A short and productive synthesis of racemic α-lipoic acid

Article abstract of DOI:10.1515/znb-1999-0513

Racemic α-lipoic acid is synthesized in four steps from the base chemicals vinyl ethyl ether and cyclohexanone. The total yield is 40%.

Full text of DOI:10.1515/znb-1999-0513

A Short and Productive Synthesis of Racemic a-Lipoic Acid
Friedhelm Balkenhohl, Joachim Paust*
Main Laboratory of BASF AG, D-67056 Ludwigshafen, Germany
Z. Naturforsch. 54b, 649-654 (1999); received December 4, 1999
Lipoic Acid, Radical Induced C-C-Bond Formation, Baeyer-Villiger Oxidation,
Ether Cleavage, Isothiuronium Salts
Racemic a-lipoic acid is synthesized in four steps from the base chemicals vinyl ethyl ether
and cyclohexanone. The total yield is 40%.
Results and Discussion
which carry functional groups in positions 1 , 6 and
8 , Scheme 2 [5].
Biochemistry
(I) Friedel-Crafts addition of adipic acid
monoester chloride to ethylene yields the unsatu-
rated keto ester 2 after spontaneous elimination
of hydrogen chloride.
(II) Prins reaction of terminal C7-olefins affords
1,3-dioxane derivatives 3.
a-Lipoic acid is involved in central biochemical
processes as a protein-bound coenzyme [1]. It oc-
curs, for example, as a cofactor of multienzyme
complexes which control energy-producing pro-
cesses such as aerobic glycolysis and photosynthe-
sis. Scheme 1 shows the biochemical role of lipoic
acid in the oxidative decarboxylation of pyruvic
acid.
(III) Baeyer-Villiger oxidation of 2-substituted
cyclohexanones 4 leads to the caprolactones 5.
In addition to the routes (I)-(III), specific pro-
cesses have also been developed for the prepara-
tion of 1, 6 , 8 -functional intermediates [5],
The introduction of sulfur groups into the inter-
mediates 2, 3 and 5 is carried out either directly
by heating with hydrohalic acids and thiourae [6 ]
or in two steps via 6 ,8 -dihalides or -disulfonates
and reaction with sulfur nucleophiles [7],
Industrial syntheses of racemic a-lipoic acid are
based mainly on the Friedel-Crafts route (I). Our
process follows the Baeyer-Villiger strategy (III),
however. It is different from the variants known
from the literature [5, 8 ], in particular in the first
two steps, Scheme 3 [9].
2-(2'-Ethoxyethyl)cyclohexanone (4, Rj = Et) is
synthesized in one stage from the base chemicals
vinyl ethyl ether and cyclohexanone. Di-terf-butyl
peroxide is particularly suitable as a catalyst. The
reaction is carried out in excess cyclohexanone as
a solvent, which can be recovered and recycled
during the distillative isolation of 4. 2-(2'-Acetoxy-
ethyl)cyclohexanone (4, R.! = AC) is analogously
formed from vinyl acetate and cyclohexanone in
35% yield.
Use
Patients who suffer form diabetes mellitus or
the consequences of alcohol abuse have reduced
lipoic acid levels. Thus, the supply of the nerve
cells with ATP is no longer guaranteed and neuro-
logical complications generally occur. The admin-
istration of lipoic acid has therefore proven suit-
able, in particular as a therapy in diabetic and
alcoholic polyneuropathy [2 ],
Together with other biological antioxidants, di-
hydrolipoic acid has a membrane-stabilizing action
and can prevent, for example, oxidative damage in
the case of reperfusion after by-pass operations
[3]-
Synthesis
After the isolation and structural elucidation [4]
of a-lipoic acid, numerous syntheses were pub-
lished in patent specifications and the scientific lit-
erature. They can be divided into three categories
with respect to the preparation of C8 precursors
The subsequent Baeyer-Villiger oxidation can
be carried out, for example, using performic acid
which is generated in situ from formic acid and
30% aqueous hydrogen peroxide [10]. Before the
* Reprint requests to Dr. J. Paust.
0932-0776/99/0500-0649 $06.00 © 1999 Verlag der Zeitschrift für Naturforschung, Tübingen • www.znaturforsch.com
N
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F. Balkenhohl-J. Paust • A Short and Productive Synthesis of Racemic «-Lipoic Acid
Protein
Protein
Scheme 1: Lipoic acid as a cofactor of the
pyruvate dehydrogenase multienzyme
comlex.
R = 3-[(4’-Amino-2’-methyl-5’-pyrimidin) methyl]-
distillative work-up, excess oxidant is decomposed is heated with concentrated hydrohalic acid in the
to carbon dioxide and water at 90 °C. Here also, presence of thiourea [6 ]. 62% hydrobromic acid
the formic acid employed in excess as a solvent has proven particularly suitable in this context.
can be removed as a water azeotrope and recycled. Hydrolysis of the initially formed 6 ,8 -bis-isothi-
uronium bromide with potassium hydroxide yields
8 -Ethoxy-6 -formyloxyoctanoic acid (6 ) is obtained
as the main product of this variant of the Baeyer- 7. In addition, the 5,8-dithiol results in a small
Villiger oxidation, accompanied by small amounts amount as a result of a rearrangement. Pure dihy-
of the 6 -hydroxy compound, of the corresponding drolipoic acid (7) is obtained by reduction of 1
lactone and of a dimeric formyloxy ester. The mix-
ture of these components can be used directly for
with sodium borohydride.
Dehydrogenation of 7 with oxygen and catalytic
the further reaction to give dihydrolipoic acid (7). amounts of iron(III) chloride yields crude 1, which
is separated from oligomeric disulfides by con-
tinuous vacuum distillation. Small amounts of the
To introduce sulfur into positions 6 and 8 , the
crude product from the Baeyer-Villiger oxidation
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F. Balkenhohl-J. Paust • A Short and Productive Synthesis of Racemic a-Lipoic Acid
CI
R-iO,
OR
CH2=CH2 [AICI3]
H2C=0 [H ® ]
HOOAcyl
OR
OR
5
OH
s-s
Scheme 2. Classical synthesis of racemic a-lipoic acid.
[tBu-O-O-tBu]
74%
E tO ^ -
1 . HBr/S=C(NH2)2
EtO
2. KOH
<
-----------------
84%
1. H20, pH 9, 0 2, [FeCI3]
2 . distillation
73%
3. crystallization
OH
OH
S -S
Scheme 3. New synthesis of racemic a-lipoic acid.
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F. Balkenhohl-J. Paust ■A Short and Productive Synthesis of Racemic a-Lipoic Acid
ide. The reflux condenser is then exchanged for a
bridge and water and formic acid are distilled off
at a bath temperature of 100 °C by reducing the
pressure. The residue ( 8 8 g) consists to about 90%
of 6 , according to HPLC analysis.
secondary component 8 [1 1 ] are separated off by
crystallization from diisopropyl ether. Based on
cyclohexanone and vinyl ethyl ether, the yield of
R,S-a-lipoic acid (1) is about 40%.
To characterize 6 , 10 g of the crude product is
continuously degassed (130 °C, 0.5 mbar) and dis-
tilled (130 °C, 0.05 mbar) in a film evaporator [12],
9.1 g of distillate with a purity of 97% is obtained,
as - determined by gas chromatography. This cor-
responds to a yield of about 65% for 6 .
‘H NMR (CDCI3 , 250 MHz): d = 1.17 (t, J =
8.3 Hz, 3H, - C //3 ), 2.36 (t, J = 7.9 Hz, 2H,
C //2 - C 0 2H), 3.42 (3H, -C H 2- O -), 5.12 (1H,
- C //- 0 - C H = 0 ) , 8.10 (s, 1H, - 0 - C //= 0 ) . -
13C NMR (DCCI3 ): 6 = 15.06, 24.41, 24.63, 33.82,
33.99,34.23,66.37,66.61,71.80 (> C H -0 -C H = 0 ),
161.08 (- 0 -C H = 0 ), 179.27 ( - C 0 2 H).
Experimental Section
The preparative work was carried out by C. T.
Wolfgang Kriegl, C. L. Markus Niebel and C. L.
Ursula Schäfer.
2-(2'-Ethoxyethyl)cyclohexanone (4, R] = Et):
1140 g (12 mol) of cyclohexanone are introduced
into a 2 1 glass reactor (stirrer, thermometer, reflux
condenser, two submerged inlets) and heated to
155 °C. When this temperature is reached, 86.4 g
(1 . 2 mol) of vinyl ethyl ether and a solution of
35 g (0.24 mol) of di-ter/-butyl peroxide in 51.4 g
of cyclohexanone are added synchronously in the
course of 8 h using two balance-controlled pumps.
During the reaction, the temperature in the reac-
tor falls to about 148 °C. About 1 h after comple-
tion of the addition, the mixture is cooled to
room temperature.
The reflux condenser is exchanged for a packed
column having about two theoretical plates, a vac-
uum of about 25 mbar is applied and about 120
g/h of cyclohexanone is distilled off while slowly
increasing the temperature of the heating jacket
to 130 °C; total amount 1100 g. 220 g of crude pro-
duct is obtained as a residue, which is transferred
to a 500 ml round-bottomed flask and purified by
distillation over a bridge: main run 80-83 °C,
3 mbar; 159 g of 4 (R[ = Et) having a purity of
95% = 74.8% yield, as determined by gas chroma-
tography.
C n H20O5 (232.27)
Calcd
C 56.88 H 8.67%
Found C 57.00 H8.90%.
6-R,S-Dihydrolipoic acid (7): 274 g (2.1 mol) of
62 percent hydrobromic acid, 182.4 g (2.4 mol) of
thiourea and 72 g of crude product from the
Baeyer-Villiger oxidation (about 0.3 mol of useful
product) are introduced into a
1
1 glass reactor
(stirrer, thermometer, reflux condenser). The mix-
ture is refluxed for 2 0 h (internal temperature
116 °C).
960 g ( 6 mol) of 35 percent aqueous potassium
hydroxide solution is introduced into a
2
1 glass
reactor (stirrer, thermometer, reflux condenser,
gas inlet tube) and heated to boiling. The solution
of the bisisothiuronium bromide is allowed to flow
from reactor 1 into reactor 2 in the course of about
0.5 h and is refluxed for a further 3 h. During this
phase, heating is carried out with extensive exclu-
sion of light and a gentle stream of nitrogen is
passed through the reaction mixture. The volatile
constituents (ethyl mercaptan, ammonia, carbon
dioxide) are absorbed in a scrubber filled with so-
'H NMR (CDC13, 250 MHz): <3 1.15 (t, J = 7.6
Hz, 3H, -C H 3), 2.34 (2H, -C //2 -C O -), 2.48
(1H, > C //-C O -), 3.41 (m, 4H, -C H 2- O -).
C10H 16 O2 (168.23)
Calcd. C 71.40 H 9.59%,
Found C 71.50 H 9.70%.
8-Ethoxy-6-formyloxyoctanoic acid (6 ). 70.7 g dium hydroxide solution and sodium hypochlo-
(0.4 mol) of 4 (R] = Et) is dissolved in 276 g rite solution.
( 6 mol) of formic acid in a 1 1 glass reactor (stirrer,
thermometer, reflux condenser, dropping funnel) temperature, acidified to pH 1 with conc. hydro-
and treated with 6 8 g (0.6 mol) of 30% aqueous
The reactor contents are then cooled to room
chloric acid (about 320 ml) and the crude dihy-
hydrogen peroxide in the course of abouth 0.4 h. drolipoic acid (7) is isolated by extracting three
The internal temperature is kept at 45 ± 5 °C dur- times with 400 ml each of methyl tert-butyl ether.
ing this time; the evolution of heat is particularly After the evaporation of the MTB solution, 7 is
high at the start of the reaction. After addition of obtained as a pale yellow oil (65.5 g). For determi-
nation of the yield and characterization, 1 0 g of
the oxidant, the mixture is stirred at 45 °C for 1 h.
To work up the reaction, the mixture is heated the crude product is separated from solvent resi-
to 100 °C in approximately 1 h, excess performic
acid decomposing with evolution of carbon diox-
dues and nonvolatile constituents by continuous
distillation in a film evaporator [12] (150 °C,
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F. Balkenhohl-J. Paust • A Short and Productive Synthesis of Racemic ot-Lipoic Acid
653
0.1 mbar). Distillate 8.4 g, purity according to GC:
The distillate is dissolved in 250 ml of diisopro-
90% 6 , 5% a-lipoic acid 1; yield 7 + 1 about 84%. pyl ether at 55 °C. The solution is filtered through
R,S-Dihydrolipoic acid (7) by hydrogenation of 10 g of silica gel, cooled to 15 °C and seeded; after
R,S-a-lipoic acid (1): A solution of 51.5 g (0.25 a few minutes crystallization starts. After about
mol) of 1, m.p. 60-61 °C and 21 g (0.25 mol) of 15 min, the mixture is cooled to -15 °C, the pro-
sodium bicarbonate in
1
1 of water is treated in duct is isolated after 30 min by filtering off with
portions with 12.8 g (0.32 mol) of 85% sodium suction, and the crystals washed with 40 ml of cold
borohydride in the course of 0.5 h while cooling diisopropyl ether and dried at room temperature
with an ice bath. The raction can be monitored
in a stream of nitrogen; 32.2 g, m.p. 57-59 °C, pu-
by thin-layer chromatography (cover the acidified rity according to GC 96%, 3% side product
8
sample with a layer of ethyl acetate; silica gel, (Hewlett-Packard 5880, 30
m DB 5, 1 0 0 ^
eluent ethyl acetate/rc-Hex = 2/1).
250 °C).
Stirring is continued at 5 °C for 0.5 h and the
disired product is taken up in ethyl acetate after
A further crystallization from diisopropyl ether
yields 30.1 g of pure 1, m.p. 60-61 °C, GC purity
acidifying to pH 1 with conc. hydrochlorid acid. 99%, 0.3% side product 8 .
After concentration in a rotary evaporator, 50.4 g
of crude product 7 is obtained, which is purified
by distillation as described above: 47.3 g (91%) of S -C H -C //2 -C H 2 -S), 2.37 (t,
]H NMR (CDCI3, 360 MHz): (3 = 1.50 (2H,
C //2), 1.68 (4H, 2 CH2), 1.92 and 2.46 (1H + 1H,
3.6 Hz,
J =
7, colorless oil, purity according to GC 99.1%.
C //2 -C O ,H ), 3.14 (2H, CH->-S), 3.57 (1H,
C H -S). - 13C NMR (CDCI3): 24.34, 28.60, 33.84,
!H NMR (CDC13, 400 MHz): d = 1.34 (d, J =
10 Hz, 1H, > C H -S //), 1.41 (t, J =
8
Hz, 1H, 34.53, 38.48, 40.19, 56.25, 180.13.
-C H 2 -S //), 2.37 (t, J = 5.5 Hz, -C H 2- C 0 ?H),
2.70 (m, 2H, -C //2 -SH ), 2.90 (m, 1H,
> C H -SH). - 13C NMR (CDC13): (3= 22.25, 24.21,
26.39, 33.89, 38.61, 39.23, 42.68, 48.47, 56.22,
180.12.
C8H 140 2S2 (206.33)
Calcd
C 46.57 H 6.84 S 31.08%,
Found C 46.72 H 6 . 6 8 S 31.18%.
The by-product 8 was identified by GC compari-
son with a preparation synthesized according to
literature details [1 0 ].
5,8-Dimercaptooctanoic acid: 'H NMR (CDCI3 ,
400 MHz): <3 = 1.40 (2H, SH), 1.57 (2H), 1.62-
1.90 (4H), 2.40 (t, J = 5.5 Hz, 2H, CH2 - C 0 2H),
2.57 (2H, CH2 -SH ), 2.79 (H, C H -SH). - 13C
NMR (CDCI3 ): (3 = 22.17, 24.33, 31.33, 33.66,
33.66, 37.48, 38.26, 40.26, 179.65.
C8H 160 2S2 (208.35)
Calcd
C 46.12 H 7.75 S 30.78%,
Found C 46.27 H 7.55 S 30.90%.
R,S-a-Lipoic acid (1): 1700 ml of water and 52 g
(about 0.2 mol) of crude dihydrolipoic acid (7) are
introduced into a 3 1glass reactor (aerating stirrer,
pH probe, dropping funnel, waste gas tube) and
treated with 2 N sodium hydroxide solution at
room temperatur to pH 8 . 8 (about 130 ml = 0.24
mol). 1.2 ml of 10 percent iron (III) chloride solu-
tion is added and the mixture is gassed with air
until the color changes from black-gray to yellow
(about 2 1/min, 2.5 h). The pH rises in the course
of this to about 11.5.
After addition of 200 ml of dichloromethane,
the mixture is adjusted to pH 1 with concentrated
hydrochloric acid. The phases are separated, the
aqueous phase is extracted with a further 1 0 0 ml
of dichloromethane, the dichloromethane solu-
tions are concentrated and the crude product is
C8H 160 2S2 (208.35)
Calcd
C 46.12 H 7.75 S 30.78%,
Found C 46.30 H7.51 S 30.90%.
C8H 160 2S2 (208.35)
Calcd
C 46.12 H 7.75 S 30.78%
Found C 46.30 H 7.51 S 30.91%.
4-(l,2-Dithian-3-yl)butyric acid (8 ): 'H NMR
(CDCI3, 400 MHz): (3 = 1.50-1.76 (4H), 1.83
(2H), 2.10 (2H), 2.40 (t, J = 5.5 Hz, 2H,
C //2 -COoH), 2.70-2.93 (3H, C H j-S).
NMR (CDCI3): (3 = 21.86, 27.63, 32.97, 33.68,
-
13C
34.28, 34.56, 45.85, 179.78.
purified by continuous distillation in a film evapo- C8H 14 0 7S2 (206.33)
rator at 150 °C, 0.05 mbar; distillate 41.6 g, residue
Calcd. C 46.57 H 6.84 S 31.08%,
Found C 46.42 H 6.80 S 31.08%.
7 a.
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