EP0000243A1 - Process for preparing 3,5:4,6- protected derivatives of L- or D- gulonic acid, their use in preparing 2- keto-L- or D- gulonic acid or their esters or L- or D- ascorbic acid, and certain novel 2-nitrato-gulonate intermediates - Google Patents
Process for preparing 3,5:4,6- protected derivatives of L- or D- gulonic acid, their use in preparing 2- keto-L- or D- gulonic acid or their esters or L- or D- ascorbic acid, and certain novel 2-nitrato-gulonate intermediates Download PDFInfo
- Publication number
- EP0000243A1 EP0000243A1 EP78300017A EP78300017A EP0000243A1 EP 0000243 A1 EP0000243 A1 EP 0000243A1 EP 78300017 A EP78300017 A EP 78300017A EP 78300017 A EP78300017 A EP 78300017A EP 0000243 A1 EP0000243 A1 EP 0000243A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- acid
- isomer
- formula
- mmol
- gulonate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 0 C1CC*CC1 Chemical compound C1CC*CC1 0.000 description 3
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/62—Three oxygen atoms, e.g. ascorbic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
- C07H7/02—Acyclic radicals
- C07H7/027—Keto-aldonic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical
- C07H9/02—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical the hetero ring containing only oxygen as ring hetero atoms
- C07H9/04—Cyclic acetals
Definitions
- 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 product 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.
- L-ascorbic acid or vitamin C
- L-ascorbic acid is required in the human diet and is widely sold in tablet form and as an additive in various foodstuffs to meet this need.
- L-ascorbic acid is biosynthetised fromD-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.
- 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.
- 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).
- US. 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. However, the yields are not very satisfactory.
- This invention is concerned with a process in which the starting material, gulono-:,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.
- L-gulonic acid (II) is prepared from L-gulono-1,4-lactone (I). 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.
- 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.
- D-gulono-1,4-lactone can be prepared from D-xylose by the process described in Organic Syntheses IV, 506 (1963).
- the first step in the present process is the formation of a 3,5:4, 6-protected intermediate. This may be effected by contacting the appropriate gulono-1,4-lactone with about two equivalents of an alkyl or aryl aldehyde.
- the preferred alkyl aldehyde is acetaldehyde and the preferred aryl aldehyde is benzaldehyde.
- the reaction is conducted in the presence of about one equivalent of an alcohol of 1 to 6 carbon atoms. 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 less than 3 is added in an amount 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 may be conducted at 0-70°C, preferably 20-30°C until the reaction is substantially complete (1-20 hours).
- the gulono-1,4-lactone is contacted with two equivalents of the appropriate aldehyde dialkyl acetal in the absence of an accompanying alcohol.
- 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 trifluoroacetic anhydride in the presence of a base such as triethylamine.
- a useful chemical combination is potassium periodate and ruthenium dioxide in the presence of a base such as potassium carbonate.
- the oxidation is conducted in an organic solvent inert to oxidation conditions.
- suitable solvents include, but are not limited to, dimethyl formamide, pyridine, dimethyl sufloxide, 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 0 to about 100°C depending on the method used to generate the sulfoxonium salts. The very low .temperature is required only when trifluoroacetic anhydride is used to generate the initial sulfoxonium salt. The reaction is preferably carried out at 0 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 roan temperature.
- the oxidized intermediate is preferably separated from a.ny excess oxidizing agent, for example, by filtration of solid catalyst residues or by extraction or recrystallisation of the product.
- 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.
- the final step in the process is the hydrolysis of the xylo-hexulsonate to the 2-ketogulonic acid ester. Temperatures in the range of about 35° to 150°C are suitable with temperatures of about 50° to 75°C being preferred.
- the choice of solvent-acid mixture is not critical with examples of useful mixtures as follows:
- the 2-ketogulonic acid ester can be hydrolysed to the free acid or it can be converted by further reaction to ascorbic acid.
- the alkyl 3, 5:4,6-di-O-proteted 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.
- the invention also includes the intermediates of the formula (III), the 2-nitrato derivatives of the compounds of the formula (II), and the intermediates of the formula wherein R is other than C 1 -C 6 alkyl; also the D- isomers of these compounds.
- Example I may be repeated replacing benzaldehyde with each of the following aldehydes:
- This material was recrystallised - from 500 ml of chloroform and 200 ml pf diisopropyl ether.
- the first crop of crystals weighed 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°: + 61.2° (DMF); i.r. (KBr) 3330, 1724 cm -1 ; n.m.r.
- Example III The method of Example III may be repeated replacing benzaldehyde diethyl acetal with each of the following aldehyde dialkyl acetals:
- 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.
- This oxidation can also be carried out using dimethylsulfoxide and acetic anhydride.
- 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.
- the reaction mixture was poured onto 2 1 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.
- Example IX to XV may be repeated replacing the L-gulonates with the D-gulonates to obtain the corresponding D-xylo-hexulosonates.
- Example XVII may be repeated replacing 3,5:
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Saccharide Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Furan Compounds (AREA)
Abstract
Description
- 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 product 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.
- 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 fromD-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.
- 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.
- 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. Chid. des Pays-Bas, 74, 1365 (1955), disclose 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).
- US. 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. However, the yields are not very satisfactory.
- This invention is concerned with a process in which the starting material, gulono-:,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.
- 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 (I). 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:-
- 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 Syntheses IV, 506 (1963).
- The first step in the present process is the formation of a 3,5:4, 6-protected intermediate. This may be effected by contacting the appropriate gulono-1,4-lactone with about two equivalents of an alkyl or aryl aldehyde. The preferred alkyl aldehyde is acetaldehyde and the preferred aryl aldehyde is benzaldehyde. The reaction is conducted in the presence of about one equivalent of an alcohol of 1 to 6 carbon atoms. 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 less than 3 is added in an amount 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 may be 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 two equivalents of the appropriate aldehyde dialkyl acetal in the absence of an accompanying alcohol.
- 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 trifluoroacetic anhydride in the presence of a base such as triethylamine. A useful chemical combination is potassium periodate and ruthenium dioxide in the presence of a base such as potassium carbonate. The oxidation is conducted in an organic solvent inert to oxidation conditions. Examples of suitable solvents include, but are not limited to, dimethyl formamide, pyridine, dimethyl sufloxide, 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 -600 to about 100°C depending on the method used to generate the sulfoxonium salts. The very low .temperature is required only when trifluoroacetic anhydride is used to generate the initial sulfoxonium salt. The reaction is preferably carried out at 00 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 roan temperature.
- Before proceeding to the next step of the process the oxidized intermediate is preferably separated from a.ny excess oxidizing agent, for example, by filtration of solid catalyst residues or by extraction or recrystallisation of the product.
- 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.
- The final step in the process is the hydrolysis of the xylo-hexulsonate to the 2-ketogulonic acid ester. Temperatures in the range of about 35° to 150°C are suitable with temperatures of about 50° to 75°C being preferred. The choice of solvent-acid mixture is not critical with examples of useful mixtures as follows:
- water-methanol, Amberlite IR-120 sulfonic acid exchange resin,
- isopropanol-water, catalytic amount of concentrated sulfuric acid,
- acetonitrile-methanol, Dowex 50-X8 sulfonic acid exchange resin water-acetic acid,
- ethylene glycol-tetrahydrofuran, methanesulfonic acid.
- 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-proteted 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.
- The invention also includes the intermediates of the formula (III), the 2-nitrato derivatives of the compounds of the formula (II), and the intermediates of the formula wherein R is other than C1-C6 alkyl; also the D- isomers of these compounds.
- 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, the white solid weighed 6.2 g (16.1 mmol), 57%; based on unrecovered gulonolactone, 82%), m.p. 177 - 1800. Recrystallisation from benzene - acetone afforded analytically pure material, m.p. 180-183°:
- Analysis: Calculated for C21H22O7: C, 65.27; H, 5.74. Found: C, 65.22; H, 5.74.
-
- 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 pf diisopropyl ether. The first crop of crystals weighed 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°:
- Analysis: Calculated for C22H24O7: C, 66.06; H, 6.05 Found: C, 65.97; H, 6.03.
- 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 .
- 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.
- To a solution of 40.4 ml (0.40 ml) of benzaldehyde and 38.2 ml of isopropanol was added 8.9 g (0.050 mol)̵ of L-gulono-1,4- 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 hour. 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 (18.5mmol, 37%) of a white solid was recovered.
- Theyield based on unrecovered L-gulono-1,4-lactone was 49%. Analytically pure material was obtained by recrystallisation from ethyl acetate, m.p. 183 - 186°: i,r, (KBr) 3356, 1715 cm-1; n.m.r. (DMSO-d6) δH 1.07 and 1.15 (two d, 6, J = 7, -CH3), 3.97- 4.40 (m, 6), 4.97 (heptet, 1, J = 7, -OCH(CH3) 2) , 5.73 (s, 2, -OCHO-), 0.06 (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).
- analysis: Calculated for C23H26O7: C, 66.65; H, 6.32 Found: C, 66.51; H, 6.25.
- 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°):
- Analysis: Calculated for C11H18O7: C, 50.37; H, 6.91 Found: C, 50.63; H, 6.86
- *A. A. D'Addieco, U.S. 2,847,421 (1958).
- ...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.
- 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 1N 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°. This material can also be recrystallised from chloroform-diisopropyl ether:
- Analysis: Calculated for C22H22O7: C, 66.32; H, 5.56 Found: . C, 66.29; H, 5.69.
- 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°, 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 1N 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.
- This oxidation can also be carried out using dimethylsulfoxide and acetic anhydride.
- 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-O-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.
- 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 -550 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 1N 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°: (KBr) 1754, 1739 cm-1; n.m.r. (DMSO-d6) δH 1.23 and 1.30 (two d, 6, J = 6, -CH3), 4.23 (m, 3), 4.73 (m, 1), 5.12 (heptet, 1, J=6, -CH(CH3)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).
- Analysis: Calculated for C23H24O7: C, 66.97; H, 5.86 Found: C, 66.10; H, 5.79.
- 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°:
- Analysis: Calculated for C22H23O9N: C, 59,32; H, 5. 20; N, 3.14 Found: C, 59.59; H, 5.28; N, 2.99.
- 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 -30 and 2°. The addition was complete in 45 minutes and the reaction mixture was allowed to warm to 70. 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 1 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. 186-1880. 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%.
- To 24 ml of diethyl ether containing 0.433 g (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° and then worked up by adding 30 ml of dichloromethane and extracting with 25 ml of 1N 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.
- 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.
- 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 - 750.
- 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.*
- 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-X8 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 methansulfonic acid this was converted to ascorbic acid
- *G. Drefahl and B. Gross, J. Prakt. Chem., 1, 153 (1955).
- 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.
Claims (15)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US05/805,880 US4232168A (en) | 1977-06-13 | 1977-06-13 | Preparation of ascorbic acid intermediates |
US805880 | 1991-12-09 |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0000243A1 true EP0000243A1 (en) | 1979-01-10 |
EP0000243B1 EP0000243B1 (en) | 1981-01-07 |
Family
ID=25192776
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP78300017A Expired EP0000243B1 (en) | 1977-06-13 | 1978-06-05 | Process for preparing 3,5:4,6- protected derivatives of l- or d- gulonic acid, their use in preparing 2- keto-l- or d- gulonic acid or their esters or l- or d- ascorbic acid, and certain novel 2-nitrato-gulonate intermediates |
Country Status (8)
Country | Link |
---|---|
US (1) | US4232168A (en) |
EP (1) | EP0000243B1 (en) |
JP (1) | JPS545917A (en) |
CA (1) | CA1096397A (en) |
DE (1) | DE2860399D1 (en) |
DK (1) | DK262178A (en) |
IE (1) | IE47197B1 (en) |
IT (1) | IT1096711B (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4283340A (en) * | 1977-06-13 | 1981-08-11 | Pfizer Inc. | Ascorbic acid intermediates |
EP0148094A2 (en) * | 1983-12-27 | 1985-07-10 | Mutsuyuki Kochi | Anti-tumor agent comprising an O-benzylidene-L-ascorbic acid or a salt thereof, and the production of the latter compound |
WO2019179774A1 (en) | 2018-03-22 | 2019-09-26 | Clariant International Ltd | Polymer composition comprising diacetal derivatives |
WO2019179773A1 (en) | 2018-03-22 | 2019-09-26 | Clariant International Ltd | Diacetal derivatives and their use as clarifier |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5569875A (en) * | 1992-03-16 | 1996-10-29 | Legend Products Corporation | Methods of making explosive compositions, and the resulting products |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CH240725A (en) * | 1941-12-01 | 1946-01-15 | Tno | Process for the production of ascorbic acid. |
GB763055A (en) * | 1953-04-21 | 1956-12-05 | Nat Res Dev | Improvements in and relating to the production of ascorbic acid |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2207991A (en) * | 1939-08-05 | 1940-07-16 | Pfizer Charles & Co | Preparation of esters of 2-ketoaldonic acids by oxidation of aldonic acids, their lactones and esters |
US2847421A (en) * | 1956-12-13 | 1958-08-12 | Du Pont | Ascorbic acid intermediates |
US4111958A (en) * | 1977-06-03 | 1978-09-05 | Pfizer Inc. | Ascorbic acid synthesis |
-
1977
- 1977-06-13 US US05/805,880 patent/US4232168A/en not_active Expired - Lifetime
-
1978
- 1978-06-05 DE DE7878300017T patent/DE2860399D1/en not_active Expired
- 1978-06-05 EP EP78300017A patent/EP0000243B1/en not_active Expired
- 1978-06-09 IE IE1171/78A patent/IE47197B1/en unknown
- 1978-06-09 CA CA305,179A patent/CA1096397A/en not_active Expired
- 1978-06-12 JP JP7070578A patent/JPS545917A/en active Granted
- 1978-06-12 DK DK262178A patent/DK262178A/en unknown
- 1978-06-12 IT IT24473/78A patent/IT1096711B/en active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CH240725A (en) * | 1941-12-01 | 1946-01-15 | Tno | Process for the production of ascorbic acid. |
GB763055A (en) * | 1953-04-21 | 1956-12-05 | Nat Res Dev | Improvements in and relating to the production of ascorbic acid |
Non-Patent Citations (1)
Title |
---|
REC. TRAV. CHIM. DES PAYS-BAS, 74 (1955) pages 1365-1370. * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4283340A (en) * | 1977-06-13 | 1981-08-11 | Pfizer Inc. | Ascorbic acid intermediates |
EP0148094A2 (en) * | 1983-12-27 | 1985-07-10 | Mutsuyuki Kochi | Anti-tumor agent comprising an O-benzylidene-L-ascorbic acid or a salt thereof, and the production of the latter compound |
EP0148094A3 (en) * | 1983-12-27 | 1986-04-16 | Mutsuyuki Kochi | Anti-tumor agent comprising an o-benzylidene-l-ascorbic acid or a salt thereof, and the production of the latter compound |
WO2019179774A1 (en) | 2018-03-22 | 2019-09-26 | Clariant International Ltd | Polymer composition comprising diacetal derivatives |
WO2019179773A1 (en) | 2018-03-22 | 2019-09-26 | Clariant International Ltd | Diacetal derivatives and their use as clarifier |
Also Published As
Publication number | Publication date |
---|---|
JPS563357B2 (en) | 1981-01-24 |
IT7824473A0 (en) | 1978-06-12 |
IE47197B1 (en) | 1984-01-11 |
CA1096397A (en) | 1981-02-24 |
US4232168A (en) | 1980-11-04 |
EP0000243B1 (en) | 1981-01-07 |
IE781171L (en) | 1978-12-13 |
DK262178A (en) | 1978-12-14 |
DE2860399D1 (en) | 1981-02-26 |
IT1096711B (en) | 1985-08-26 |
JPS545917A (en) | 1979-01-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0000092B1 (en) | Method of preparing ascorbic acid and intermediates specially adapted for use therein | |
CA2574401C (en) | Method for the preparation of d-erythro-2,2-difluoro-2-deoxy-1-oxoribose derivative | |
JPH07291975A (en) | Production of ginkgolide b from ginkgolide c | |
EP0000243B1 (en) | Process for preparing 3,5:4,6- protected derivatives of l- or d- gulonic acid, their use in preparing 2- keto-l- or d- gulonic acid or their esters or l- or d- ascorbic acid, and certain novel 2-nitrato-gulonate intermediates | |
KR100761959B1 (en) | Method for preparating crystalline 3-o-alkyl-ascorbic acid | |
JP3351563B2 (en) | Method for producing 3-hydroxybutyric acid derivative | |
DK153483B (en) | PROCEDURE FOR MANUFACTURING GAMMA PYRONS | |
US4421924A (en) | Ascorbic acid intermediates and their preparation | |
US4283340A (en) | Ascorbic acid intermediates | |
KR20090066910A (en) | Efficient prepartion of l-3-o-substituted-ascorbic acid | |
EP0094769B1 (en) | Preparing 7-alkoxybenzofurans and intermediates used therein | |
SU1277897A3 (en) | Method of producing 1,1-dioxo-6-brom(or-6,6-dibromine) penicillanoyloxymethyl ethers of 6-(2-azido-2-phenylacetamido)penicillanic acid | |
Matin | Synthesis of D-glucose derived oxetane: 1, 2-O-isopropylidene-4-(S)-3-O, 4-C-methylene-5-O-methanesulfonyl-bL-threopento-1, 4-furanose | |
US3946085A (en) | Acetals derived from negatively substituted aldehydes and polynitro- or halonitroethanols | |
JPH0662591B2 (en) | Novel thioproline derivative | |
KR100548989B1 (en) | Manufacturing of 3-O-Alkyl-ascorbic Acid | |
US4048219A (en) | Acetals derived from negatively substituted aldehydes and polynitro- or halonitroethanols | |
FR2495157A1 (en) | NEW PROCESS FOR PREPARING TETRAHYDRO-5, 6, 7, 7A 4H-THIENO (3, 2-C) PYRIDINONES-2 | |
EP0611758B1 (en) | Process for synthesizing 4-halo-5(hydroxymethyl) imidazole compounds and certain novel 4-halo-5(hydroxymethyl) imidazole compounds | |
Krutošíková et al. | The synthesis and reactions of arylfurocondensed derivatives | |
KR890002253B1 (en) | Process for preparing thiazole compound | |
US4153631A (en) | Process for processing silver halide developing agents | |
SU1698253A1 (en) | Process for preparing hexahydro-5-hydroxy-4-hydroxymethyl-2h-cyclopentafuran-2-one derivatives | |
RU2247720C1 (en) | 1-(2-pyridyl)-1,2-ethandiol preparation method | |
SU765270A1 (en) | Octahydroimidazo-/4,5-e/-thiazolo-/3,2-b/-1,2,4-triazinediones-3,7 and their preparation method |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
AK | Designated contracting states |
Designated state(s): BE CH DE FR GB LU NL |
|
17P | Request for examination filed | ||
GRAA | (expected) grant |
Free format text: ORIGINAL CODE: 0009210 |
|
AK | Designated contracting states |
Designated state(s): BE CH DE FR GB LU NL |
|
REF | Corresponds to: |
Ref document number: 2860399 Country of ref document: DE Date of ref document: 19810226 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LU Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 19810630 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: LU Payment date: 19830401 Year of fee payment: 6 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: FR Payment date: 19840321 Year of fee payment: 7 Ref country code: DE Payment date: 19840321 Year of fee payment: 7 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: BE Payment date: 19840630 Year of fee payment: 7 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: CH Payment date: 19840726 Year of fee payment: 7 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: NL Payment date: 19860630 Year of fee payment: 9 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: CH Effective date: 19870630 |
|
BERE | Be: lapsed |
Owner name: PFIZER INC. Effective date: 19870630 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: NL Effective date: 19880101 |
|
NLV4 | Nl: lapsed or anulled due to non-payment of the annual fee | ||
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: FR Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 19880226 |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: PL |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: DE Effective date: 19880301 |
|
GBPC | Gb: european patent ceased through non-payment of renewal fee | ||
REG | Reference to a national code |
Ref country code: FR Ref legal event code: ST |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: GB Effective date: 19881117 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: BE Effective date: 19890630 |
|
PLBE | No opposition filed within time limit |
Free format text: ORIGINAL CODE: 0009261 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT |