convertible to a hydroxyl group by hydrolysis are functional groups which can be converted to the hydroxyl group relatively easily. Examples which may be mentioned are ether groups such as
and —O—C(CH
3
)
3
silyl ether groups such as —O—Si(CH
3
)
3
, —O—Si(CH
2
CH
3
)
3
, —O—Si(isopropyl)
3
, —O—Si(CH
3
)
2
(tert-butyl) and —O—Si(CH
3
)
2
(n-hexyl), or substituted methyl ether groups such as the &agr;-alkoxyalkyl ether groups of the formulae —O—CH
2
—O—CH
3
,
and suitable pyranyl ether groups such as the tetrahydropyranyloxy group and the 4-methyl-5,6-dihydro-2H-pyranyloxy group.
The group used for R
2
is particularly advantageously the tetrahydropyranyloxy group:
or the &agr;-ethoxyethoxy group of the formula
Conditions for cleaving the abovementioned protective groups can be found inter alia in T. Greene “Protective Groups in Organic Chemistry”, John Wiley & Sons, 1981, Chapter 2.
In one preferred process variant, the reducing agent used is a mixture of zinc and at least one ammonium salt of formula V:
in which the substituents independently of one another are defined as follows:
R
6
to R
8
are hydrogen, C
1
-C
6
-alkyl or aryl; and
Y
−
is an anion of an organic or inorganic acid.
Alkyl radicals R
6
to R
8
which may be mentioned are linear or branched C
1
-C
6
-alkyl chains, e.g. methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl. Preferred alkyl radicals are methyl, ethyl, n-propyl and 1-methylethyl.
Hydrogen may be mentioned as the particularly preferred radical for R
6
to R
8
.
Aryl is to be understood as meaning aromatic rings or ring systems having from 6 to 18 carbon atoms in the ring system, for example phenyl or naphthyl, which can optionally be substituted by one or more radicals such as halogen, e.g. fluorine, chlorine or bromine, amino, C
1
-C
4
-alkylamino, C
1
-C
4
-dialkylamino, hydroxyl, C
1
-C
4
-alkyl, C
1
-C
4
-alkoxy or other radicals. Optionally substituted phenyl, methoxyphenyl and naphthyl are preferred.
Y
−
is generally an anion of an organic or inorganic acid.
Organic acids are to be understood as meaning, inter alia, aliphatic and aromatic carboxylic acids, for example benzoic acid or C
1
-C
12
-alkanoic acids, preferably C
1
-C
6
-alkanoic acids such as formic acid, acetic acid, propionic acid, butyric acid or caproic acid, particularly preferably acetic acid, or dicarboxylic acids such as oxalic acid, malonic acid or succinic acid.
Y
−
can also be an anion of an organic sulfonic acid, such as methanesulfonate or para-toluenesulfonate.
Examples of inorganic acids are, inter alia, hydrochloric acid, hydrobromic acid, carbonic acid, sulfuric acid, sulfurous acid, nitric acid, nitrous acid and phosphoric acid.
The present invention further relates to a process for the preparation of cyclohexene derivatives of formulae I or II wherein the reducing agent used is a mixture of zinc and at least one copper salt selected from the group consisting of copper(I) bromide, copper(I) chloride, copper(II) acetate, copper(II) bromide, copper(II) carbonate, copper(II) chloride, copper(II) nitrate, copper(II) oxalate and copper(II) sulfate. Copper(II) sulfate may be mentioned as the preferred copper salt.
In another embodiment of the process according to the invention, the reducing agent used is a mixture of zinc and at least one alkali metal or alkaline earth metal salt selected from the group consisting of sodium bromide, sodium chloride, sodium acetate, sodium carbonate, sodium hydrogencarbonate, sodium oxalate, sodium sulfate, potassium bromide, potassium chloride, potassium acetate, potassium carbonate, potassium hydrogencarbonate, potassium oxalate, potassium sulfate and the corresponding lithium salts, calcium bromide, calcium chloride, calcium acetate, cal

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