DK154649B - METHOD FOR PREPARING 2-KETOGULONIC ACID - Google Patents
METHOD FOR PREPARING 2-KETOGULONIC ACID Download PDFInfo
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- DK154649B DK154649B DK470179AA DK470179A DK154649B DK 154649 B DK154649 B DK 154649B DK 470179A A DK470179A A DK 470179AA DK 470179 A DK470179 A DK 470179A DK 154649 B DK154649 B DK 154649B
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- DK
- Denmark
- Prior art keywords
- acid
- diketogluconate
- borane
- process according
- amine
- Prior art date
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- 239000002253 acid Substances 0.000 title claims description 37
- 238000000034 method Methods 0.000 title claims description 37
- RKFLKNFLAJISPF-OGXRZFKVSA-L calcium;(3s,4s)-3,4,6-trihydroxy-2,5-dioxohexanoate Chemical compound [Ca+2].OCC(=O)[C@@H](O)[C@H](O)C(=O)C([O-])=O.OCC(=O)[C@@H](O)[C@H](O)C(=O)C([O-])=O RKFLKNFLAJISPF-OGXRZFKVSA-L 0.000 claims description 44
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 43
- 229910000085 borane Inorganic materials 0.000 claims description 27
- 150000001412 amines Chemical class 0.000 claims description 20
- 239000000243 solution Substances 0.000 claims description 15
- RXMWXENJQAINCC-DMTCNVIQSA-N 2,5-didehydro-D-gluconic acid Chemical group OCC(=O)[C@@H](O)[C@H](O)C(=O)C(O)=O RXMWXENJQAINCC-DMTCNVIQSA-N 0.000 claims description 13
- 125000004432 carbon atom Chemical group C* 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 13
- 125000005907 alkyl ester group Chemical group 0.000 claims description 12
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- -1 methyl 2,5-diketogluconate Chemical compound 0.000 claims description 11
- 239000011734 sodium Substances 0.000 claims description 11
- 229910052708 sodium Inorganic materials 0.000 claims description 11
- 229910052783 alkali metal Inorganic materials 0.000 claims description 10
- 150000001340 alkali metals Chemical class 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000007864 aqueous solution Substances 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 5
- NNTOJPXOCKCMKR-UHFFFAOYSA-N boron;pyridine Chemical compound [B].C1=CC=NC=C1 NNTOJPXOCKCMKR-UHFFFAOYSA-N 0.000 claims description 5
- 229910052791 calcium Inorganic materials 0.000 claims description 5
- 239000011575 calcium Substances 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 4
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 4
- 239000006184 cosolvent Substances 0.000 claims description 3
- 125000005207 tetraalkylammonium group Chemical group 0.000 claims description 3
- 125000004429 atom Chemical group 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 35
- 238000006722 reduction reaction Methods 0.000 description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 20
- VBUYCZFBVCCYFD-JJYYJPOSSA-N 2-dehydro-D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C(=O)C(O)=O VBUYCZFBVCCYFD-JJYYJPOSSA-N 0.000 description 17
- 235000010323 ascorbic acid Nutrition 0.000 description 15
- 229960005070 ascorbic acid Drugs 0.000 description 15
- 239000011668 ascorbic acid Substances 0.000 description 15
- 239000007858 starting material Substances 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 9
- 238000004458 analytical method Methods 0.000 description 8
- 239000003638 chemical reducing agent Substances 0.000 description 8
- 150000004702 methyl esters Chemical class 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 238000000855 fermentation Methods 0.000 description 6
- 230000004151 fermentation Effects 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- CIWBSHSKHKDKBQ-DUZGATOHSA-N D-araboascorbic acid Natural products OC[C@@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-DUZGATOHSA-N 0.000 description 5
- 239000007795 chemical reaction product Substances 0.000 description 5
- 235000010350 erythorbic acid Nutrition 0.000 description 5
- 239000004318 erythorbic acid Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 239000003456 ion exchange resin Substances 0.000 description 5
- 229920003303 ion-exchange polymer Polymers 0.000 description 5
- 229940026239 isoascorbic acid Drugs 0.000 description 5
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 3
- 238000011946 reduction process Methods 0.000 description 3
- 239000011347 resin Substances 0.000 description 3
- 229920005989 resin Polymers 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 2
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 229910052796 boron Inorganic materials 0.000 description 2
- RJTANRZEWTUVMA-UHFFFAOYSA-N boron;n-methylmethanamine Chemical compound [B].CNC RJTANRZEWTUVMA-UHFFFAOYSA-N 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 159000000007 calcium salts Chemical class 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 238000007273 lactonization reaction Methods 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 150000005621 tetraalkylammonium salts Chemical class 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- JYHRLWMNMMXIHF-UHFFFAOYSA-N (tert-butylamino)boron Chemical compound [B]NC(C)(C)C JYHRLWMNMMXIHF-UHFFFAOYSA-N 0.000 description 1
- SIWVGXQOXWGJCI-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;2-ethenylbenzenesulfonic acid Chemical compound C=CC1=CC=CC=C1C=C.OS(=O)(=O)C1=CC=CC=C1C=C SIWVGXQOXWGJCI-UHFFFAOYSA-N 0.000 description 1
- PKAUICCNAWQPAU-UHFFFAOYSA-N 2-(4-chloro-2-methylphenoxy)acetic acid;n-methylmethanamine Chemical compound CNC.CC1=CC(Cl)=CC=C1OCC(O)=O PKAUICCNAWQPAU-UHFFFAOYSA-N 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- DTAFLBZLAZYRDX-UHFFFAOYSA-N OOOOOO Chemical compound OOOOOO DTAFLBZLAZYRDX-UHFFFAOYSA-N 0.000 description 1
- JWOLLWQJKQOEOL-UHFFFAOYSA-N OOOOOOOOOOOOO Chemical compound OOOOOOOOOOOOO JWOLLWQJKQOEOL-UHFFFAOYSA-N 0.000 description 1
- RTYZCUMXOXNVSI-UHFFFAOYSA-N OOOOOOOOOOOOOOOOOO Chemical compound OOOOOOOOOOOOOOOOOO RTYZCUMXOXNVSI-UHFFFAOYSA-N 0.000 description 1
- FYKAKDPHDGCKTF-UHFFFAOYSA-N OOOOOOOOOOOOOOOOOOO Chemical compound OOOOOOOOOOOOOOOOOOO FYKAKDPHDGCKTF-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 235000012501 ammonium carbonate Nutrition 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- JBANFLSTOJPTFW-UHFFFAOYSA-N azane;boron Chemical compound [B].N JBANFLSTOJPTFW-UHFFFAOYSA-N 0.000 description 1
- 238000010923 batch production Methods 0.000 description 1
- QFLVHLKRNQNMGT-UHFFFAOYSA-N boron;methanamine Chemical compound [B].NC QFLVHLKRNQNMGT-UHFFFAOYSA-N 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000010924 continuous production Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000001030 gas--liquid chromatography Methods 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- KPHIBLNUVRGOGU-WDCZJNDASA-N methyl (3s,4r,5r)-3,4,5,6-tetrahydroxy-2-oxohexanoate Chemical compound COC(=O)C(=O)[C@@H](O)[C@H](O)[C@H](O)CO KPHIBLNUVRGOGU-WDCZJNDASA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000010352 sodium erythorbate Nutrition 0.000 description 1
- 239000004320 sodium erythorbate Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- RBWSWDPRDBEWCR-RKJRWTFHSA-N sodium;(2r)-2-[(2r)-3,4-dihydroxy-5-oxo-2h-furan-2-yl]-2-hydroxyethanolate Chemical compound [Na+].[O-]C[C@@H](O)[C@H]1OC(=O)C(O)=C1O RBWSWDPRDBEWCR-RKJRWTFHSA-N 0.000 description 1
- 238000011916 stereoselective reduction Methods 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical class C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/377—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
iin
DK 154649 BDK 154649 B
Opfindelsen angår en fremgangsmåde til fremstilling af 2-ketogulonsyre, dens alkylestere og salte ved selektiv reduktion af 2,5-diketogluconsyre, alkylestere eller salte deraf. 2-Ketogulonsyre er anvendelig som 5 mellemprodukt ved fremstillingen af ascorbinsyre.The invention relates to a process for the preparation of 2-ketogulonic acid, its alkyl esters and salts by selectively reducing 2,5-diketogluconic acid, alkyl esters or salts thereof. 2-Ketogulonic acid is useful as an intermediate in the preparation of ascorbic acid.
Den fuldstændige reduktion af 2,5-diketogluconsyre med et overskud af natriumborhydrid er blevet beskrevet som en del af en strukturbestemmelse af syren, se Agr. Biol. Chem., 28, 819 (1964); J. Biol. Chem., 10 204, 34 (1953) og Antonie Van Leeuwenhoeck, 37, 185 (1971). Den katalytiske reduktion af 2,5-diketoglucon-syre under anvendelse af Raney-nikkel-katalysator og hydrogen giver et lavt udbytte af en blanding af 2-ke-togluconsyre og 2-ketogulonsyre med 2-ketogluconsyre 15 som det væsentlige produkt, Agr. Biol. Chem.,' 38, 819 (1964). United States patent nr. 4.159.990 beskriver en fremgangsmåde til reduktion af et 2,5-diketogluco-nat med én ækvivalent alkalimetalborhydrid til dannelse af en blanding af 2-ketogulonsyre og 2-ketogluconsyre.The complete reduction of 2,5-diketogluconic acid with an excess of sodium borohydride has been described as part of a structural determination of the acid, see Agr. Biol. Chem., 28, 819 (1964); J. Biol. Chem., 10,204,34 (1953) and Antonie Van Leeuwenhoeck, 37, 185 (1971). The catalytic reduction of 2,5-diketogluconic acid using Raney nickel catalyst and hydrogen gives a low yield of a mixture of 2-ketogluconic acid and 2-ketogulonic acid with 2-ketogluconic acid 15 as the major product, Agr. Biol. Chem., 38, 819 (1964). United States Patent No. 4,159,990 discloses a process for reducing a 2,5-diketogluconate with one equivalent of alkali metal borohydride to form a mixture of 2-ketogulonic acid and 2-ketogluconic acid.
20 Det har nu vist sig, at et 2,5-diketogluconat kan reduceres med større regioselektivitet og stereoselektivitet, hvorved der opnås højere udbytter af den ønskede 2-ketogulonsyre til påfølgende omdannelse til ascorbinsyre ved hjælp af et amin-boranreducereride 25 middel ved en pH mellem ca. 2 og 7. Således kan der f.eks. opnås udbytter af 2-ketogulonsyre og 2-keto-gluconsyre på 94% eller højere med ca. 96% af produktet som den ønskede 2-ketogulonsyre ved denne fremgangsmåde. Disse højere udbytter kan opnås uden at udføre 30 reduktionsreaktionen i nærværelse af et borkompleks-dannende middel, som er nødvendigt for optimale udbytter i alkalimetalborhydridreduktionen. Det har også vist sig, at 2-ketogulonsyre, der er dannet ved denne fremgangsmåde, ikke udsættes for yderligere reduktion, 35 dvs. reduktion af 2-ketogruppen med en middel hastighed endog i nærværelse af overskydende amin-boranreduce-ringsmiddel. 2-Ketogruppen af 2-ketogulonsyre reduceres imidlertid hurtigt af et alkalimetalborhydrid, 2It has now been found that a 2,5-diketogluconate can be reduced with greater regioselectivity and stereoselectivity, thereby obtaining higher yields of the desired 2-ketogulonic acid for subsequent conversion to ascorbic acid by an amine-borane reducing agent at a pH between approx. 2 and 7. Thus, e.g. yields of 2-ketogulonic acid and 2-keto-gluconic acid of 94% or higher are obtained by approx. 96% of the product as the desired 2-ketogulonic acid by this process. These higher yields can be obtained without carrying out the reduction reaction in the presence of a boron complexing agent necessary for optimal yields in the alkali metal borohydride reduction. It has also been found that 2-ketogulonic acid formed by this process is not subjected to further reduction, i.e. reduction of the 2-keto group at an average rate even in the presence of excess amine boron reducing agent. However, the 2-keto group of 2-ketogulonic acid is rapidly reduced by an alkali metal borohydride, 2
DK 154649 BDK 154649 B
hvilket resulterer i udbytter af 2-ketogulonsyre, der er mindre end det optimale, når det fremstilles ved al-kalimetalborhydridreduktionen af et 2,5-diketogluconat og udelukker anvendelsen af overskydende alkalimetal-5 borhydrid for at forøge reduktions- og omdannelseshastigheden af 2,5-diketogluconatudgangsmaterialet. Yderligere er 2,5-diketogluconatet mest stabil under de sure betingelser, der anvendes i den omhandlede amin-boran-reduktion.resulting in yields of 2-ketogulonic acid which are less than optimal when prepared by the alkali metal borohydride reduction of a 2,5-diketogluconate and preclude the use of excess alkali metal borohydride to increase the rate of reduction and conversion of 2.5 -diketogluconatudgangsmaterialet. Further, the 2,5-diketogluconate is most stable under the acidic conditions used in the subject amine-borane reduction.
10 Opfindelsen angår en fremgangsmåde til frem stilling af et 2-ketogulonat, der omfatter reduktion af et 2,5-diketogluconat med en amin-boran med formlen 1 2 R R NH.BHg eller med pyridin-boran i opløsning ved en pH mellem ca. 2 og 7 ved en temperatur mellem ca.The invention relates to a process for the preparation of a 2-ketogulonate comprising the reduction of a 2,5-diketogluconate with an amine borane of the formula I 2 R R NH.BHg or with pyridine-borane in solution at a pH between about 2 and 7 at a temperature between ca.
15 -20 til 70°C, hvori R^" og R^ hver vælges blandt hydrogen og alkyl med fra 1 til 4 carbonatomer, og det nævnte 2,5-diketogluconat vælges blandt 2,5-diketoglucon-syre, en normal alkylester af nævnte syre, hvori den nævnte alkylgruppe har fra 1 til 4 carbonatomer, og 20 saltet af den nævnte syre med en modion, der vælges blandt et alkalimetal, et jordalkalimetal, ammonium og tetraalkylammonium med fra 1 til 4 carbonatomer i hver alkylgruppe.15 to 20 to 70 ° C, wherein R ^ and R ^ are each selected from hydrogen and alkyl of from 1 to 4 carbon atoms and said 2,5-diketogluconate is selected from 2,5-diketogluconic acid, a normal alkyl ester of said acid wherein said alkyl group has from 1 to 4 carbon atoms and the salt of said acid having a counterion selected from an alkali metal, an alkaline earth metal, ammonium and tetraalkylammonium having from 1 to 4 carbon atoms in each alkyl group.
Foretrukne amin-boranreduceringsmidler med form-1 2 25 len R R HN.BHg omfatter ammoniak-boran, methylamin-boran, dimethylamin-boran og t-butylamin-boran. Pyridin-boran er også en foretrukken aminboran.Preferred amine-borane reducing agents of the formula R 2 HN.BHg include ammonia-borane, methylamine-borane, dimethylamine-borane and t-butylamine-borane. Pyridine borane is also a preferred amine borane.
Omsætningen udføres fortrinsvis ved temperaturer i området 0 til 25°C, fortrinsvis ved en pH i området 30 4 til 6. Foretrukne 2,5-diketogluconatudgangsmaterialer omfatter 2,5-diketogluconsyre, natrium-2,5-diketoglu-conat, calcium-2,5-diketogluconat og methyl-2,5-diketogluconat.The reaction is preferably carried out at temperatures in the range 0 to 25 ° C, preferably at a pH in the range 30 to 6. Preferred 2,5-diketogluconate starting materials include 2,5-diketogluconic acid, sodium 2,5-diketogluconate, calcium-2 , 5-diketogluconate and methyl 2,5-diketogluconate.
Den omhandlede fremgangsmåde giver en regio- og 35 stereoselektiv reduktion af et 2,5-diketogluconat med en amin-boran. Reaktionsproduktet er i det væsentlige et 2-ketogulonat, idet der kun dannes mindre mængder, ca. 2 til 12% af et 2-ketogluconat. Reaktionsproduktet 3The present process provides a regio- and stereoselective reduction of a 2,5-diketogluconate with an amine borane. The reaction product is essentially a 2-ketogulonate, with only minor amounts being formed, ca. 2 to 12% of a 2-ketogluconate. The reaction product 3
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er derfor velegnet til fremstilling af ascorbinsyre med kendte metoder, f.eks. den basekatalyserede lactonise-ring af de lavere alkylestere af 2-ketogulonsyre. Om ønsket kan de mindre mængder 2-ketogluconsyre, der er 5 til stede i reaktionsproduktet, omdannes til erythorbin-syre ved lignende metoder enten separat eller samtidig med omdannelsen af 2-ketogulonatet til ascorbinsyre.is therefore suitable for the preparation of ascorbic acid by known methods, e.g. the base-catalyzed lactonization of the lower alkyl esters of 2-ketogulonic acid. If desired, the smaller amounts of 2-ketogluconic acid present in the reaction product can be converted to erythorbic acid by similar methods either separately or simultaneously with the conversion of the 2-ketogulonate to ascorbic acid.
2,5-Diketogluconatet, der anvendes som udgangsmateriale . ifølge opfindelsen, kan enten være 2,5-dike-10 togluconsyre eller salte af syren. Passende salte omfatter de,der som modion har et alkalimetal, et jordal-kalimetal, ammonium og tetraalkylammonium, hvor alkyl-grupperne har fra 1 til 4 carbonatomer. Anvendelige som udgangsmateriale til den omhandlede fremgangsmåde 15 er også de normale alkylestere af 2,5-diketogluconsyre, hvori alkylgruppen har fra 1 til 4 carbonatomer. Som anvendt i denne beskrivelse og medfølgende krav omfatter udtrykkene 2,5-diketogluconat, 2-ketogulonat og 2-ketogluconat de frie syrer og passende alkylestere 20 og salte deraf som beskrevet tidligere. 2,5-Diketoglu-consyren og saltene deraf kan fremstilles ved en vilkårlig kendt metode. I almindelighed fremstilles 2,5-diketogluconatet som calciumsaltet i vandig opløsning ved gæring under anvendelse af fremgangsmåder, der er 25 velkendte inden for gæringsindustrien, og kan anvendes direkte i denne form som udgangsmateriale ved den omhandlede fremgangsmåde. 2,5-Diketogluconatet kan også fremstilles ved gæring i nærværelse af andre ioner såsom natrium,og det fremkomne natrium-2,5-diketoglu-30 conat kan ligeledes anvendes direkte i den omhandlede fremgangsmåde. Ved en alternativ metode fremstilles 2,5-diketogluconatet på den sædvanlige måde som calcium- 2,5-diketogluconatet og omdannes til den ønskede forbindelse ved tilsætning af et salt, der er effektivt 35 til at udfælde calcium og efterlade 2,5-diketogluconatet i opløsning med den ønskede modion. Således kan f.eks. natrium- eller ammonium-2,5-diketogluconatet fremstilles ved tilsætning af henholdsvis natrium- 4The 2,5-diketogluconate used as starting material. according to the invention can be either 2,5-dike-10-trigluconic acid or salts of the acid. Suitable salts include those which, as a counterion, have an alkali metal, an alkaline earth metal, ammonium and tetraalkylammonium, the alkyl groups having from 1 to 4 carbon atoms. Also useful as starting material for the present process 15 are the normal alkyl esters of 2,5-diketogluconic acid, wherein the alkyl group has from 1 to 4 carbon atoms. As used in this specification and accompanying claims, the terms 2,5-diketogluconate, 2-ketogulonate and 2-ketogluconate include the free acids and appropriate alkyl esters 20 and salts thereof as previously described. The 2,5-diketogluconic acid and its salts can be prepared by any known method. In general, the 2,5-diketogluconate is prepared as the calcium salt in aqueous solution by fermentation using methods well known in the fermentation industry and can be used directly in this form as a starting material in the process of the present invention. The 2,5-diketogluconate may also be prepared by fermentation in the presence of other ions such as sodium, and the resulting sodium 2,5-diketogluconate may also be used directly in the process of the present invention. In an alternative method, the 2,5-diketogluconate is prepared in the usual manner as the calcium 2,5-diketogluconate and converted to the desired compound by the addition of a salt which is effective to precipitate calcium and leave the 2,5-diketogluconate in solution with the desired counterion. Thus, e.g. the sodium or ammonium 2,5-diketogluconate is prepared by adding sodium 4, respectively
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eller ammoniumcarbonat til en opløsning af calcium-2,5-diketogluconat, der er fremstilles ved gæring. Calcium udfældes som calciumcarbonat, hvilket efterlader 2,5-diketogluconatet i opløsning med natrium- eller ammo-5 niummodionerne. Den frie syre kan også neutraliseres med et passende hydroxid eller andet salt. Om ønsket kan 2,5-diketogluconatet isoleres, renses og genopløses.or ammonium carbonate to a solution of calcium 2,5-diketogluconate prepared by fermentation. Calcium is precipitated as calcium carbonate, leaving the 2,5-diketogluconate in solution with the sodium or ammonium counterions. The free acid can also be neutralized with a suitable hydroxide or other salt. If desired, the 2,5-diketogluconate can be isolated, purified and redissolved.
De normale alkylestere af 2,5-diketogluconsyre, 10 hvori alkyl har 1 til 4 carbonatomer, kan fremstilles ved at opvarme en opløsning af 2,5-diketogluconsyre eller et passende salt deraf i den passende normale alkanol ved 50°C til 100°C i nærværelse af en katalytisk mængde stærk syre, såsom koncentreret svovlsyre, 15 saltsyre, p-toluensulfonsyre og lignende til dannelse af den tilsvarende alkyl-2,5-diketogluconat-5,5-di-alkylacetal. Salte af 2,5-diketogluconsyre, der er passende til fremstilling af estrene på denne måde, omfatter alkalimetal-, jordalkalimetal-, ammonium-20 og tetraalkylammoniumsaltene,. hvori hver alkylgruppe i tetraalkylammoniumionen har fra 1 til 4 carbonatomer. Acetalen hydrolyseres derpå med vandig syre ved en temperatur mellem ca. -10°C og 30°C til opnåelse af den ønskede alkylester af 2,5-diketogluconsyre. Passen-25 de syrer omfatter vandig saltsyre, trifluoreddikesyre, svovlsyre, sulfonsyreionbytterresiner og lignende.The normal alkyl esters of 2,5-diketogluconic acid, wherein alkyl has 1 to 4 carbon atoms, can be prepared by heating a solution of 2,5-diketogluconic acid or a suitable salt thereof in the appropriate normal alkanol at 50 ° C to 100 ° C. in the presence of a catalytic amount of strong acid such as concentrated sulfuric acid, hydrochloric acid, p-toluenesulfonic acid and the like to form the corresponding alkyl 2,5-diketogluconate-5,5-di-alkyl acetal. Salts of 2,5-diketogluconic acid suitable for preparing the esters in this manner include the alkali metal, alkaline earth metal, ammonium-20 and tetraalkylammonium salts. wherein each alkyl group in the tetraalkylammonium ion has from 1 to 4 carbon atoms. The acetal is then hydrolyzed with aqueous acid at a temperature between ca. -10 ° C and 30 ° C to give the desired alkyl ester of 2,5-diketogluconic acid. Suitable acids include aqueous hydrochloric acid, trifluoroacetic acid, sulfuric acid, sulfonic acid ion exchange resins and the like.
Såfremt der anvendes et alkalimetal-2,5-diketo-gluconat som udgangsmateriale i den omhandlede amin-boranreduktionsfremgangsmåde foretrækkes natriumsaltet.If an alkali metal 2,5-diketo-gluconate is used as starting material in the subject amine borane reduction process, the sodium salt is preferred.
30 Et foretrukkent jordalkali-2,5-diketogluconat er calciumsaltet. Når der anvendes tetraalkylammoniumsalte foretrækkes tetramethylammoniumsaltet. Et foretrukkent alkylesterudgangsmateriale er methyl-2,5-diketogluco-nat.A preferred alkaline earth 2,5-diketogluconate is the calcium salt. When tetraalkylammonium salts are used, the tetramethylammonium salt is preferred. A preferred alkyl ester starting material is methyl 2,5-diketogluconate.
35 Reduktionen af 2,5-diketogluconatet udføres ved at bringe en opløsning af 2,5-diketogluconatet i kontakt med en effektiv mængde af en amin-boran med 12 12 formlen R R HN.BH^, hvori R og R er defineret som 5The reduction of the 2,5-diketogluconate is accomplished by contacting a solution of the 2,5-diketogluconate with an effective amount of an amine borane of the formula R 12 HN.BH ^ wherein R and R are defined as 5
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tidligere eller med pyridin-boran. Fortrinsvis udføres omsætningen i vandig opløsning eventuelt indeholdende organiske medopløsningsmidler, såsom,men ikke begrænset til, alkanoler med 1 til 4 carbonatomer, alkandioler 5 med fra 2 til 4 carbonatomer og lignende. Methanol er et foretrukkent medopløsningsmiddel. Koncentrationen af 2,5-diketogluconatet er ikke kritisk, men ligger fortrinsvis mellem ca. 5 og 20 vægt%. Koncentrationen af 2,5-diketogluconatet, der fremstilles ved gæring 10 er i almindelighed inden for dette område og giver derfor en passende vandig opløsning af udgangsmaterialet i den omhandlede fremgangsmåde. Når der anvendes en alkylester som udgangsmateriale, kan omsætningen blive udført i anhydride opløsningsmidler, såsom alka-15 noler især methanol. Under alle omstændigheder er det ikke nødvendigt, at alt 2,5-diketogluconatet er opløst i opløsningsmidlet, forudsat at en væsentlig del af udgangsmaterialets materiale er i opløsning.previously or with pyridine-borane. Preferably, the reaction is carried out in aqueous solution optionally containing organic co-solvents such as, but not limited to, alkanols having 1 to 4 carbon atoms, alkanediols 5 having from 2 to 4 carbon atoms and the like. Methanol is a preferred co-solvent. The concentration of the 2,5-diketogluconate is not critical, but is preferably between ca. 5 and 20% by weight. The concentration of the 2,5-diketogluconate produced by fermentation 10 is generally within this range and therefore provides a suitable aqueous solution of the starting material in the process of the present invention. When an alkyl ester is used as a starting material, the reaction can be carried out in anhydride solvents such as alkanols, especially methanol. In any case, it is not necessary that all of the 2,5-diketogluconate be dissolved in the solvent, provided that a substantial portion of the starting material is dissolved.
Amin-boranerne, der er anvendelige som reduce-20 ringsmidler ved den omhandlede fremgangsmåde er velkendte for fagmanden og er i almindelighed kommercielt tilgængelige, se f.eks. C. F. Lane, Aldrichimica' 6_, 51 (1973). Om ønsket kan de fremstilles ved kendte metoder, f.eks. ved omsætning af diboran med en passende amin 1 2 25 med formlen R R NH til dannelse af amin-boranen 1 2 R R HN.BH^, idet omsætningen i almindelighed udføres ved temperaturer omkring 0°C eller mindre.The amine boranes useful as reducing agents in the process of the present invention are well known to those skilled in the art and are generally commercially available, see e.g. C. F. Lane, Aldrichimica '6_, 51 (1973). If desired, they can be prepared by known methods, e.g. by reacting diborane with a suitable amine 1 2 25 of the formula R R NH to form the amine borane 1 2 R R HN.BH 2, the reaction being generally carried out at temperatures around 0 ° C or less.
Mængden af amin-boran, der anvendes i reduktionsreaktionen vil bestemme den mængde af 2,5-diketoglu-30 conatudgangsmaterialet, der er til stede i reaktionsblandingen, der vil blive omdannet til det ønskede reaktionsprodukt. Fortrinsvis anvendes tilstrækkeligt amin-boran til at omdanne alt 2,5-diketogluconatudgangsmate-rialet, der er til stede i reaktionsblandingen, eftersom 35 dette vil give optimale udbytter af det ønskede 2-keto-gulonat, der er velegnet til påfølgende omdannelse til ascorbinsyre. Om ønsket kan der imidlertid anvendes mindre mængder af amin-boranreduceringsmidlet for at 6The amount of amine borane used in the reduction reaction will determine the amount of the 2,5-diketogluconate starting material present in the reaction mixture which will be converted into the desired reaction product. Preferably, sufficient amine borane is used to convert all of the 2,5-diketogluconate starting material present in the reaction mixture, as this will provide optimal yields of the desired 2-keto-gulonate suitable for subsequent conversion to ascorbic acid. However, if desired, smaller amounts of the amine borane reducing agent may be used to 6
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opnå lavere omdannelse, dvs. reduktion af kun en del af 2,5-diketogluconatet, der er til stede i reaktionsblandingen. Uomsat 2,5-diketogluconat kan derpå føres tilbage og udsættes for yderligere reduktionsreaktioner.achieve lower conversion, ie. reduction of only a portion of the 2,5-diketogluconate present in the reaction mixture. Unreacted 2,5-diketogluconate can then be returned and subjected to further reduction reactions.
5 Det er tilsigtet,at beskrivelsen og de vedhæftede krav omfatter såvel de ovennævnte måder at udføre den omhandlede opfindelse på som andre fremgangsmåder til at udføre reduktionen,og som er nærliggende for fagmanden såsom, men ikke begrænset til, at udføre reduktionen 10 som enten en batch- eller kontinuert proces.It is intended that the disclosure and the appended claims include both the aforementioned ways of carrying out the present invention as well as other methods for effecting the reduction and which are apparent to those skilled in the art such as, but not limited to, the reduction 10 as either a batch or continuous process.
Et mol af en amin-boran indeholder tre ækvivalenter hydridion. Således kan der opnås høje udbytter af det ønskede 2-ketogulonat ved at anvende mellem ca. 0,3 til ca. 0,4 mol, fortrinsvis ca. 0,33 mol, amin-boran 15 pr. mol 2,5-diketogluconatudgangsmateriale i reaktionsblandingen. Efter som 2-ketogruppen i produktet 2-keto-gulonat kun reduceres meget langsomt af overskydende amin-boranreduceringsmiddel,især såfremt R og R begge er forskellige fra hydrogen, kan der imidlertid om 20 ønsket opnås større reduktionshastigheder for 5-keto-gruppen ved anvendelse af relativt større mængder reduceringsmiddel, f.eks. op til ca. 2 til 3 mol amin-boran pr. mol 2,5-diketogluconat og anvendelsen af et sådant overskud sikrer fuldstændig omdannelse af 25 2,5-diketogluconatudgangsmaterialet i reaktionsblandingen. Amin-boranreduceringsmidlet kan sættes til opløsningen af 2,5-diketogluconat enten på en gang ved reaktionens start eller i portioner under reaktionens forløb og kan tilsættes enten som fast stof eller som 30 en opløsning.One mole of an amine borane contains three equivalents of hydride ion. Thus, high yields of the desired 2-ketogulonate can be obtained by using between ca. 0.3 to approx. 0.4 mol, preferably approx. 0.33 mole, amine borane 15 pr. mole of 2,5-diketogluconate starting material in the reaction mixture. However, since the 2-keto group in the product 2-keto-gulonate is only very slowly reduced by excess amine-borane reducing agent, especially if R and R are both different from hydrogen, however, if desired, greater reduction rates for the 5-keto group can be obtained if used. of relatively larger amounts of reducing agent, e.g. up to approx. 2 to 3 moles of amine borane per day. mole of 2,5-diketogluconate and the use of such excess ensures complete conversion of the 2,5-diketogluconate starting material into the reaction mixture. The amine borane reducing agent can be added to the solution of 2,5-diketogluconate either at once at the start of the reaction or in portions during the course of the reaction and can be added either as a solid or as a solution.
Under reduktionen af 2,5-diketogluconatet med amin-boranen bør opløsningens pH holdes ved mellem ca.During the reduction of the 2,5-diketogluconate with the amine borane, the pH of the solution should be maintained at between ca.
2 og 7, fortrinsvis mellem ca. 4 og 6. For at holde pH i det ovennævnte område kan reaktionsblandingen tilsæt-35 tes en syre såsom en mineralsyre, f.eks. saltsyre, svovlsyre, phosphorsyre og lignende eller en organisk syre såsom en lavere alkylcarboxylsyre, f.eks. en C^-Cg alkylcarboxylsyre. pH i en vandig opløsning af natrium- 72 and 7, preferably between ca. 4 and 6. To maintain the pH in the above range, the reaction mixture may be added to an acid such as a mineral acid, e.g. hydrochloric acid, sulfuric acid, phosphoric acid and the like or an organic acid such as a lower alkyl carboxylic acid, e.g. and C ^-Cg alkyl carboxylic acid. pH in an aqueous solution of sodium 7
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eller calcium-2,5-diketogluconat fremstillet ved gæring er i almindelighed lavere end 5, og en sådan opløsning er derfor velegnet til anvendelse i den omhandlede reduktionsproces.or calcium-2,5-diketogluconate produced by fermentation is generally lower than 5, and such a solution is therefore suitable for use in the present reduction process.
5 Det tidsrum, der er nødvendig for at færdiggøre reduktionen, vil afhænge af temperaturen og de anvendte mængder af reagenser. I almindelighed vil reaktionstiderne imidlertid være relativt korte, idet reaktionen i det væsentlige er færdig inden for et tidsrum fra 10 ca. 15 minutter til ca. 3 timer. Ved afslutning af den selektive reduktion kan alt uomsat 2,5-diketogluconat føres tilbage til yderligere reaktion, eller det kan fjernes effektivt fra reaktionsblandingen ved opvarmning med en syre eller base efterfulgt af filtrering.5 The amount of time needed to complete the reduction will depend on the temperature and amounts of reagents used. Generally, however, reaction times will be relatively short, with the reaction being substantially complete within a period of about 10 minutes. 15 minutes to approx. 3 hours. Upon completion of the selective reduction, all unreacted 2,5-diketogluconate may be returned to further reaction or it may be effectively removed from the reaction mixture by heating with an acid or base followed by filtration.
15 2-Ketogulonatet, der er fremstillet ved den oven nævnte fremgangsmåde, kan isoleres sammen med mindre mængder af 2-ketogluconatet ved at filtrere reaktionsblandingen og indstille filtratets pH til mellem ca.The 2-ketogulonate prepared by the above process can be isolated together with smaller amounts of the 2-ketogluconate by filtering the reaction mixture and adjusting the pH of the filtrate to between ca.
1,5 og 2 ved tilsætning af en syre såsom koncentreret 20 svovlsyre og affiltrering og fjernelse af ethvert dannet bundfald.Det ønskede produkt kan opsamles ved at fjerne vandet eller vandet og det organiske med- opløsningsmiddel f.eks. ved frysetørring eller opvarmning under reduceret tryk. Forholdet mellem 2-ketogulonsyre og 2-25 ketogluconsyre i blandingen kan bestemmes ved gasvæske-chromatografi af de pertrimethylsilylerede methylestere under anvendelse af en fem fods OV-1210 (Ohio Valley Specialty Co.) søjle ved 135°C. Imidlertid kan der anvendes andre analysemetoder f.eks. væskechromatografi 30 eller tyndtlagschromatografi. Det ved den omhandlede reduktionsproces dannede 2-ketogulonsyre kan let konverteres til ascorbinsyre ved metoder, der er kendte for fagmanden. De små mængder 2-ketogluconat i reaktionsblandingen kan adskilles f.eks. ved chromatografi og 35 2-ketogulonatet omdannes til ascorbinsyre. Imidlertid kan blandingen af 2-ketogulonat, der indeholder små mængder 2-ketogluconat anvendes direkte i den efterfølgende omsætning, idet 2-ketogluconatet omsættes til 81.5 and 2 by the addition of an acid such as concentrated sulfuric acid and the filtration and removal of any precipitate formed. The desired product can be collected by removing the water or water and the organic co-solvent e.g. by freeze-drying or heating under reduced pressure. The ratio of 2-ketogulonic acid to 2-25 ketogluconic acid in the mixture can be determined by gas-liquid chromatography of the pertrimethylsilylated methyl esters using a five-foot OV-1210 (Ohio Valley Specialty Co.) column at 135 ° C. However, other methods of analysis may be used e.g. liquid chromatography or thin layer chromatography. The 2-ketogulonic acid formed in the process of reduction can be readily converted to ascorbic acid by methods known to those skilled in the art. The small amounts of 2-ketogluconate in the reaction mixture can be separated e.g. by chromatography and the 2-ketogulonate is converted to ascorbic acid. However, the mixture of 2-ketogulonate containing small amounts of 2-ketogluconate can be used directly in the subsequent reaction, converting the 2-ketogluconate to 8
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erythorbinsyre, der kan adskilles fra det dannede ascor-binsyre. Således kan f.eks. blandingen af 2-ketosyrerne omdannes til methylestrene ved tilbagesvaling i methanol i nærværelse af en syrekatalysator såsom saltsyre eller 5 en sulfonionbytterresin i ca. 3 til 24 timer. Andre estre kan fremstilles på denne måde under anvendelse af den passende alkohol. Estrene dannes direkte, når en alkylester af 2,5-diketogluconsyre er udgangsmateriale for den selektive reduktion: Blandingen af methyl-10 estere kan adskilles og tilbagesvales derpå i methanol i nærværelse af en base såsom natriumhydrogencarbonat i en inert atmosfære. Ved afkøling udfælder natriumas-corbat og natriumerythorbat. De rå salte opsamles ved filtrering, blandes med vand og afioniseres med en kat-15 ionbytterresin såsom Dowex 50 (Dow Chemical Co.).erythorbic acid separable from the ascorbic acid formed. Thus, e.g. the mixture of the 2-keto acids is converted to the methyl esters by refluxing in methanol in the presence of an acid catalyst such as hydrochloric acid or a sulfonic ion exchange resin for approx. 3 to 24 hours. Other esters can be prepared in this way using the appropriate alcohol. The esters are formed directly when an alkyl ester of 2,5-diketogluconic acid is the starting material for the selective reduction: The mixture of methyl esters can be separated and then refluxed in methanol in the presence of a base such as sodium bicarbonate in an inert atmosphere. Upon cooling, sodium ash-corbate and sodium erythorbate precipitate. The crude salts are collected by filtration, mixed with water and deionized with a cation exchange resin such as Dowex 50 (Dow Chemical Co.).
Vandet fjernes og ascorbinsyre og erythrobinsyre omkrystalliseres i methanol-vand til opnåelse af ascorbinsyre, der indeholder små mængde erythorbinsyre. Om ønsket kan ascorbinsyre opnås ved omkrystallisation i 20 f.eks. en 4:1 methanol-vandopløsning. Andre passende opløsningsmidler eller medopløsningsmidler kan anvendes om ønsket. Om ønsket kan methylestrene af 2-ketogulon-syre og 2-ketogluconsyre adskilles og omdannes til henholdsvis ascorbinsyre og erythorbinsyre under an-25 vendelse af de samme betingelser som beskrevet ovenfor for blandingen af estrene.The water is removed and ascorbic acid and erythrobic acid are recrystallized in methanol-water to give ascorbic acid containing small amounts of erythorbic acid. If desired, ascorbic acid can be obtained by recrystallization in e.g. a 4: 1 methanol-aqueous solution. Other suitable solvents or co-solvents may be used if desired. If desired, the methyl esters of 2-ketogulonic acid and 2-ketogluconic acid can be separated and converted into ascorbic acid and erythorbic acid, respectively, using the same conditions as described above for the mixture of the esters.
Ascorbinsyre kan også fremstilles selektivt udfra 2-ketogulonatet, der indeholder små mængder af 2-ketogluconatet og som er opnået ved den omhandlede 30 reduktionsproces ved opvarmning i et passende organisk opløsningsmiddel såsom benzen, toluen, xylen og lignende ved ca. 50°C til 130°C, fortrinsvis 60°C til 90°C i nærværelse af en syre valgt blandt saltsyre, bromsyre, svovlsyre og sulfonionbytterresiner skønt andre lignen-35 de syrer kan anvendes. En foretrukkken syre er saltsyre. Efter opvarmning i et tidsrum af ca. 3 til 12 timer afhængig af den anvendte reaktion er lactonisering af 2-ketogulonatet til ascorbinsyre i det væsentlige 9Ascorbic acid may also be selectively prepared from the 2-ketogulonate containing small amounts of the 2-ketogluconate and obtained by the present reduction process by heating in a suitable organic solvent such as benzene, toluene, xylene and the like at ca. 50 ° C to 130 ° C, preferably 60 ° C to 90 ° C in the presence of an acid selected from hydrochloric, bromic, sulfuric and sulfonic ion exchange resins, although other similar acids may be used. A preferred acid is hydrochloric acid. After heating for a period of approx. 3 to 12 hours, depending on the reaction used, lactonization of the 2-ketogulonate to ascorbic acid is essentially 9
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færdig. Ved denne fremgangsmåde fremstilles erythorbin-syre ikke udfra de små mængder 2-ketogluconat, der er til stede, og denne metode frembyder derfor en enkel metode til selektivt at danne ascorbinsyre udfra reak-5 tionsproduktet fra den omhandlede amin-boranreduktion.done. In this process, erythorbic acid is not prepared from the small amounts of 2-ketogluconate present, and this method therefore provides a simple method to selectively generate ascorbic acid from the reaction product of the subject amine borane reduction.
Den omhandlede opfindelse belyses af de følgende eksempler. Det bør imidlertid bemærkes, at opfindelsen ikke er begrænset til de særlige detaljer i disse eksempler.The present invention is illustrated by the following examples. However, it should be noted that the invention is not limited to the particular details of these examples.
10 Eksempel 1Example 1
Til 100 ml 15% (w/v) vandig opløsning af 2,5-di-ketogluconsyre ved en temperatur på 6-8°C og pH 3,0 blev sat 4,6 g (1,07 mol) borandimethylaminkompleks.To 100 ml of 15% (w / v) aqueous solution of 2,5-di-ketogluconic acid at a temperature of 6-8 ° C and pH 3.0 was added 4.6 g (1.07 mol) of borane dimethylamine complex.
Efter en time angav højtryksvæskechromatografianalyse 15 (Aminex A-21 resin i formatform, ammoniumformatbuffer ved pH 5,0),at fuldstændig reduktion var foregået, hvorefter der blev sat 30 ml acetone til,og opløsningen langsomt hældt over i en opslemning af 150 ml Dowex 50 ionbytterresin (hydrogenform). Efter at hydrogenudvik-20 lingen var ophørt, blev resinen fjernet ved filtrering, opløsningsmidlet fjernet ved rotationsfordampning og resten anbragt i 200 ml vandfrit methanol. Der tilsat-tes Amberlyst 15 ionbytterresinkatalysator (20 ml hydrogenform) ,og methanol/trimethylboratazeotropen blev 25 afdestilleret ved atmosfæretryk med ledsagende esteri-ficering af 2-ketogulonsyren. Methanolopløsningen blev filtreret og reduceret til 30 ml, hvorefter krystallisering gik igang og ved isolering gav 6,9 g methyl-2-keto-gulonat (smp. 152-154°C, lit. 153-154°C). Moderluden 30 blev inddampet in vacuo til et fast stof, der indeholdt 3,5 g methyl-2-ketogulonat og methyl-2-ketogluconat i et forhold på 77:23 (ved glpc analyse af de persilylere-de methylestere på en fem fods OV-210 søjle ved 135°C) svarende til en total reduktionsstereoselektivitet på 35 92:8, 2-ketogulon-: 2-ketogluconsyrer.After one hour, high pressure liquid chromatography analysis 15 (Aminex A-21 resin format, ammonium format buffer at pH 5.0) indicated that complete reduction had taken place, then 30 ml of acetone was added and the solution slowly poured into a slurry of Dowex 150 ml. 50 ion exchange resin (hydrogen form). After hydrogen evolution had ceased, the resin was removed by filtration, the solvent removed by rotary evaporation and the residue placed in 200 ml of anhydrous methanol. Amberlyst 15 ion exchange resin catalyst (20 ml of hydrogen form) was added and the methanol / trimethylborate zeotrope was distilled off at atmospheric pressure with accompanying esterification of the 2-ketogulonic acid. The methanol solution was filtered and reduced to 30 ml, after which crystallization proceeded and on isolation yielded 6.9 g of methyl 2-keto-gulonate (mp 152-154 ° C, lit. 153-154 ° C). The mother liquor 30 was evaporated in vacuo to a solid containing 3.5 g of methyl 2-ketogulonate and methyl 2-ketogluconate in a ratio of 77:23 (by glpc analysis of the persilylated methyl esters on a five foot OV -210 column at 135 ° C) corresponding to a total reduction stereoselectivity of 92: 8, 2-ketogulonic-: 2-ketogluconic acids.
DK 154649 BDK 154649 B
1010
Eksempel 2Example 2
Fremgangsmåden fra eksempel 1 blev gentaget, idet pH blev holdt ved 3,5 med 6 N HC1. Analyse med hlpc (Dowex 50 ionbytterresin i calciumformen 0,01 M 5 CaC^-kuffer ved pH 8) efter 3 timer ved 0°C viste både 2-ketogulonat og 2-ketogluconat i et forhold på 94:6. Omsætningen blev behandlet som beskrevet i eksempel og gav efter esterificering en 96:4 blanding (ved glpc analyse) af methyl-2-ketogulonat og methyl-2-10 ketogluconat.The procedure of Example 1 was repeated, maintaining the pH at 3.5 with 6 N HCl. Analysis with hlpc (Dowex 50 ion-exchange resin in the calcium form 0.01 M 5 CaCl 2 case at pH 8) after 3 hours at 0 ° C showed both 2-ketogulonate and 2-ketogluconate in a ratio of 94: 6. The reaction was treated as described in Example and after esterification gave a 96: 4 mixture (by glpc analysis) of methyl 2-ketogulonate and methyl 2-10 ketogluconate.
Eksempel 3-22Examples 3-22
Reduktionen af natrium-2,5-diketogluconat blev udført med et antal amin-boraner under forskellige temperatur- og pH-betingelser ved den følgende fremgangs-15 måde:The reduction of sodium 2,5-diketogluconate was carried out with a number of amine boranes under various temperature and pH conditions by the following procedure:
Til en omrørt opløsning af 10,5% (w/v) natrium-2, 5-diketogluconat med fastlagt temperatur og pH sættes den faste amin-boran i én portion. For fuldstændighedens skyld følges reaktionerne med hplc analyse (Aminex-25 20 resin i formatform, ammoniumformatbuffer ved pH 5,3) og udbytter bestemmes med hplc analyse med indre standard baseret på de anvendte hydridækvivalenter. Forholdet mellem 2-ketogulon- og 2-ketogluconsyre i eksemplerne 3-20 blev bestemt ved omdannelse som beskrevet i eksem-25 pel 1 til de tilsvarende methylestere og glpc analyse af deres tilsvarende pertrimethylsilylerede methylestere. (5 fod OV-210 søjle ved 135°C). Forhold mellem 2-ketogulon- og 2-ketogluconsyre i eksemplerner 21 til 23 blev bestemt ved omdannelse til ascorbin- og erythor-30 binsyre og analyse af deres tilsvarende pertrimethylsilylerede methylestere ved glpc analyse som beskrevet tidligere.To a stirred solution of 10.5% (w / v) sodium 2,5-diketogluconate at a fixed temperature and pH is added the solid amine borane in one portion. For completeness, the reactions are followed by hplc analysis (Aminex-20 resin in format, ammonium format buffer at pH 5.3) and yields are determined by hplc analysis of internal standard based on the hydride equivalents used. The ratio of 2-ketogulonic to 2-ketogluconic acid in Examples 3-20 was determined by conversion as described in Example 1 to the corresponding methyl esters and glpc analysis of their corresponding pertrimethylsilylated methyl esters. (5 foot OV-210 column at 135 ° C). Relationships between 2-ketogulonic and 2-ketogluconic acid in Examples 21 to 23 were determined by conversion to ascorbic and erythorboxylic acid and analysis of their corresponding pertrimethylsilylated methyl esters by glpc analysis as described previously.
De opnåede resultater var som følger:The results obtained were as follows:
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Claims (10)
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US96562678A | 1978-12-01 | 1978-12-01 | |
US96562678 | 1978-12-01 | ||
US2428479 | 1979-03-26 | ||
US06/024,284 US4212988A (en) | 1979-03-26 | 1979-03-26 | Preparation of 2-ketogulonic acid |
Publications (3)
Publication Number | Publication Date |
---|---|
DK470179A DK470179A (en) | 1980-06-02 |
DK154649B true DK154649B (en) | 1988-12-05 |
DK154649C DK154649C (en) | 1989-05-08 |
Family
ID=26698275
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Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DK470179A DK154649C (en) | 1978-12-01 | 1979-11-06 | METHOD FOR PREPARING 2-KETOGULONIC ACID |
Country Status (10)
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---|---|
CA (1) | CA1140147A (en) |
CH (1) | CH641472A5 (en) |
DE (1) | DE2947741C2 (en) |
DK (1) | DK154649C (en) |
FR (1) | FR2442855A1 (en) |
GB (1) | GB2036740B (en) |
IE (1) | IE49219B1 (en) |
IT (1) | IT1126454B (en) |
LU (1) | LU81936A1 (en) |
NL (1) | NL177313C (en) |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
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MX4533E (en) * | 1976-12-10 | 1982-06-03 | Pfizer | PROCEDURE FOR PREPARING A MIXTURE OF 2-KETOGULONATE AND 2-KETOGLUCONATE |
-
1979
- 1979-11-06 DK DK470179A patent/DK154649C/en not_active IP Right Cessation
- 1979-11-27 GB GB7940847A patent/GB2036740B/en not_active Expired
- 1979-11-27 DE DE2947741A patent/DE2947741C2/en not_active Expired
- 1979-11-29 LU LU81936A patent/LU81936A1/en unknown
- 1979-11-29 CA CA000340867A patent/CA1140147A/en not_active Expired
- 1979-11-29 IE IE2294/79A patent/IE49219B1/en not_active IP Right Cessation
- 1979-11-29 CH CH1063179A patent/CH641472A5/en not_active IP Right Cessation
- 1979-11-30 IT IT27761/79A patent/IT1126454B/en active
- 1979-11-30 FR FR7929467A patent/FR2442855A1/en active Granted
- 1979-11-30 NL NLAANVRAGE7908678,A patent/NL177313C/en not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
GB2036740A (en) | 1980-07-02 |
FR2442855A1 (en) | 1980-06-27 |
NL177313C (en) | 1985-09-02 |
CH641472A5 (en) | 1984-02-29 |
DE2947741A1 (en) | 1980-06-04 |
GB2036740B (en) | 1983-01-19 |
IT7927761A0 (en) | 1979-11-30 |
FR2442855B1 (en) | 1983-02-25 |
DE2947741C2 (en) | 1982-07-01 |
CA1140147A (en) | 1983-01-25 |
NL177313B (en) | 1985-04-01 |
LU81936A1 (en) | 1980-06-05 |
DK470179A (en) | 1980-06-02 |
IE792294L (en) | 1980-06-01 |
IE49219B1 (en) | 1985-08-21 |
DK154649C (en) | 1989-05-08 |
NL7908678A (en) | 1980-06-03 |
IT1126454B (en) | 1986-05-21 |
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