Convenient large-scale synthesis of D-glucaro-1,4:6,3-dilactone

Article abstract of DOI:10.1021/jo9015985

(Chemical Equation Presented) Calcium D-glucarate was converted into D-glucaro-1,4:6,3-dilactone on 32-g, 1-kg, and 22-kg scale, using azeotropic distillation with methyl isobutyl ketone to drive the dehydration. The crystalline product was g99.5% pure by

Full text of DOI:10.1021/jo9015985

pubs.acs.org/joc
acylating agents and cross-linkers because they are more
Convenient Large-Scale Synthesis of
D-Glucaro-1,4:6,3-dilactone
reactive than the corresponding diesters and because they
generate no byproduct when forming new ester or amide
1
0,11
bonds. Unlike mixtures of lactone esters,
aldarodilac-
Troy C. Gehret, A. Stephen Frobese, James S. Zerbe, and
H. Keith Chenault*
tones such as 1,4:6,3-mannarodilactone and 1,4:6,3-glucaro-
dilactone (1) are crystalline solids that can be stored
indefinitely at room temperature and dispensed in known
stoichiometric amounts.
Central Research & Development, E. I. DuPont de Nemours &
Co., Experimental Station, Wilmington, Delaware 19880
We sought a method to convert commercially available
calcium D-glucarate into 1 on a large scale. In contrast to the
h-keith.chenault@usa.dupont.com
Received July 23, 2009
2
b,4b,6,8a,12,13
relative ease of formation of mannarodilactone,
the synthesis of 1 is somewhat difficult, requiring the heating
1
0,13,14
of a molten solid under vacuum
or repeated azeotrop-
2
ing from dioxane. While these methods are satisfactory for
laboratory-scale synthesis, the need for high vacuum, the
need for high surface area and efficient heat transfer within a
molten solid, difficulties in product recovery from large-scale
equipment, and concern over the use of dioxane precluded
their scale-up. In the end, we developed a method consisting
of acidification of calcium D-glucarate in aqueous acetone,
addition of methyl isobutyl ketone (MiBK, 4-methyl-2-
pentanone), distillation of the acetone and azeotropic re-
moval of water, and crystallization of 1 from the reaction
mixture upon cooling (Scheme 1). Each element of this
procedure is important to providing 1 in high yield and high
purity.
Calcium D-glucarate was converted into D-glucaro-
1
azeotropic distillation with methyl isobutyl ketone to
drive the dehydration. The crystalline product was
g99.5% pure by GC and NMR, and overall yield was
as high as 72%.
,4:6,3-dilactone on 32-g, 1-kg, and 22-kg scale, using
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DOI: 10.1021/jo9015985
r 2009 American Chemical Society
Published on Web 09/24/2009
J. Org. Chem. 2009, 74, 8373–8376 8373

Gehret et al.
JOCNote
SCHEME 1. Synthesis of 1
For the dehydration step, we initially examined carefully
the heating of a molten mixture of D-glucaric acid and its
monolactones under vacuum. This method was found to
suffer not only from incomplete conversion but also from the
1
3,14
generation of L-threo- and L-erythro-4-deoxyhex-4-enaro-
6
1
,3-lactones 5 and 6 (Table 2), presumably by thermal
5
elimination of 1 (Scheme 2). The product, 1, was obtained as
a brown, glassy solid.
We also investigated sparging with dry nitrogen as an
alternate method of driving the dehydration without incur-
ring significant thermal decomposition of reactants or pro-
duct. Acidification of calcium D-glucarate tetrahydrate with
sulfuric acid in 9:1 v/v acetone-water, followed by filtration
and removal of acetone under reduced pressure, gave a
concentrated aqueous solution (about 67% w/w solids)
containing an approximately 37:30:30:3 mol ratio of 2, 3,
4
, and 1. This mixture was sparged with dry nitrogen and
then heated at 110-130 °C with stirring and continued
sparging for 2.5-3.5 h. The brown, glassy product
(
(
90-94% yield, 93-95% 1) contained trace impurities of 3
3-4%), 4 and 5 (0-1%), and an unknown (0-2%, Table 2).
We examined several acids for the acidification of calcium
D-glucarate. Key to success was the essentially quantitative
precipitation of calcium salt byproduct while keeping glu-
caric acid and its monolactones in solution. Oxalic acid was
the preferred acid for acidifying calcium D-glucarate in water
since the solubility of calcium oxalate is only about 50 μM.
However, oxalic acid is more expensive than common miner-
al acids. Hydrofluoric acid was also used satisfactorily to
acidify calcium glucarate in water and in 9:1 (v/v) acetone-
water. However, hydrofluoric acid poses significant safety
risks and is even more expensive than oxalic acid. Further-
more, the byproduct, calcium fluoride, is somewhat soluble
in water (0.2-0.3 mM).
Sulfuric acid proved to be the most convenient and
economical acid to use for the acidification, even though
calcium sulfate is appreciably soluble in water (10-20 mM).
When the acidification was performed in water alone, 2% or
more of the calcium sulfate remained in the filtrate with
the organic product, requiring evaporation of water, disso-
lution of the turbid, syrupy residue in an organic solvent,
and filtration to remove the residual calcium sulfate. Thus, to
drive the precipitation of calcium sulfate to completion, the
acidification was conducted in aqueous acetone. The water-
miscible, organic cosolvent had the additional benefit
of enriching the intermediate product mixture in 1 and
minimizing the amount of water to be removed during the
dehydration step (Table 1). The presence of some water,
however, was necessary to facilitate proton transfer and
to keep the more polar D-glucaric acid and its monolactones
in solution. If the acidification was performed in neat
acetone, product yield was reduced by 10-20% because of
precipitation of glucaric acid and its monolactones with
the calcium sulfate. At least 50% (v/v) acetone was necessary
to maximize precipitation of calcium sulfate, and at
least 2.5-5.0% water was necessary to facilitate proton
exchange and maintain solubility of all of the glucaric acid
species. While 9:1 acetone-water maximized the yield of
total glucaric acid species in solution after 17 h at
room temperature or 2-4 h at reflux, a bit less water
Crystallization from methyl ethyl ketone-toluene gave 1 of
99.0% purity in 71% overall yield.
A key feature of this synthesis was its use of a mixture of
glucaric acid and monolactones as the substrate for dehy-
dration. As water was removed, melting point depression
allowed the mixture of compounds to remain a syrup even at
room temperature. Syntheses of 1 with a pure monolactone
or monolactone ester starting material melting from 98 to
165 °C require heating to a much higher initial temperature
to melt the substrate and effect dehydration. Crystallization
of 1 during the synthesis was slow enough that it often failed
to solidify, even if it was formed at 80 °C.
The sparging process was quite sensitive to the flow
rate and efficiency of gas dispersion. Increasing the
flow rate from moderate to vigorous reduced the reaction
half-life at 130 °C from approximately 45 min to about
16 min. At 100-g scale, if run at 110 or 120 °C, however,
the reaction mixture did occasionally solidify, risking da-
mage to the stirrer or reaction vessel. When the reaction was
run at 130 °C for 3 h, increased levels of elimination products
(7%) and color were formed. In practice, it was difficult
to find the precise end point where consumption of 3
was maximized and formation of elimination products was
minimized.
Key to discovering the current azeotropic method was the
observation that recrystallizing crude 1 from MiBK gener-
ated a higher level of 1 in both the crystallized solid and
the mother liquor than was present initially. Although a
number of solvents were screened, including propyl acetate
(bp 102 °C), diethyl ketone (bp 102 °C), cyclopentanone
(bp 131 °C), cyclohexanone (bp 155 °C), glyme (bp 85 °C),
dioxane (bp 102 °C), 1,2-diethoxyethane (bp 121 °C), and
diglyme (bp 162 °C), MiBK (bp 118 °C) was unique in its
ability to keep all of the various glucaric acid species in
solution, facilitate azeotropic removal of water, minimize the
formation of elimination products, and allow the crystal-
lization of 1 in reasonable yield, purity, and color upon
(15) (a) Heslop, D.; Smith, F. J. Chem. Soc. 1944, 577–584. (b) Heslop,
(
2.5-5.0%) gave better overall yield of 1 after the dehydra-
D.; Smith, F. J. Chem. Soc. 1944, 637–642. (c) Palmer, D. R. J.; Gerlt, J. A.
J. Am. Chem. Soc. 1996, 118, 10323–10324.
tion (vide infra).
8
374 J. Org. Chem. Vol. 74, No. 21, 2009

Gehret et al.
JOCNote
TABLE 1. Acidification of Calcium D-Glucarate Tetrahydrate
b
composition (mol %)
a
solvent, acetone:water
:100
temp
time (h)
yield (%)
1
2
3
4
0
ambient
ambient
ambient
ambient
ambient
reflux
reflux
reflux
reflux
1
72
17
17
17
17
4
1
2
4
100
98
91
100
81
87
96
12
18
26
30
68
52
54
45
15
25
8
12
5
0
3
1
2
14
31
33
32
27
14
24
19
23
32
32
41
30
38
18
21
26
30
39
7
8
9
0:30
0:20
0:10
1
1
00:0
00:0
9
9
9
0:10
0:10
0:10
99
100
a
b
13
Isolated yield. Determined by H or C NMR after acidification with 1 mol equiv of sulfuric acid and removal of solvent at 20-40 °C.
a
TABLE 2. Scouting Synthesis of 1 by Various Methods
c
product composition (mol %)
b
method
temp (°C)
time (h)
scale (mol)
yield (%)
1
3
4
5
6
vacuum melt
vacuum melt
vacuum melt
sparging
90
95
3.0
2.25
1.0
3.0
3.5
2.5
-
0.05
0.05
0.05
0.50
0.50
0.156
0.10
0.10
0.10
87
87
76
91
90
94
50
62
71
97.0
94.7
0.0
0.0
0
0.0
0.0
0.0
0.2
0.1
0.1
1.5
4.3
0
2.1
0.2
3.4
0.2
0.1
0.1
1.1
0.7
14
0.4
0.3
1.1
0.1
0.1
0.0
0.4
0.3
6
0.0
0.0
0.5
0.0
0.0
0.0
d
130
110
120
130
120
120
120
59
e
f
94.0
94.7
93.2
99.5
99.7
99.5
sparging
sparging
azeotroping
azeotroping
azeotroping
g
h
i
-
j
k
-
a
Calcium D-glucarate tetrahydrate (1 M in 9:1 v/v acetone:water) was acidified with 1 mol equiv of sulfuric acid at ambient temperature for 2-6 h,
filtered, and (a) stripped of solvent by rotary evaporation before being heated at 1 Torr (vacuum melt), (b) concentrated under reduced pressure to
remove acetone before being heated and sparged with nitrogen (sparging), or (c) diluted with 1 volume of acetone-water and 2.5 volumes of MiBK
b
c
1
d
before being concentrated by distillation (azeotroping). Isolated yield. Determined by H NMR. Product also contained 20% of an unknown and 1%
e
of 3-hydroxy-2H-pyran-2-one. Product also contained 3.5% of unknown impurities. Product also contained 4.8% of unknown impurities. Product
f
g
h
also contained 1.8% of unknown impurities. Acidification of calcium D-glucarate was conducted at reflux for 3 h. Calcium D-glucarate was acidified in
i
j
k
5:5 v/v acetone:water at reflux for 4 h. Calcium D-glucarate was acidified in 97.5:2.5 v/v acetone:water at reflux for 4 h. Product also contained 0.3% of
9
an unknown impurity.
SCHEME 2. Thermal Decomposition of 1
where it tended to decompose thermally and reduce the
overall yield of 1. Thus, a mixture of MiBK and acetone
was required to keep all of the glucaric acid species homo-
geneous in solution.
However, when MiBK was added to a mixture of glucaric
acid and its monolactones in 9:1 acetone-water (produced
by the acidification described above), an aqueous layer in
which the polar glucarate compounds dissolved selectively
phase-separated. As water was removed azeotropically, the
glucarate species in the aqueous phase failed to return to bulk
solution and were lost as a dark syrupy deposit on the walls
of the reaction vessel. Thus, although a certain amount of
water was advantageous to maximize the yield of the acidi-
fication step, it became problematic in the azeotropic dehy-
dration step conducted with MiBK and was therefore kept at
a minimum. We examined the ability of quaternary solvent
systems (adding an additional organic cosolvent to
MiBK-acetone-water) and an extensive range of surfac-
cooling of the reaction mixture. Somewhat surprisingly, the
use of MiBK also resulted in essentially no acetal formation
as the dehydration proceeded.
As the azeotropic synthesis of 1 with MiBK was opti-
mized, several facts came to light. First, the yield of 1 was
maximized by maintaining all of the glucaric acid species
homogeneous in solution during the course of acidification
and azeotropic dehydration. Because D-glucaric acid and its
monolactones are poorly soluble in MiBK, operating in neat
MiBK was unfeasible. Conducting the initial acidification of
calcium D-glucarate in neat MiBK resulted in about 70% of
the glucarate species being lost as a deposit on the precipi-
tated calcium sulfate. Even at dilute initial concentrations,
glucaric acid and monolactones separated from solution,
pulling 1 out with them. Upon heating, the syrupy deposit of
glucarate species remained stuck to the walls of the flask,
1
6
tants to maintain a single liquid phase throughout the
reaction, all without success.
In practice, the best overall yields of highly pure GDL
were obtained by removing the solvent in two steps, cooling
the mixture, and collecting a crop of crystalline GDL after
each distillation. The mother liquor could ultimately be
recycled to maximize the yield if the process was practiced
repeatedly.
(16) PEG, PEG-PPG random copolymers, Pluronics, sorbitan esters,
Tween and Brij surfactants, SDS, and tetraalkylammonium salts.
J. Org. Chem. Vol. 74, No. 21, 2009 8375

Gehret et al.
JOCNote
Experimental Section
with stirring under a blanket of dry nitrogen. The solution was
seeded with 0.5-0.6 g of 1 and cooled to room temperature.
Once the mixture had reached room temperature, crystallization
was allowed to continue for 2-3 h or overnight. The white,
crystalline 1 was collected by filtration, rinsed with one 750-mL
portion of MiBK, and dried under a stream of nitrogen and then
Synthesis of 1 (1-kg scale). Sulfuric acid (312.5 g, 3.122 mol)
was added over a period of 30 min to a stirred suspension of
calcium D-glucarate tetrahydrate (1000 g, 3.122 mol) in 3.1 L of
9
5:5 (v/v) acetone-water. The stirred mixture was heated at
reflux for 4 h, cooled to room temperature, stirred at room
temperature for 1-2 h, and then filtered with suction to remove
the precipitated calcium sulfate. At no time did the reaction
become homogeneous. The precipitate was washed three times
with 1.0 L of 95:5 acetone-water.
1
under vacuum: yield 250-270 g (46-50%), purity 99.5% by H
NMR, 99.8% by GC.
The mother liquor from the first crystallization (about 4.7 L)
was further concentrated to 1.9 L by distillation. The concen-
trated mother liquor was filtered hot, cooled with stirring under
a blanket of dry nitrogen as before, and seeded with 0.3 g of 1.
Once the mixture had reached room temperature, crystallization
was allowed to continue for 2-3 h or overnight. The white,
crystalline 1 was collected by filtration, rinsed with one 375-mL
portion of MiBK, and dried under a stream of nitrogen and then
Since some of the acetone was lost by evaporation during
filtration, the filtrate and washings were combined and adjusted
to 6.2 L by addition of acetone (about 1.6 L). MiBK (6.75 L)
was added to the solution, which was stirred and heated (pot
6
5-95 °C) so as to remove 6.2 L of acetone containing some
water and MiBK by fractional distillation (still head 56-85 °C).
Distillation continued until the pot temperature reached
1
under vacuum: yield 125 g (23%), purity 99.6% by H NMR,
9
9.9% by GC.
1
15-119 °C, at which point distillation was discontinued, and
the reaction was heated at reflux for 30 min. Then, distillation
was resumed until a total of 8.56 L had been removed from the
original reaction volume.
Supporting Information Available: General experimental
methods, synthesis of 1 by sparging with nitrogen (160-g scale)
1
and by azeotroping with MiBK (22-kg scale), and H and
13
The reaction mixture was filtered hot to separate the solution
from about 30 g of a brown oil that adhered to the surface of the
glass reaction vessel. The reaction filtrate was allowed to cool
C
NMR data for all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
8
376 J. Org. Chem. Vol. 74, No. 21, 2009