Process for the preparation of cis-6-hexadecenoic acid

Details Process for the preparation of cis-6-hexadecenoic acid Process for the preparation of cis-6-hexadecenoic acid

2002-02-04

2004-08-24

Carr, Deborah D. (Department: 1621)

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

Organic compounds

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

C554S128000

Reexamination Certificate

active

06781004

ABSTRACT:

The invention relates to a process for the preparation of cis-6-hexadecenoic acid.
cis-6-Hexadecenoic acid (sapienic acid) is the most common unsaturated fatty acid present in human skin sebum. Because of its antimicrobial action, cis-6-hexadecenoic acid is a desired active ingredient for cosmetic and dermatological applications.
For the preparation of cis-6-hexadecenoic acid and esters thereof, microbiological and also chemical processes are known.
For example, WO 96/13591 describes the stereoselective elimination of hydrogen from palmityl esters by means of microorganisms.
A chemical synthesis route for obtaining cis-6-hexadecenoic acid is described in WO 98/16104. However, the multistage synthesis produces only small yields and, moreover, uses reagents which are questionable with regard to safety, such as, for example, liquid ammonia and potassium cyanide.
It is an object of the present invention to provide a novel process for the preparation of cis-6-hexadecenoic acid which proceeds with a high Z/E selectivity and does not have the disadvantages of the hitherto known processes with regard to safety.
We have found that this object is achieved by a process for the preparation of cis-6-hexadecenoic acid of the formula I
which comprises reacting
a
1
) a triphenylphosphonium salt of the formula II,
R
1
OOC—(CH
2
)
5
—P(R
2
)
3
+
X
−
  II
 in which the substituents, independently of one another, have the following meanings:
R
1
is C
1
-C
12
-alkyl, aryl;
R
2
is aryl and
X
−
is an anion equivalent of an inorganic or organic acid with decanal of the formula III
H
3
C—(CH
2
)
8
—CH═O  III
 in a Wittig reaction, or reacting
a
2
) a triphenylphosphonium salt of the formula IV,
H
3
C—(CH
2
)
9
—P(R
2
)
3
+
X
−
  IV
 in which the substituents R
2
and X
−
, independently of one another, have the meanings given above:
with an aldehyde of the formula V,
R
1
OOC—(CH
2
)
4
—CH═O  V
in which R
1
has the meaning given above,
in a Wittig reaction
and
b) saponifying the ester, formed by process step a
1
) or a
2
), of the formula VI,
 in which R
1
has the meaning given above.
Alkyl radicals for R
1
which may be mentioned are branched or unbranched C
1
-C
12
-alkyl chains, such as 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, 1-ethyl-2-methylpropyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl and n-dodecyl. Preferred alkyl radicals are C
1
-C
4
-alkyl groups, particularly preferably methyl, ethyl, n-propyl and 1-methylethyl, very particularly preferably methyl and ethyl.
Aryl for R
1
is to be understood as meaning aromatic rings or ring systems having 6 to 18 carbon atoms in the ring system, for example phenyl or naphthyl, which may optionally be substituted by one or more radicals such as halogen, e.g. fluorine, chlorine or bromine, cyano, nitro, 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. Preference is given to phenyl, methoxyphenyl and naphthyl.
The term aryl for R
2
refers to customary aryl radicals occurring in phosphines and phosphonium salts, such as phenyl, toluene, naphthyl, in each case optionally substituted, preferably phenyl.
The radical X
−
is an anion equivalent of an inorganic or organic acid, preferably a strong inorganic or organic acid.
The expression strong acid includes hydrohalic acids (in particular hydrochloric acid and hydrobromic acid), sulfuric acid, phosphoric acid, sulfonic acids and other inorganic or organic acids with a comparable degree of dissociation. Strong organic acids in this connection are also to be understood as meaning C
1
-C
6
-alkanoic acids.
Particularly preference is given to anions of such acids, chosen from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid and sulfonic acid. Very particular preference is given to Cl
−
, Br
−
, C
n
H
2n+1
—SO
3
−
(where n=1-4), Ph—SO
3
−
, p-Tol—SO
3
−
or CF
3
—SO
3
−
,
The invention provides, in particular, a process for the preparation of cis-6-hexadecenoic acid wherein, in process step a), a triphenylphosphonium salt of the formula II is reacted with decanal of the formula III.
A further preferred embodiment of the process involves using a triphenylphosphonium salt of the formula IIa,
R
1
OOC—(CH
2
)
4
—P(Ph)
3
+
X
−
  IIa
in which the substituents, independently of one another, have the following meanings:
R
1
is C
1
-C
4
-alkyl, in particular methyl, ethyl, n-propyl and 1-methylethyl;
Ph is phenyl;
X
−
is an anion equivalent of a strong inorganic or organic acid, in particular Cl
−
, Br
−
, C
n
H
2n+1
—SO
3
−
where n=1-4, Ph—SO
3
−
, p-Tol—SO
3
−
or CF
3
—SO
3
−
.
The reaction of the phosphonium salts II to IV to give the cis-6-hexadecenoic esters of the formula VI can take place under the conditions customary for Wittig reactions.
The reaction in step a) usually takes place in temperatures between −30° C. and +50° C., preferably between −10 and +30° C., particularly preferably between +10° C. and +25° C.
In this connection, it is possible either to initially introduce both starting compounds (phosphonium salt and aldehyde) in the solvent and to add the base, or else to initially introduce a solution of the phosphonium salt, to add the base and only then to add a solution of the aldehyde.
Bases which can be used are all bases customary for Wittig condensations, e.g. alkali metal hydroxides, such as sodium hydroxide, potassium hydroxide or lithium hydroxide; alkali metal hydrides, such as sodium hydride or potassium hydride.
Also suitable as bases are organolithium compounds, such as, for example, n-butyllithium, tert-butyllithium, phenyllithium or alkali metal amides, such as lithium amide, potassium amide or sodium amide, lithium diisopropylamide and also alkali metal hexamethyldisilazides. Preferred bases used for the Wittig reaction according to the invention are sodium or potassium hexamethyldisilazide, and potassium amide or sodium amide.
The amount of base used is usually in the range from 0.8 to 5 mol, preferably 1 to 3 mol per mole of the phosphonium salt II or IV used.
Suitable solvents for the process step a) are, inter alia, aromatic hydrocarbons, such as toluene, xylene or benzene, cyclic or open-chain ethers, such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,4-dioxane or THF, and DMF or DMSO. Preferred solvents are toluene, THF and/or DMSO.
When conversion is complete, the reaction mixture is hydrolyzed, and the ester formed is removed from the aqueous solution by extraction.
The extractants used are advantageously hexane, heptane or ethyl acetate. It is, however, also possible to use all other water-immiscible organic solvents, such as ethers, aliphatic hydrocarbons, halogenated and aromatic hydrocarbons, for the extraction.
The solvents, in particular the DMF or DMSO, remain largely in the aqueous phase during this extraction and also retain the triphenylphosphine oxide, formed in the Wittig reaction, largely in the aqueous phase.
The process according to the invention is notable for the fact that the Wittig reaction in process step a) takes place with a Z/E selectivity greater than 90/10, preferably with a Z/E selectivity between 92/8 and 99/1, particularly preferably between 94/6 and 97/3.
The saponification in process step b) is usually carried out by initially introducing the cis-6-hexadecenoic

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