[0001] A synthetic route to ascorbic acid is provided in which a 3,5:4,6-protected derivative
of gulonic acid is prepared from gulono-1,4-lactone. Oxidation of the derivative and
hydrolysis of the resulting products affords 2-ketogulonic acid or ester thereof which
can be readily converted to ascorbic acid by known methods. The invention also relates
to certain intermediates prepared by said route.
[0002] L-ascorbic acid, or vitamin C, is required in the human diet and is widely sold in
tablet form and as an additive in various foodstuffs to meet this need. In all animals
except primates and guinea pigs L-ascorbic acid is biosynthetised from D-glucose.
The final step in this biosynthesis is the enzymatic conversion of L-gulono-1,4-lactone
to L-ascorbic acid. British Patent 763,055 discloses the conversion of L-gulono-1,4-lactone
to L-ascorbic acid in about 40% yield by the use of an enzymatic oxidation system.
[0003] L-ascorbic acid and some of its derivatives are employed as antioxidants in foodstuffs
to prevent rancidity, to prevent browning of cut fruit and in meat curing. D-ascorbic
acid may also be used.
[0004] Attempts to effect the direct conversion of gulono-1,4-lactone to ascorbic acid by
chemical means have only partly been successful since over-oxidation and degradation
reactions produce undesirable by-products. However, low yields of L-ascorbic acid
have been produced by oxidation. For example, Berends and Konings, Rec. Trav. Chim.
des Pays-Bas, 74, 1365 (1955), discloses the use of Fenton's reagent to give a 10%
yield of L-ascorbic acid. The most successful and common method of producing L-ascorbic
acid is based on a multi-step synthesis from D-glucose going through sorbose and 2-ketogulonic
acid as described by Reichstein and Grussner, Helv. Chim. Acta., 17, 311 (1934).
[0005] U.S. Patent 2,847,421 discloses a process for the production of intermediates 3,5:4,6-diethylidene-L-gulonic
acid and its simple esters and salts in the synthesis of ascorbic acid from D-sorbitol.
It also discloses methyl-2-keto-3,5:4,6-diethylidene-L gulonate and its corresponding
ethyl, propyl and n-butyl esters as having utility in the preparation of ascorbic
acid
[0006] This invention is concerned with a process in which the starting material, gulono-1,4-lactone
is reacted with a dialkyl aldehyde acetal or an aldehyde and an alkanol to provide
a 3,5:4,6-protected derivative of gulonic acid. Oxidation affords the ester of xylo-hexulosonic
acid. Hydrolysis yields 2- ketogulonic acid or ester or ascorbic acid.
[0007] In the process of the present invention, a 3,5:4,6-protected derivative of L-gulonic
acid (II) is prepared from L-gulono-1,4-lactone (1). Oxidation yields the L-xylo-hexulosonate
(III) which on hydrolysis affords 2-keto-L-gulonic acid or its ester (IV) or directly
affords L-ascorbic acid. The complete synthetic scheme is represented as follows:-
wherein R, is alkyl of 1 to 6 carbon atoms and R
2 is alkyl having 1 to 6 carbon atoms, phenyl, monosubstituted or disubstituted phenyl
wherein the substituents are alkyl having 1 to 6 carbon atoms, alkoxy having 1 to
6 carbon atoms, chloro, bromo, fluoro or nitro.
[0008] It is to be understood that the process of the present invention is also applicable
for the preparation of intermediates for the synthesis of D-ascorbic acid starting
with D-gulono-1,4-lactone in place of L-gulono-1,4-lactone. D-gulono-1,4-lactone can
be prepared from D-xylose by the process described in Organic Synthesis IV, 506 (1963).
[0009] The first step in the present process is the formation of a 3,5:4,6-protected derivative
of L- or D-gulonic acid. This may be effected by contacting the appropriate gulano-1,4-lactone
with at least two equivalents of an alkyl or aryl aldehyde of the formula R
2CHO. The preferred alkyl aldehyde is acetaldehyde and the preferred aryl aldehyde
is benzaldehyde. The reaction is conducted in the presence of at least one equivalent
of an alcohol of the formula R,OH. A modest excess of alcohol may be used with the
excess considered a solvent or diluent. The preferred alcohols are methanol, ethanol,
propanol or isopropanol. A catalytic amount of an acid having a pK
a less than 3 is added in an amount preferably between about 0.05 and 1.5 moles per
mole of gulono-1,4-lactone. Suitable acid catalysts include, but are not limited to,
hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, p-toluenesulfonic
acid and sulfonic ion exchange resins. The reaction is conducted at 0―70∘C, preferably
20-30°C until the reaction is substantially complete (1-20 hours). Alternatively,
the gulono-1,4-lactone is contacted with at least two equivalents of an aldehyde dialkyl
acetal of formula R
2CH(OR,)
2 in the absence of an accompanying alcohol; but also in the presence of an acid having
a pK
. less than 3 at a temperature of 0° to 70°C.
[0010] The second step in the present process is the oxidation of the unprotected hydroxy
group at the 2- position of the protected lactone to keto. This may be effected by
any method known in the art for the oxidation of secondary alcohols to ketones. A
preferred oxidising agent is a sulfoxonium salt formed from a mixture of dimethyl
sulfoxide and, for example, acetic anhydride or trifluoracetic anhydride in the presence
of a base such as triethylamine. A useful cemical combination is potassium periodate
and ruthenium dioxide in the presence of a base such as potassium carbonate. The oxidation
is typically conducted in an organic solvent inert to oxidation conditions. Examples
of suitable solvents include, but are not limited to, dimethyl formamide, pyridine,
dimethyl sulfoxide, dichloromethane and acetone. It is not necessary that the intermediate
be fully soluble in the organic medium. Temperatures suitable for the oxidation reaction
will vary according to the type of oxidation employed. For example, in oxidation via
sulfoxonium salts, the oxidation may be conducted at -60° to about 100°C depending
on the method used to generate the sulfoxonium salts. The very low temperature is
required only when trifluoracetic anhydride is used to generate the initial sulfoxonium
salt. The reaction is preferably carried out at 0° to 50°C. Oxidation by potassium
periodate and ruthenium dioxide is conducted at about -10°C to about 50°C preferably
about 0°C to room temperature. Before proceeding to the next step of the process the
oxidized intermediate is preferably separated from any excess oxidizing agent, for
example, by filtration of solid catalyst residues or by extraction or recrystallisation
of the product.
[0011] The oxidation process may also be accomplished by first contacting the di-O-alkylidene
or arylidene-gulonate at about -20°C with acetic anhydride and nitric acid to form
the 2- nitrato- gulonate. The isolated product in a solvent such as diethyl ether
at 0-5°C is stirred for about 15 minutes following the addition of triethylamine.
The resulting homogeneous solution following the addition of dichloromethane is further
stirred at 0-5° and then worked up to yield the xylo-hexulosonate.
[0012] The final step in the process is the hydrolysis of the xylo-hexulsonate to the 2-ketogulonic
acid or. ester, under acid conditions at a temperature in the range of about 35° to
150°C. Temperatures of about 50° to 75°C are preferred. The choice of solvent-acid
mixture is not critical with examples of useful mixtures as follows:
water-methanol, Amberlite (Registered Trade Mark) IR-120 sulfonic acid exchange resin,
isopropanol-water, catalytic amount of concentrated sulfuric acid.
acetonitrile-methanol, Dowex (Registered Trade Mark) 50-X8 sulfonic acid exchange
resin, water-acetic acid,
ethylene glycor-tetrahydrofuran, methanesulfonic acid.
[0013] The 2-ketogulonic acid ester can be hydrolysed to the free acid or it can be converted
by further reaction to ascorbic acid. Alternatively, the alkyl 3,5:4,6-di-O-protected
xylo-hexulsonate can be converted to ascorbic acid under acid catalysed hydrolysis
conditions which are known to convert 2- ketogulonic acid, methyl 2-ketogulonate or
diacetone-2-ketogulonic acid or ester to ascorbic acid.
[0014] The invention also includes the 2-nitrato derivatives of the compounds of the formula
(II); also the D- isomers of these compounds.
Example I
Methyl 3,5:4,6-Di-O-benzylidene-L-gulonate
[0015] To 11.2 ml (113 mmol) of benzaldehyde and 2.3 ml (57 mmol) of methanol was added
5.04 g (28.3 mmol) of L-gulono-1,4-lactone followed by 1.12 ml (13.4 mmol) of concentrated
hydrochloric acid. On stirring for 20 hours at room temperature the initially mobile
slurry turned solid. The reaction mixture was triturated with ether and filtered.
The solids were washed with ether, two times with water, and then ether After drying
in vacuo, white solid weighed 6.2 g (16.1 mmol), 57% based on unrecovered gulonolactone,
82%), m.p. 177-180°. Recrystallisation from benzene-acetone afforded analytically
pure material, m.p. 180-183°: [œ]
2g + 64.5° (DMF); i.r. (KBr) 3340, 1733 cm-1: n.m.r. (DMSO-d
s) 8
H 3.65 (s, 3, -OCH
3), 3.86-4.53 (m, 6), 5.66 (s, 2, -OCHO-), 6.10 (d, 1, J = 5, -OH), 7.2-7.63 (m, 10,
aromatic); ms 386 (1.9), 385 (5.2), 297 (13.1), 149 (25.9), 107 (40.6), 106 (21.7),
105 (100), 91 (57.8), 79 (26.5), 78 (10.7), 77 (38.9).
Example II
[0016] The method of Example I may be repeated replacing benzaldehyde with each of the following
aldehydes:
Example III
Ethyl 3,5:4,6-Di-O-benzylidene-L-gulonate
[0017] To a 250 ml flask under nitrogen was added 10.1 g (56.7 mmol) of L-gulono-1,4-lactone,
44g (244 mmol) of benzaldehyde diethyl acetal, and 2.5 ml (30 mmol) of concentrated
hydrochloric acid. The reaction was initially exothermic. After 2 hours the reaction
was solid and this solid mixture stood at room temperature for 17 hours. The reaction
was worked up by triturating with 100 ml of ether three times, water two times, and
ether two times. After drying under vacuum, the resulting crystalline solid weighed
21.0 g (52.5 mmol, 92.6%) which was pure by t.l.c. This material was recrystallised
from 500 ml of chloroform and 200 ml of diisopropyl ether. The first crop of crystals
weiged 16.7 g (41.7 mmol, 74%) and the second crop of crystals weighed 2.3 g (5.7
mmol, 10%) m.p. 203―204∘:
(DMF); i.r. (KBr) 3330, 1724 cm
-1: n.m.r. (DMSO-d
6) δ
H 1.13 (t, 3, J = 6.5,―CH
3), 4.07 (m, 8), 5.68 (s, 2, ―OCHO―), 6.03 (d, 1, J = 5, -OH), 7.40 (s, 10, aromatic);
n.m.r. (DMSO-d
6) 8
c 172.2 (I, s, ―CO
2―), 138.4, 138.0 (2, s, aromatic), 128.6, 127.9, 126.0, 125.9, (6, -CH-, aromatic),
99.4, 99.1 (2, d, ―OCHO―), 78.4, 69.83, 67.8 (4, each a d, -OCH-), 69.79 (1, t, -CH
20-), 60.1 (1, t, ―OCH
2CH
3), 14.2 (1, q, ―CH
2); ms 400 (0.8), 297 (10.1), 149 (20.7), 107 (33.3), 106 (28.4), 105 (100), 91 (45.0),
81 (10.6), 79 (18.2), 77 (38.6), 51 (13.1), 44 (10.6), 43 (10.2).
Example IV
[0018] The method of Example III may be repeated replacing benzaldehyde diethyl acetal with
each of the following aldehyde dialkyl acetals:
acetaldehyde diethyl acetal
acetaldehyde dimethyl acetal
propionaldehyde dipropyl acetal
n-valeraldehyde dimethyl acetal
n-hexaldehyde dibutyl acetal
o-nitrobenzaldehyde dihexyl acetal
o-fluorobenzaldehyde diethyl acetal
o-bromobenzaldehyde diethyl acetal
o-methylbenzaldehyde dimethyl acetal
m-methylbenzaldehyde dipropyl acetal
3,4-dichlorobenzaldehyde diethyl acetal
o-chlorobenzaldehyde diethyl acetal
o-methoxybenzaldehyde diethyl acetal
o-chlorobenzaldehyde diethyl acetal
o-butoxybenzaldehyde dimethyl acetal
o-hexoxybenzaldehyde diethyl acetal
Example V
Ethyl 3,5:4,6-Di-O-benzylidene-L-gulonate from Benzaldehyde and Ethanol
[0019] To 11.2 ml (113 mmol) of benzaldehyde and 1.63 ml (28.3 mmol) of ethanol was added
5.04 g (28.3 mmol) of L-gulono-1,4-lactone followed by 1.12 ml (13.4 mmol) of concentrated
hydrochloric acid. The reaction mixture was initially a mobile slurry which turned
solid on stirring at room temperature for 20 hours. The reaction mixture was triturated
with ether and then filtered. The solid was washed with ether and then two times with
water. After drying, this white crystalline solid weighed 2.92 g (7.3 mmol, 26%).
Based on unrecovered gulonolactone the yield was 47%. This material was identical
with that prepared in Example III.
Example VI
Isopropyl 3,5:4,6-Di-O-benzylidene-L-gulonate
[0020] To a solution of 40.4 ml (0.40 ml) of benzaldehyde and 38.2 ml of ispropanol was
added 8.9 g (0.050 mol) of L-gulono-4,4-lactone followed by 2.0 ml (0.024 mol) of
concentrated hydrochloric acid. The reaction mixture was stirred at room temperature
for 30 minutes at which time 0.10 g of seed crystals was added. This solution was
stirred at room temperature for 72 hours. It was then triturated with ether, filtered,
and the solids were washed three times with ether, three times with water, and two
times with ether. After drying under vacuum, 7.67 g (18.5 mmol, 37%) of a white solid
was recovered. The yield based on unrecovered L-gulano1,4-lactone was 49%. Analytically
pure material was obtained by recrystallisation from ethyl acetate, m.p. 183-186
0: i,r, (KBr) 3356, 1715 cm
-1: n.m.r. (DMSO-d
s) 8
H 1.07 and 1.15 (two d, 6, J = 7, ―CH
3), 3.97-4.40 (m, 6), 4.97 (heptet, 1, J = 7, -OCH(CH
3)
2), 5.73 (s, 2, -OCHO-), 6.06 (m, 1, -OH), 7.47 (s, 10, aromatic); ms 414 (0.6), 413
(3.4), 297 (16.6), 149 (28.5), 107 (38.0), 106 (20.9), 105 (100), 91 (42.0), 77 (25.3),
44 (16.4), 43 (11.0).
Example VII
Methyl 3,5:4,6-Di-O-ethylidene-L-gulonate
[0021] To 5.0 g (28.1 mmol) of L-gulono-1,4-lactone was added 12.2 ml (112.3 mmol) of acetaldehyde
dimethyl acetal. Hydrogen chloride gas was bubbled through the heterogeneous solution.
The reaction mixture gradually became homogeneous and was stirred at room temperature
for 20 hours. The reaction mixture was concentrated and the resulting solid was triturated
with ether affording 3.67 g (14.0 mmol, 50%) of material. In addition, the ether filtrate
afforded 2.93 g (11.2 mmol, 40%) of solid which by t.l.c. was pure material. The triturated
solid was recrystallised from chloroform and then ethyl acetate to afford analytically
pure material, m.p. 137―140∘ (lit.
* 144-145.5
0):
(DMF); i.r. (KBr) 3436, 1748 cm
-1: n.m.r. (DMSO-d
6) δ
H 1.20 (d, 3, J = 5, -CH
3), 1.25 (d, 3, J = 5, -CH
3), 3.67 (s, 3, -OCH
3), 3.72-4.33 (m, 6), 4.77 (g, 2, J = 5, -CHCH
3), 5.22 (d, 1, J = 6, -OH); n.m.r. (DMSO-d
s) 8
c 172.7 (s, ―CO
2―), 97.60 (d, -OCHO-), 97.55 (d, -OCHO
-), 78.0, 69.1, 67.5, 67.0 (d, ―CO―), 68.7 (t, ―CH
2O―), 51.4 (q, -OCH
3), 20.9 (q, ―CH
3), 20.7 (q, ―CH
3); exact mass (C
11H
18O
7―H), 261.0988 (calculated 261.1002).
*A. A. D'Addieco, U.S. 2,847,421 (1958).
Example VIII
[0022] The methods of Examples I to VII may be repeated replacing L-gulono-1,4-lactone with
D-gulono-1,4-lactone to obtain the corresponding D-gulonates.
Example IX
Ethyl 3,5:4,6-Di-O-benzylidene-L-xylo-hexulosonate
[0023] To a dry 250 ml 3-neck flask under nitrogen was added 30 ml of dry dichloromethane.
To this was added at -60° 1.4 ml (10 mmol) of trifluoroacetic anhydride followed by
10 mmol (0.71 ml) of dry dimethylsulfoxide. This solution was stirred at ―60∘ or lower
for 30 minutes and then 2.00 g (5.0 mmol) of ethyl 3,5:4,6-di-O-benzylidene-L,gulonate
in 30 ml of dry chloromethane was added over a 10 minute period while maintaining
the temperature below ―45∘. The resulting solution was stirred at less than ―60∘ for
30 minutes, then 2 ml (14.4 mmol) of triethylamine was added. After 20 minutes at
less than ―60∘, the solution was allowed to warm to room temperature and stirred for
2.25 hours. An additional 40 ml of dichloromethane was added to the reaction mixture
which was then extracted two times with 50 ml of 1 N hydrochloric acid, two times
with 50 ml of water, one time with 50 ml of brine and dried with sodium sulfate. Removal
of the solvent in vacuo afforded 1.94 g (4.9 mmol, 98%) of an off-white solid which
was one spot by t.l.c. Recrystallisation from benzene-acetone afforded analytically
pure material, m.p. 192-194
0. This material can also be recrystallised from chloroform-diisopropyl ether:
(DMF); i.r. (KBr) 1754, 1733 cm
-1: n.m.r. (DMSO-dg) δ
H 1.27 (t, 3, J = 7, -CH
3), 4.27 (m, 5), 4.78 (m, 1), 5.53 (d, 1, J = 2, -COCHO), 5.72 (s, 1, -OCHO-), 5.88
(s, 1, -OCHO-), 7.40 (m, 10, aromatic); n.m.r. (DMSO-d
s) δ
c 188.0 (1, CO), 159.8 (1, ―CO
2―), 137.8, 137.6 (2, C, aromatic), 128.9, 128.6, 128.0, 126.2, 125.7 (10, -CH, aromatic),
99.1, 98.6 (2, -OCHO-), 80.3, 69.8, 69.0, 68.8 (4), 62.2 (1, -OCH
2CH
3), 13.9 (1, -CH
3); ms 397 (0.1 ), 396 (0.6), 298 (13.8), 297 (69.8), 191 (14.9), 149 (10.6), 107 (36.7),
106 (23.1), 105 (94.8), 91 (100), 85 (41.5), 79 (28.4), 78 (10.0), 77 (39.7), 57 (10.4),
51 (11.5).
[0024]
Example X
Ethyl 3,5:4,6-Di-O-benzylidene-L-xylo-hexulosonate
[0025] To a dry 1-1 3-neck flask under nitrogen was added 100 ml of dry dichloromethane
followed by 4.3 ml (4.73 g, 60.6 mmol) of dry dimethyl sulfoxide. This solution was
cooled to ―60∘ and 8.5 ml (60.0 mmol) of trifluoroacetic anhydride was added while
maintaining the reaction temperature below ―55∘. After 30 minutes at ―60∘ or less,
290 ml of dichloromethane containing 12.0 g (30.0 mmol) of ethyl 3,5:4,6-di-O-benzylidene-L-gulonate
was added over a 45 minute period. The reaction temperature was kept below ―50∘. The
reaction was stirred for an additional 30 minutes at ―55∘ and then 12.6 ml (90 mmol)
of triethylamine was added. After 30 minutes at -55
0, the solution was stirred at room temperature for 2 hours. An additional 200 ml of
dichloromethane was added and the reaction mixture was extracted two times with 300
ml of 1 N hydrochloric acid, two times with 300 ml of water, and two times with 300
ml of brine. After drying the organic layer with sodium sulfate, the solvent was removed
in vacuo affording 11.78 g (29.6 mmol, 98.7%) of a white solid which was identical
with material prepared in Example IX.
[0026] This oxidation can also be carried out using dimethyl-sulfoxide and acetic anhydride.
Example XI
Ethyl 3,5:4,6-Di-O-benzylidene-L-xylo-hexulosonate
[0027] To a 35 ml flask was added 7 ml of dichloromethane and 0.40 g (1.0 mmol) of ethyl
3,5:4,6-di-0-benzylidene-L-gulonate followed by 33 mg (0.24 mmol) of potassium carbonate,
0.299 g (1.30 mmol) of potassium periodate, and 7 mg of ruthenium dioxide. After 6
hours, an additional 33 mg (0.24 mmol) of potassium carbonate, 0.299 g (1.30 mmol)
of potassium periodate, and 7 mg of ruthenium dioxide was added. The reaction mixture
was stirred for 18 hours and then diluted with dichloromethane, extracted two times
with water, two times with brine, and dried with sodium sulfate. Concentration in
vacuo afforded a white solid (0.328 g, 0.82 mmol, 82%) which was recrystallised from
ethyl acetate. This afforded 0.188 g (0.47 mmol, 47%) of white needles, m.p. 195-198°.
This material was identical with material prepared in Example IX.
Example XII
Isopropyl 3,5:4,6-Di-O-benzylidene-L-xylo-hexulosonate
[0028] To a dry 50 ml 3-neck flask under nitrogen was added 12 ml of dry dichloromethane
and 0.85 ml (6 mmol) of trifluoroacetic anhydride. This solution was cooled to -60°
and 0.43 ml (6 mmol) of dimethylsulfoxide was added. After stirring for 30 minutes,
17 ml of dichloromethane containing 1.24 g (3.0 mmol) of isopropyl 3,5:4,6-di-O-benzylidene-L-gulonate
was added to the reaction mixture while maintaining the temperature below ―50∘. After
30 minutes at ―55∘ or lower, 1.26 ml (9 mmol) of triethylamine was added. The resulting
solution was stirred at -55° for 45 minutes and then at room temperature for 2.5 hours.
The reaction was worked up by adding dichloromethane and extracting two times with
1 N hydrochloric acid, three times with water, and once with brine. After drying with
sodium sulfate, the solvent was removed in vacuo affording 1.29 g (3.15 mmol, 104%)
of a white solid. Recrystallisation from chloroform isopropyl ether afforded 0.649
g (1.58 mmol, 52.5%) of analytically pure white needles, m.p. 188-191
0: (KBr) 1754, 1739 cm
-1: n.m.r. (DMSO-d
6) δ
H 1.23 and 1.30 (two d, 6, J = 6, -CH
3), 4.23 (m, 3), 4.73 (m, 1), 5.12 (heptet, 1, J = 6, -CH(CH
3)
2), 5.50 (d, 1, J = 3, -OCCHO-), 5.70 (s, 1, -OCHO-), 5.87 (s, 1 -OCHO-), 7.43 (m,
10, aromatic); ms 413 (0.1), 412 (0.3), 411 (1.7), 298 (16.4), 297 (76.9), 191 (20.1),
149 (19.7), 107 (61.0), 106 (20.9), 105 (86.4), 91 (100), 85 (35.9), 79 (17.2), 77
(18.5), 44 (10.1).
[0029]
Example XIII
Ethyl 3,5:4,6-Di-O-benzylidene-2-nitrato-L-gulonate
[0030] To a 25 ml 3-neck flask containing 5 ml of acetic anhydride at -20° was added dropwise
2 ml of nitric acid. This solution was then warmed to ―10∘ at which point an exothermic
reaction took place causing the temperature to rise to 5°. After cooling to -10°,
4.4 ml of this solution was added with stirring to a solution of 1.16 g (2.90 mmol)
of ethyl 3,5:4,6-di-O-benzylidene-L-gulonate in 30 ml of dry dichloromethane and 2
ml of acetic anhydride at ―15∘. After 25 minutes the reaction mixture was poured onto
200 ml of ice-water. After stirring for 30 minutes, the reaction mixture was extracted
with dichloromethane which was washed with saturated sodium bicarbonate, brine, and
then dried with sodium sulfate. The solvent was removed in vacuo affording 1.254 g
(2.82 mmol. 97%) of a white solid. Recrystallisation from isopropyl alcohol afforded
0.81 g (1.82 mmol, 63%) of white crystals, m.p. 189―190∘:
(DMF); i.r. (KBr) 3333, 1745, 1642, 1252 cm
-1: n.m.r. (DMSO-d
6) δ
H 1.1 (t, 3 J = 7, -CH
3), 2.97-4.77 (m, 8), 5.53 (d, 1, J = 8, -HCON0
2), 5.72 (s, 1, -OCHO-), 5.80 (s, 1, -OCHO-), 7.40 (s, 10, aromatic); ms 445 (4.2),
444 (54.4), 443 (98.1),398 (26.8), 107 (12.4), 106 (34.4) 105 (100.0), 91 (43.2),
77 (56.5), 51 (13.3),44 (59.2), 43 (11.3), 40 (32.4).
Example XIV
Ethyl 3,5:4,6-Di-O-benzylidene-2-nitrato-L-gulonate
[0031] To a 500 ml 3-neck flask was added 10.0 g (25 mmol) of ethyl 3,5:4,6-di-O-benzylidene-L-gulonate
followed by 258 ml of dichloromethane. After cooling the resulting slurry to-15°,
17.2 ml of acetic anhydride was added. To a 100 ml 3-neck flask was added 27 ml of
acetic anhydride. After cooling to 0°, 10.9 ml of 70% nitric acid was added dropwise
maintaining the reaction temperature between ―3∘ and 2°. The addition was complete
in 45 minutes and the reaction mixture was allowed to warm to 7°. Under these conditions
no exothermic reaction occurred. After cooling to less than 0°, this solution was
added via a jacketed addition funnel cooled with methanol-ice to the acetic anhydride
solution containing 3,5:4,6-di-O-benzylidene-L-gulonate. The reaction mixture was
maintained at ―10∘ to ―15∘ during the addition. The white slurry gradually became
homogeneous. After 30 minutes, the reaction mixture was poured onto 2 I of ice-water
and mechanically stirred for 0.5 hours. This solution was extracted eight times with
100 ml of dichloromethane, then the combined organic layers were extracted two times
with 300 ml of saturated sodium bicarbonate and 300 ml of brine. After drying with
sodium sulfate, the solvent was removed in vacuo affording a white solid which was
recrystallised from 800 ml of isopropanol. The first crop of crystals weighed 7.59
g (17.1 mmol, 68%), m.p. 186―188∘. An additional 1.24 g of material was obtained by
concentration of the mother liquor and crystallisation (2.80 mmol, 11 %) for a total
yield of 79%.
Example XV
Ethyl 3,5:4,6-Di-O-benzylidene-L-xylo-hexulosonate from Ethyl 3,5:4,6-Di-O-benzylidene-2-nitrato-L-gulonate
[0032] To 24 ml of diethyl ether containing 0.433 (0.97 mmol) of ethyl 3,5:4,6-di-O-benzylidene-2-
nitrato-L-gulonate at 0―5∘ was added 0.14 ml (1.0 mmol) of triethylamine. This heterogeneous
solution was stirred for 15 minutes, then 20 ml of dichloromethane was added. The
resulting homogeneous solution was stirred for 5 minutes at 0-5
0 and then worked up by adding 30 ml of dichloromethane and extracting with 25 ml of
1 N hydrochloric acid two times, 25 ml of saturated sodium bicarbonate two times,
50 ml of brine, and finally drying with sodium sulfate. Removal of the solvent in
vacuo afforded 0.374 g (0.94 mmol, 97%) of the desired ketone contaminated with residual
starting material. Recrystallisation afforded material which was identical with that
prepared in Example IX to XI.
Example XVI
[0033] The methods of Example IX to XV may be repeated replacing the L-gulonates with the
D-gulonates to obtain the corresponding D-xylo-hexulosonates.
Example XVII
Ethyl 2-Keto-L-gulonate
[0034] To 15 ml of 70% acetic acid-water was added 1.19 g (3.0 mmol) of ethyl 3,5:4,6-di-O-benzylidene-L-xylo-hexulosonate.
The resulting heterogeneous solution was heated at 70-75
0. After 3 hours the solution was homogeneous and was heated for an additional hour.
The solvent was removed in vacuo affording a white foam, 0.574 g (2.59 mmol, 86%).
This material was identical by t.l.c., h.p.l.c., i.r.,
1H-n.m.r. and
13C-n.m.r. with an authentic sample of ethyl 2-keto-L-gulonate prepared according to
the method of Drefahl and Gross.
*
[0035] This hydrolysis has also been carried out using: water-methanol, Amberlite IR-120
sulfonic acid cation exchange resin
isopropanol-water, catalytic amount of concentrated sulfuric acid
acetonitrile-methanol, Dowex 50-XB sulfonic acid cation exchange resin
ethylene glycol-tetrahydrofuran, methanesulfonic acid; under these conditions ethyl
2-keto-L-gulonate was initially produced but on standing with the residual quantities
of ethylene glycol and methanesulfonic acid this was converted to ascorbic acid
Example XVIII
[0036] The method of Example XVII may be repeated replacing 3,5:4,6-di-O-benzylidene-L-xylo-hexulosonate
with the corresponding D-xylo-hexulosonate to obtain ethyl 2-keto-D-gulonate.