Note: Descriptions are shown in the official language in which they were submitted.
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TITLE
SYNTHESIS OF ALDONOLACTONES, ALDAROLACTONES, AND
ALDARODILACTONES USING AZEOTROPIC DISTILLATION
FIELD OF INVENTION
This invention is directed to processes for producing lactones or
dilactones from aldonic acids, aldaric acids or aidarolactones, or salts
thereof. The processes include dehydratively cyclizing a reaction mixture
comprising a 5- to 8-carbon aidonic acid, 5- to 8-carbon aidaric acid or 5-
to 8-carbon aldarolactone, or mixture thereof, in a solvent mixture, and
removing water by azeotropic distillation.
BACKGROUND
Lactones and dilactones derived ultimately from renewable
carbohydrate resources are highly functionalized monomers that are
useful as synthetic intermediates, chiral starting materials, enzyme
inhibitors, and monomers for polymer synthesis.
Aldaric acids and aldonic acids are oxidized derivatives of aldose
carbohydrates. When only the aldehyde of an aidose is oxidized, an
aidonic acid is formed. If both the aldehyde and terminal alcohol of an
aldose are oxidized, an aldaric acid is formed. Lactones and dilactones
can be produced from these acids via dehydrative cyclization, typically by
heating the parent aidonic or aidaric acid under vacuum (Hirasaka, Y.;
Umemoto, K. Chem. Pharm. Bull. 1965, 13, 325-329). Recent
publications and patents demonstrate that this technology has not
changed for many years (U.S. Patent No. 6,049,004). Even with heating
under vacuum, conversion to the desired lactone is often incomplete
(Conchie, J.; Hay, A. J.; Strachan, I.; Levvy, G. A. Biochem. J. 1967, 102,
929-941), requiring purification of the desired lactone by recrystallization
(lsbell, H. S.; Frush, H. L. Bur. Standards J. Research 1933, 11, 649-664)
or column chromatography. Furthermore, heating under vacuum often
generates impurities due to thermal decomposition.
Hashimoto, et al. (Hashimoto, K.; et al., Makromol. Chem., Rapid
Commun. 1990, 11, 393-396) disclose the synthesis of D-glucaro-1,4:6,3-
dilactone by repeated lyophilization of glucaric acid from dioxane.
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Although synthesis of an aldonolactone using an alcohol to effect
azeotropic removal of water has been described (U.S. Patent No.
1,830,618), the method suffers from the formation esters as by-products.
While known processes may be acceptable for generating grams to tens
of grams of material, they can be impractical for preparing tens to
thousands of pounds of material. High vacuum, long residence time, and
the high substrate surface area required by the solvent-free method are all
impediments to practicing these methods on large scale.
What is needed, therefore, is a process that can be effectively
carried out on a larger scale than previously reported methods, and that
will also generate lower quantities of decomposition by-products.
SUMMARY OF THE INVENTION
The present invention provides processes for preparing lactones or
dilactones comprising the dehydrative cyclization of a reaction mixture
comprising a 5- to 8-carbon aldonic acid, 5- to 8-carbon aidaric acid or 5-
to 8-carbon aldarolactone, or mixture thereof, in a solvent mixture
comprising one or more suitable solvents, wherein water is removed by
azeotropic distillation.
One aspect of the present invention is a process for preparing a
lactone or dilactone comprising:
a) providing a reaction mixture comprising:
i) a solvent mixture comprising about 0 to about 50
volume % of water and about 100 to about 50 volume
% of a suitable solvent, based on the total volume of
the solvent mixture; and
ii) a starting material comprising one or more compounds
selected from 5- to 8-carbon aldonic acids, 5- to 8-
carbon aldaric acids, and 5- to 8-carbon aidarolactones;
and
b) heating the reaction mixture to effect dehydrative cyclization of the
compound in the starting material and removal of water by
azeotropic distillation.
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In some embodiments, the suitable solvent comprises an ether,
ketone, or ester having a boiling point of about 80 to about 150 C, that
forms an azeotrope with water, the azeotrope having a boiling point below
that of water and below that of the suitable solvent. Preferably the
suitable solvent has a boiling point of about 100 to about 120 C. In
preferred embodiments, the solvent is methyl ethyl ketone, methyl isobutyl
ketone, 3-pentanone, cyclopentanone, dioxane, ethylene glycol diethyl
ether or propyl acetate. Also preferably, the lactone or dilactone is soluble
in the suitable solvent above about 25 C and precipitates at or below 25
C. The solvent mixture can further comprise water or acetone.
In some embodiments, the reaction mixture comprises an
equilibrium mixture of an aldaric acid and one or more of the
corresponding aidarolactone or aidarodilactone, or an equilibrium mixture
of an aldonic acid and the corresponding aldonolactone. In some
embodiments the aldaric acid is glucaric acid. In some embodiments, the
aidonic acid is gluconic acid.
In some embodiments, the aldonic acid, aidaric acid or
aldarolactone contains one or more protected hydroxyl groups. The
hydroxyl groups can be protected as ethers, acetals, carboxylic esters, or
sulfonate esters.
In some embodiments, the 5- to 8-carbon aldonic acid, 5- to 8-
carbon aldaric acid or 5- to 8-carbon aldarolactone is D, L, racemic or a
nonracemic mixture in its enantiomeric configuration. The reaction
mixture can also comprise an aldaric acid that has a plane of symmetry
and thus exists in only a meso configuration.
In some embodiments, the aidonic acid, aldaric acid or
aldarolactone is generated in situ from the corresponding Group I, Group
II, or ammonium salt, or mixture thereof by acidification. The salt can be a
sodium, potassium, lithium, cesium, magnesium, calcium, or ammonium
salt, and the acid can be sulfuric acid, HCI, phosphoric acid, HF, oxalic
acid, trifluoroacetic acid, or an acidic cation exchange resin. Optionally
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any precipitate formed during the generation of the aldonic acid, aldaric
acid or aldarolactone in situ can be removed.
DETAILED DESCRIPTION
The present invention provides processes for the preparation of a
lactone or dilactone by dehydrative cyclization of a 5- to 8-carbon aldonic
acid, 5- to 8-carbon aldaric acid or 5- to 8-carbon aldarolactone, or mixture
thereof, in a solvent mixture, where the solvent mixture comprises one or
more of a suitable solvent, wherein water is removed by azeotropic
distillation.
The reaction mixture can comprise, for example, gluconic,
mannonic, galactonic, idonic, allonic, altronic, gulonic, talonic, ribonic,
xylonic, arabinonic, lyxonic, glucaric, mannaric, galactaric, idaric, allaric,
altraric, ribaric, xylaric or arabinaric acid.
As used herein, an aldaric acid is a derivative of an aldose
carbohydrate in which the terminal aldehyde and alcohol groups have
been converted to carboxylic acids. An example of an aldaric acid is the
aidaric acid derived from glucose, glucaric acid: HOOC-(CHOH)4-COOH.
Any aldaric acid that can form a lactone or dilactone is suitable for the
instant invention, as described below. The aidaric acid can be in any
enantiomeric form. Aldaric acid starting materials include but are not
limited to glucaric (= gularic), mannaric, galactaric, idaric, allaric,
altraric
talaric), ribaric, xylaric, and arabinaric (= lyxaric) acids. Preferred are
five
to eight carbon aidaric acids; more preferred is glucaric acid; most
preferred is D-glucaric acid.
Six-carbon aldaric acids that can form two cis-fused five-membered
lactones (y-lactones) do so and thus generate dilactone products. The
other six-carbon aidaric acids and the five-carbon aldaric acids form
monolactones as their ultimate lactonization products.
Pictured below are the ultimate products formed when six- and five-
carbon aldaric acids are dehydratively lactonized. In cases where the
starting material is optically active, only one enantiomeric product is
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pictured. It is understood that the other enantiomeric starting material
would form the enantiomeric product (e.g., L-mannaric acid would give L-
mannaro-1,4:6,3-lactone) and that mixtures of stereoisomers, including
racemates, would form corresponding mixtures of stereoisomeric
products. It is also understood that various salts of the aldaric acids may
be converted into the free acid in situ and then lactonized.
H H H QH QH
O O O O O O
= O
O 0~ - -
HO H HO H HO H
D-glucaro-1,4:6,3-dilactone D-mannaro-1,4:6,3-dilactone D-idaro-1,4:6,3-
dilactone
(= L-gularo-1,4:6,3-dilactone)
O O
HO1'.. ~ HO'.. HO'l.. O HO,P..
C02H C02H OaH Q CO2H
HO pH HO pH H(5 OH HO OH
galactaro-6,3-lactone allaro-6,3-Iactone D-altraro-6,3-Iactone D-talaro-6,3-
lactone
(= D-talaro-1,4-lactone) (= D-altraro-1,4-lactone)
O 0 0 0
HCY- HOll.. q HOO- HO~.. 0
OCO2H C02H OCO2H CO2H
HO H(5 HO HO
ribaro-5,24actone D-arabinaro-5,24actone xylaro-5,2-Iactone D-Iyxaro-5,2-
Iactone
(= D-Iyxaro-1,44actone) (= D-arabinaro-1,4-Iactone)
Because the molecules have carboxyl groups at both ends, there is
potential for numbering from either end (e.g., D-glucaric acid has the same
absolute structure as L-gularic acid, and D-altraro-6,3-lactone has the
same absolute structure as D-talaro-1,4-lactone).
D-Glucaric acid (CAS Reg. No. 87-73-0, = L-gularic acid) gives D-
glucaro-1,4:6,3-dilactone (CAS Reg. No. 826-91-5, = L-gularo-1,4:6,3-
dilactone). L-Glucaric acid (CAS Reg. No. 5627-26-9, = D-gularic acid)
gives L-glucaro-1,4:6,3-dilactone (= D-gularo-1,4:6,3-dilactone).
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D-Mannaric acid (CAS Reg. No. 22076-54-60) gives D-mannaro-
1,4:6,3-dilactone (CAS Reg. No. 2900-01-8). L-Mannaric acid gives L-
mannaro-1,4:6,3-dilactone (CAS Reg. No. 214038-58-1, although this
CAS registry number is incorrectly named L-mannonic acid di-y-lactone).
o-Idaric acid (CAS Reg. No. 33012-63-4) gives D-idaro-1,4:6,3-
dilactone. L-Idaric acid (CAS Reg. No. 80876-58-0) gives L-idaro-1,4:6,3-
dilactone.
Galactaric acid (CAS Reg. No. 526-99-8, meso and thus optically
inactive) gives (racemic) DL-galactaro-6,3-dilactone (= DL-galactaro-1,4-
dilactone).
Allaric acid (CAS Reg. No. 527-00-4, meso and thus optically
inactive) gives (racemic) DL-allaro-6,3-dilactone (= DL-allaro-1,4-dilactone).
D-Altraric acid (CAS Reg. No. 117468-78-7, = D-talaric acid) gives a
mixture of D-altraro-1,4-lactone (CAS Reg. No. 91547-68-1, = D-talaro-6,3-
lactone, although incorrectly named in CAS registry as D-talomucic acid
1,4-lactone) and D-altraro-6,3-lactone (CAS Reg. No. 91547-67-0, = D-
talaro-1,4-Iactone, although incorrectly named in CAS registry as D-
talomucic acid 6,3-lactone). L-Altraric acid (CAS Reg. No. 117468-79-8, _
L-talaric acid) gives a mixture of L-altraro-1,4-Iactone (= L-talaro-6,3-
lactone) and L-altraro-6,3-Iactone (= L-talaro-1,4-lactone).
Ribaric acid (meso, CAS Reg. No. 33012-62-3) gives (racemic) DL-
ribaro-5,2-lactone (CAS Reg. No. 85114-92-7, DL-ribaro-1,4-lactone).
D-Arabinaric acid (CAS Reg. No. 20869-04-9, = D-Iyxaric acid) gives
a mixture of D-arabinaro-1,4-lactone (= D-Iyxaro-5,2-lactone) and D-
arabinaro-5,2-lactone (= D-Iyxaro-1,4-Iactone). L-Arabinaric acid (CAS
Reg. No. 608-54-8, = D-Iyxaric acid) gives a mixture of L-arabinaro-1,4-
lactone (= L-lyxaro-5,2-lactone) and L-arabinaro-5,2-lactone (= L-Iyxaro-
1,4-lactone).
Xylaric acid (meso, CAS Reg. No. 10158-64-2) gives (racemic) DL-
xylaro-5,2-Iactone (= DL-xylaro-1,4-lactone).
An aldonic acid, as used herein, is a derivative of an aldose
carbohydrate in which the terminal aldehyde group has been converted to
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a carboxylic acid. An example of an aldonic acid is the aldonic acid
derived from glucose, gluconic acid: HOOC-(CHOH)4-CH2OH. Any
aldonic acid that can form a lactone is suitable for the instant invention, as
described below. The aidonic acid can be in any enantiomeric form.
Suitable aldonic acids include, but are not limited to, gluconic, mannonic,
galactonic, idonic, allonic, altronic, gulonic, talonic, ribonic, xylonic,
arabinonic, and lyxonic acids. Preferred are 5-8 carbon acids; most
preferred is gluconic acid.
Pictured below are the 12 1,4-lactones (y-lactones) formed by the
8 six-carbon and 4 five-carbon aldonic acids. Because aldonic acids have
only one carboxyl group, they can form only one lactone ring. Some of the
products shown below will be formed in the presence of their
corresponding 1,5-lactone (S-lactone), but the 1,4-lactone is usually the
major product, especially at higher temperatures.
0 0 0 0
HO O HCY, O HO O HG- O
OH OH OH OH
HO OH HO OH HO OH HO OH
D-gi'ucono-1,4-Iactone D-mannono-1,4-iactone D-allono-1,4-Iactone D-altrono-
1,4-Iactone
O O O O
HO O H0- O HO- O HO~- O
~OH OH OH OH
HO OH HO OH HO OH HO OH
D-gulono-1,4-Iactone D-idono-1,4-lactone D-galactono-1,4-lactone D-talono-1,4-
Iactone
O O O
HO O OH Ha- O OH HO- O OH Ha, Q OH
HO HO HO HO
D-ribono-1,4-lactone D-arabinono-1,44actone D-xylono-1,4-Iactone D-lyxono-1,4-
Iactone
As with the aldarolactones above, only one enantiomeric form of
each aldonolactone is pictured. One skilled in the art will recognize that
the other enantiomeric starting material will give the enantiomeric product
and that mixtures of stereoisomers, including racemates, will form
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corresponding mixtures of stereoisomeric products. Salts of the aldonic
acids can be converted into the free acid in situ and then lactonized.
D-Gluconic acid (CAS Reg. No. 526-95-4) gives p-glucono-1,4-
lactone (1198-69-2). L-Gluconic acid (CAS Reg. No. 157663-13-3) gives
L-glucono-1,4-lactone (CAS Reg. No. 74464-44-1).
D-Mannonic acid (CAS Reg. No. 642-99-9) gives D-mannono-1,4-
lactone (CAS Reg. No. 26301-79-1). L-Mannonic acid (CAS Reg. No.
51547-37-6) gives L-mannono-1,4-lactone (CAS Reg. No. 22430-23-5).
D-Allonic acid (CAS Reg. No. 21675-42-3) gives D-allono-1,4-
lactone (CAS Reg. No. 29474-78-0). L-Allonic acid gives L-allono-1,4-
lactone (CAS Reg. No. 78184-43-7).
D-Altronic acid (CAS Reg. No. 22430-69-9) gives D-altrono-1,4-
lactone (CAS Reg. No. 83602-36-2). L-Altronic acid gives L-altrono-1,4-
lactone (CAS Reg. No. 119008-75-2).
D-Gulonic acid (CAS Reg. No. 20246-33-7, or CAS Reg. No.
66905-24-6 for the monohydrate) gives D-gulono-1,4-lactone (CAS Reg.
No. 6322-07-2). L-Gulonic acid (CAS Reg. No. 526-97-6) gives L-gulono-
1,4-lactone (CAS Reg. No. 1128-24-1).
D-ldonic acid (CAS Reg. No. 488-33-5) gives D-idono-1,4-Iactone
(CAS Reg. No. 161168-87-2). L-Idonic acid (CAS Reg. No. 1114-17-6)
gives L-idono-1,4-lactone (CAS Reg. No. 1128-24-1).
D-Galactonic acid (CAS Reg. No. 576-36-3) gives D-galactono-1,4-
lactone (CAS Reg. No. 2782-07-2). L-Galactonic acid (CAS Reg. No.
28278-17-3) gives L-galactono-1,4-Iactone (CAS Reg. No. 1668-08-2).
D-Talonic acid (CAS Reg. No. 20246-35-9) gives D-talono-1,4-
lactone (CAS Reg. No. 23666-11-7). L-Talonic acid gives L-talono-1,4-
lactone (CAS Reg. No. 127997-10-8).
D-Ribonic acid (CAS Reg. No. 642-98-8) gives D-ribono-1,4-lactone
(CAS Reg. No. 5336-08-3). L-Ribonic acid gives L-ribono-1,4-lactone
(CAS Reg. No. 133908-85-7).
D-Arabinonic acid (CAS Reg. No. 488-30-2) gives D-arabinono-1,4-
lactone (CAS Reg. No. 2782-09-4). L-Arabinonic acid (CAS Reg. No. 608-
53-7) gives L-arabinono-1,4-Iactone (CAS Reg. No. 51532-86-6).
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D-Xylonic acid (CAS Reg. No. 526-91-0) gives D-xyfono-1,4-lactone
(CAS Reg. No. 15384-37-9). L-Xylonic acid (CAS Reg. No. 4172-44-5)
gives L-xylono-1,4-lactone (CAS Reg. No. 68035-75-6).
D-Lyxonic acid (CAS Reg. No. 526-92-1) gives D-Iyxono-1,4-lactone
(CAS Reg. No. 15384-34-6). L-Lyxonic acid (CAS Reg. No. 4172-43-4)
gives L-Iyxono-1,4-lactone (CAS Reg. No. 104196-15-8).
The starting reactants can contain one or more hydroxyl groups
that have been modified to give either a "deoxy" or a protected derivative.
By "protected" is meant blocking the reactivity of a hydroxyl group with one
or more reagents while a chemical reaction is carried out at an alternative
reactive site of the same compound. Protecting groups are well known in
the art and any suitable group can be used. Useful hydroxyl protecting
groups include ethers, acetals, and carboxylic or sulfonate esters.
Since many aldonic and aidaric acids exist in solution in equilibrium
with their lactone and (if possible) dilactone derivatives, the starting
material may be an equilibrium mixture of an aldonic or aldaric acid and its
various lactone and (if possible) dilactone derivatives. Furthermore, since
aidonic and aldaric acids generally exist in both D and L enantiomeric
configurations, the starting material may be D, L, racemic (DL), or an
unequal mixture of enantiomers. Some aldaric acids have a plane of
symmetry and thus exist in only a meso configuration.
The starting aldonic or aidaric acid or corresponding lactone may
be generated by acidifying a Group I, Group II, or ammonium salt
precursor of the parent acid or monolactone. Salts that may serve as
precursors include but are not limited to sodium, potassium, lithium,
cesium, magnesium, calcium, and ammonium salts. A mixture of salt
forms having different cations may also be used as a precursor to form the
aidonic or aidaric acid. Acids useful for generating aldonic and aidaric
acids by acidifying precursor salts include strong mineral acids, carboxylic
acids, or polymer bound acids, such as but not limited to sulfuric,
hydrochloric, phosphoric, hydrofluoric, oxalic, and trifluoroacetic acids,
hydrogen chloride, hydrogen fluoride, and polymeric or solid-phase acids
(e.g., strongly acidic cation exchange resins). The starting aidonic or
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aldaric acid can be generated in solution in water, in a suitable organic
solvent such as acetone, or in a mixture of said solvent and water. Any
precipitate formed may optionally be removed by any means, such as
filtration, before proceeding.
The starting material may optionally be a mixture of different
aldonic and/or aldaric acids having different numbers of carbon atoms,
different diastereomeric configurations, and/or different numbers of
carboxylic acid groups. The mixtures can also be generated in whole or in
part by acidifying the appropriate precursor salts.
In some embodiments, the starting material can be a mixture of one
or more of an aidonic acid, an aldaric acid, an aldonolactone, an
aidarolactone, and an aldarodilactone. The mixture can be an equilibrium
mixture of an aidaric acid or an aldonic acid with its corresponding
aidarolactone, aldonolactone, and/or its corresponding aidarodilactone if
one exists. Preferably, the aidonic acids, aldaric acids, aldonolactones,
aldarolactones and aidarodilactones contain from 5 to 8 carbon atoms.
In a process of the present invention, the starting materials are
combined with a suitable solvent. The starting materials can be first
dissolved in water, acetone, or a water-acetone mixture before combining
with the suitable solvent. The amount of starting material dissolved in the
suitable solvent is not critical, and is limited primarily by the quantity of
material that will dissolve in the solvent. While the concentration at which
the process is run is limited only by the solubility of the starting material,
the process is preferably run at about 1 to about 50 weight % solids
loading. That is, the starting material is typically dissolved initially in
about
1 to about 99 weight equivalents of solvent. More preferably, the process
is run at about 10 to about 45 weight % solids loading. That is, the
substrate is dissolved initially in about 1.2 to about 9 weight equivalents of
solvent.
The combined mixture is then heated, thereby promoting the
formation of a lactone or dilactone by dehydrative cyclization, and
azeotropically distilling the combined mixture, to remove water.
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As used herein, "suitable solvent" means any solvent or mixture of
solvents that is substantially inert to all reagents and products, dissolves
the starting materials, and forms an azeotrope with water that has a
boiling point below that of water and below that of the suitable solvent.
Suitable solvents include ethers, ketones, and esters, such as but not
limited to methyl ethyl ketone, methyl isobutyl ketone, 3-pentanone,
cyclopentanone, dioxane, ethylene glycol diethyl ether and propyl acetate.
The suitable solvent can also further comprise water or acetone.
Preferred solvents have a boiling point about 80 to 150 C, more preferred
about 90 to 130 C; and even more preferred about 100 to 120 C.
Solvents with alcoholic functionalities, such as butanol, ethanol,
cyclohexanol and phenol, are generally not preferred, as they can lead to
the formation of aldonic or aldaric acid esters. For ease in separation, the
product is preferably soluble in the suitable solvent when the solvent is hot
but precipitates when the solvent is cooled to -30 to 25 C, allowing the
product to be collected by filtration, centrifugation, or other physical
separation processes.
It is believed that the choice of solvent or the temperature at which
lactonization is conducted may affect the product distribution and thus
may favor one particular regioisomeric lactone over another, either
kinetically or thermodynamically. For example, aldonic and aldaric acids
often can form either five-membered (y) or six-membered (8) ring lactones.
Talaric acid (also known as altraric) can form either the 1,4- or 6,3-lactone,
and arabinaric acid (also known as lyxaric acid) can form either the 1,4- or
5,2-lactone. It is not intended that the processes of the present invention
be limited to the formation of any particular enantiomer or mixture thereof.
The processes disclosed herein are useful for converting glucaric
acid or glucarolactone into glucaro-1,4:6,3-dilactone, mannaric acid or
mannarolactone into mannaro-1,4:6,3-dilactone, and idaric acid or
idarolactone into idaro-1,4:6,3-dilactone. Other 5 and 6-carbon aldonic
and aldaric acids form monolactone products.
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EXAMPLES
The following materials are used in the Examples:
Calcium D-glucarate tetrahydrate (D-saccharic acid, calcium salt),
Spectrum Chemicals, 1001, FW 320.27
Sulfuric Acid, reagent grade, 95-98%, FW 98.07, d 1.84
Acetone, reagent grade, 99.5+%
Methyl isobutyl ketone (MiBK, 4-methyl-2-pentanone), reagent grade,
99+%
EXAMPLE 1
Sulfuric acid (312.5 g, 3.122 moles) was added over a period of 30
minutes to a stirred suspension of calcium D-glucarate tetrahydrate (1000
g, 3.122 moles) in 3.1 L of 97.5:2.5 acetone-water (prepared by mixing
3044 mL of acetone with 78 mL of water).
The stirred mixture was heated at reflux for 4 hours, allowed to cool
to room temperature (20-25 C), stirred at room temperature for 1-2 hours,
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 97.5:2.5 acetone-water, each time
suspending the precipitate in the solvent and then sucking the solvent
through.
Since some of the acetone was lost by evaporation during the
filtration process, the filtrate and washings were combined and adjusted
back up to 6.2 L by addition of acetone, typically about 1.6 L. MiBK (7.75
L) was added to the aqueous acetone solution, and the vigorously stirred
solution was heated so as to remove the acetone by fractional distillation.
Thus, 6.2 L of acetone containing some water and some MiBK was
distilled off (pot temp. 65-95 C, still head temp. 56-85 C). Distillation
was continued until the pot temperature reached 115-119 C. At this
point, distillation was discontinued and the reaction was heated at reflux
for 30 minutes. After 30 minutes at reflux, distillation was resumed until a
total of 8.1 L had been removed from the original reaction volume.
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
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vessel. The reaction filtrate was allowed to cool with vigorous stirring
under a blanket of dry nitrogen. The solution was seeded with 0.5-0.6 g of
GDL (D-glucaro-1,4:6,3-dilactone) and cooled to room temperature. Once
the mixture had reached room temperature, crystallization was allowed to
continue for 2-3 hours or overnight.
The white, crystalline GDL was collected by filtration, rinsed with
one 750-mL portion of MiBK, dried under a stream of nitrogen and then in
vacuo. Yield was 250-270 g (46-50%).
The mother liquor from the first crystallization (about 4.7 L) was
further concentrated to 1.9 L by distillation. The concentrated mother
liquor was filtered hot, cooled with vigorous stirring under a blanket of dry
nitrogen as before, and seeded with 0.3 g of GDL. Once the mixture had
reached room temperature, crystallization was allowed to continue for 2-3
hours or overnight.
The white, crystalline GDL was collected by filtration, rinsed with
one 375-mL portion of MiBK, dried under a stream of nitrogen and then in
vacuo. Yield was 125 g (23%).
Analysis was performed by I H NMR and by GC (silylation with
BSTFA-TMSCI, J&W DB-17MS 30 m x 0.32 mm x 0.25 m column, oven
temperature120-300 C).
EXAMPLE 2
D-Gluconic acid (20 g of a 50 wt % solution in water) and 100 mL of
cyclopentanone were combined and heated until a total of 22.5 mL of
solvent had been removed by distillation. The reaction mixture was
filtered hot, and the filtrate was allowed to begin cooling under an
atmosphere of dry nitrogen. The solution was seeded with 5 mg of D-
gluconolactone and allowed to sit overnight. The white, crystalline D-
gluconolactone was collected by filtration, rinsed with 3 10-mL portions of
MiBK, and dried under vacuum. Yield 3.1 g (34%) of what was by 1 H and
13C NMR a 2:1 mixture of d-glucono-1,4-lactone and D-glucono-1,5-
lactone. More product was collected and was shown by 1 H and 13C NMR
to be a 3:2 mixture of D-glucono-1,4-lactone and D-glucono-1,5-lactone.
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EXAMPLE 3
A 50-gallon reactor was charged with 113 lb of acetone and 48.5 lb
of calcium D-glucarate tetrahydrate over a period of I h, the charge port
and funnel being rinsed through to the reactor with 4.0 lb of DI water.
Sulfuric acid (15.2 Ib) was charged to a stainless steel bomb and pumped
from there into the reactor over a period of 1 hour, during which time the
pot temperature rose from 22.8 to 27.8 C. The bomb and transfer lines
were rinsed through to the reactor with 3.5 lb of DI water. The mixture
was stirred overnight (19 h) at 50 rpm, at ambient temperature, under
nitrogen.
The mixture was then filtered through a sparkler filter dressed with
duck cloth and 40-pm Dacron cloth to give 81.5 lb of filtrate. The kettle
and filter cake were rinsed through with a mixture of 109.5 lb of acetone
and 7.2 lb of DI water, divided into three portions. The combined filtrate
and washings (209.5 Ib) were adjusted to 275 lb by addition of 65.5 lb of
acetone and stored in a 55-gallon polylined drum.
The cleaned 50-gallon reactor was than charged with exactly half
(137.5 Ib) of the product solution from above and 131 lb of MiBK (methyl
isobutyl ketone) over a period of 32 min. The mixture was stirred at 50
rpm and heated to reflux over the next 2 hours. Over the next 7 hours,
175.5 lb of acetone/water/MiBK were distilled off.
The contents of the 50-gallon reactor were transferred through a
line heated at 80 C and a 200-pm in-line filter to a 20-gallon kettle, which
was cooled to 40 C and then 32 C. About 50 mL of the solution was
removed, seeded with crystals of GDL to initiate crystallization, and then
returned to the 20-gallon reactor to initiate crystallization of the product.
After stirring gently overnight, the material was transferred to a
sparkler filter, and 14.5 lb of MiBK were used to rinse out the reactor and
rinse through the filter cake. The filter cake (12 Ib) was dried in a vacuum
oven at 50 C with a slight nitrogen purge for about a day and a half to
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give 3.244 kg of crystalline GDL (27.1 % yield), purity 99.4% by 1 H NMR
and 99.6% by GC.
The second half of the product solution (137.3 Ib) was treated as
above, except that only 170.0 lb of acetone/water/MiBK were removed.
Dried GDL weighed 2.248 kg (18.8% yield) and was 99.7% pure by 1 H
NMR and GC.
The combined mother liquors and MiBK rinses were returned to the
50-gallon reactor, stirred at 50 rpm and heated to reflux over the next 4
hours. Over the next 4.5 hours, 100.0 lb of solvent were distilled off.
The contents of the 50-gallon reactor were transferred to the 20-
gallon kettle as above. An aliquot was removed, seeded, and returned to
the mixture at 42 C.
After the slurry had stirred overnight, the material was transferred to
a sparkler filter, and 17.5 lb of MiBK were used to rinse out the reactor
and rinse through the filter cake. The filter cake was rinsed with an
additional 7.0 lb of MiBK and dried in a vacuum oven to give 1.879 kg
(15.6 /Qyield) of GDL that was 99.5% pure by 1 H NMR and 99.8% pure by
GC.
