GB2036740A - Process for the preparation of 2- ketogulonic acid - Google Patents
Process for the preparation of 2- ketogulonic acid Download PDFInfo
- Publication number
- GB2036740A GB2036740A GB7940847A GB7940847A GB2036740A GB 2036740 A GB2036740 A GB 2036740A GB 7940847 A GB7940847 A GB 7940847A GB 7940847 A GB7940847 A GB 7940847A GB 2036740 A GB2036740 A GB 2036740A
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- United Kingdom
- Prior art keywords
- borane
- acid
- diketogluconate
- amine
- carbon atoms
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- 238000000034 method Methods 0.000 title claims description 40
- 238000002360 preparation method Methods 0.000 title claims description 6
- 229910000085 borane Inorganic materials 0.000 claims abstract description 57
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims abstract description 57
- 239000002253 acid Substances 0.000 claims abstract description 39
- RXMWXENJQAINCC-DMTCNVIQSA-N 2,5-didehydro-D-gluconic acid Chemical compound OCC(=O)[C@@H](O)[C@H](O)C(=O)C(O)=O RXMWXENJQAINCC-DMTCNVIQSA-N 0.000 claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 125000005907 alkyl ester group Chemical group 0.000 claims abstract description 14
- 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 51
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 239000000243 solution Substances 0.000 claims description 17
- 125000004432 carbon atom Chemical group C* 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 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 10
- 229910052783 alkali metal Inorganic materials 0.000 claims description 10
- 229910052708 sodium Inorganic materials 0.000 claims description 10
- 150000001340 alkali metals Chemical class 0.000 claims description 9
- 239000011734 sodium Substances 0.000 claims description 9
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical group [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 7
- 229910052791 calcium Inorganic materials 0.000 claims description 7
- 239000011575 calcium Substances 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- -1 methyl 2,5-diketogluconate Chemical compound 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 239000006184 cosolvent Substances 0.000 claims description 6
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 4
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 4
- NNTOJPXOCKCMKR-UHFFFAOYSA-N boron;pyridine Chemical group [B].C1=CC=NC=C1 NNTOJPXOCKCMKR-UHFFFAOYSA-N 0.000 claims description 4
- RJTANRZEWTUVMA-UHFFFAOYSA-N boron;n-methylmethanamine Chemical group [B].CNC RJTANRZEWTUVMA-UHFFFAOYSA-N 0.000 claims description 3
- JYHRLWMNMMXIHF-UHFFFAOYSA-N (tert-butylamino)boron Chemical group [B]NC(C)(C)C JYHRLWMNMMXIHF-UHFFFAOYSA-N 0.000 claims description 2
- JBANFLSTOJPTFW-UHFFFAOYSA-N azane;boron Chemical group [B].N JBANFLSTOJPTFW-UHFFFAOYSA-N 0.000 claims description 2
- QFLVHLKRNQNMGT-UHFFFAOYSA-N boron;methanamine Chemical group [B].NC QFLVHLKRNQNMGT-UHFFFAOYSA-N 0.000 claims description 2
- 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
- 238000006243 chemical reaction Methods 0.000 description 23
- 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 16
- 235000010323 ascorbic acid Nutrition 0.000 description 16
- 239000011668 ascorbic acid Substances 0.000 description 15
- 229960005070 ascorbic acid Drugs 0.000 description 15
- 239000007858 starting material Substances 0.000 description 15
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 239000000203 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
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 7
- 150000007513 acids Chemical class 0.000 description 6
- 235000010350 erythorbic acid Nutrition 0.000 description 6
- 238000000855 fermentation Methods 0.000 description 6
- 230000004151 fermentation Effects 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 5
- 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
- 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
- 150000002148 esters Chemical class 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000011946 reduction process Methods 0.000 description 4
- 239000002904 solvent Substances 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
- 239000002585 base Substances 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 229920001467 poly(styrenesulfonates) Polymers 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-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
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical group OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 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
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 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
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000007273 lactonization reaction Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 125000005207 tetraalkylammonium group Chemical group 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
- 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
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-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
- 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
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 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
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 238000010923 batch production Methods 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 229910052799 carbon 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
- 239000000463 material Substances 0.000 description 1
- ZXFVOORFLHHQMG-UHFFFAOYSA-N methanol;trimethyl borate Chemical compound OC.COB(OC)OC ZXFVOORFLHHQMG-UHFFFAOYSA-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
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 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
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 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
- 150000005621 tetraalkylammonium salts Chemical class 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
- 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
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- 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)
Abstract
2,5-Diketogluconic acid, alkyl esters or salts thereof, are reduced regioselectively and stereoselectively by an amine-borane to 2-ketogulonic acid, or alkyl esters or salts thereof.
Description
SPECIFICATION
Process for the preparation of 2-ketogulonic acid
This invention relates to a process for preparing 2-ketogulonic acid, its alkyl esters and salts by the selective reduction of 2,5-diketogluconic acid, alkyl esters or salts thereof. 2-ketogulonic acid is useful as an intermediate for the preparation of ascorbic acid.
The complete reduction of 2,5-diketogluconic acid with an excess of sodium borohydride has been reported as part of a structural determination of the acid, see Agr. Biol. Chem. 28, 819 (1964), J. Biol. Chem.
204, 34 (1953) and Antonie Van Leeuwenhoeck 37, 185 (1971). The catalytic reduction of 2,5-diketogluconic acid using a Raney nickel catalyst and hydrogen gives a low yield of a mixture of 2-ketogluconic acid and 2-ketogulonic acid, with 2-ketogluconic acid being the major product, Agr. Biol. Chem. 28, 819 (1964).
Applicant's United States Patent No. 4159990 discloses a process for the reduction of a 2,5-diketogluconate with one equivalent of an alkali metal borohydride to form a mixture of 2-ketogulonic acid and 2-ketogluconic acid.
It has now been found that a 2,5-diketogluconate can be reduced with greater regioselectivity and stereoselectivity, thereby giving higher yields of the desired 2-ketogulonic acid for subsequent conversion to ascorbic acid, by use of an amine-borane reducing agent at a pH between about 2 and 7. Thus, for example yields of 2-ketogulonic acid and 2-ketogluconic acid of 94% or higher, with about 96% of the product mixture being the desired 2-ketogulonic acid, may be obtained by this process. These higher yields can be obtained without conducting the reduction reaction in the presence of a boron-complexing agent as is required for optimum yields in the alkali metal borohydride reduction.It has also been found that 2-ketogulonic acid formed by this process is not subject to further reduction i.e. reduction of the 2-keto group, at a reasonable rate even in the presence of excess amine-borane reducing agent. The 2-keto group of 2-ketogulonic acid is, however, rapidly reduced by an alkali metal borohydride, resulting in less than optimum yields of 2-ketogulonic acid when formed by the alkali metal borohydride reduction of a 2,5-diketogluconate and precluding the use of excess alkali metal boro-hydride to increase rates of reduction and conversions of the 2,5-diketogluconate starting material. Further, the 2,5-diketogluconate is most stable under the acidic conditions employed in the present amine-borane reduction.
Thus according to the present invention a process for preparing a 2-ketogulonate comprises reducing a 2,5-diketogluconate with an amine-borane of the formula R1R2HN.BH3 or with pyridine-borane in solution at a pH between 2 and 7 at a temperature between -20 to 70"C, wherein R1 and R2 are each hydrogen or alkyl of 1 to 4 carbon atoms; and said 2,5-diketogluconate is 2,5-diketogluconic acid, a normal alkyl ester of said acid wherein said alkyl group is of 1 to 4 carbon atoms, or a salt of said acid having as counterion an alkali metal, an alkaline earth metal, ammonium ortetraalkyl-ammonium having from 1 to 4 carbon atoms in each alkyl group.
Preferred amine-borane reducing agents of the formula R1R2HN.BH3 include ammonia-borane, methylamine-borane, dimethylamine-borane, and t-butylamine-borane. Pyridine-borane is also a preferred amine-borane.
The reaction is preferably conducted at temperatures in the range 0-25"C, preferably at a pH in the range 4 to 6. Preferred 2,5-diketogluconate starting materials include 2,5-diketogluconic acid, sodium 2,5diketogluconate, calcium 2,5-diketogluconate and methyl 2,5-diketogluconate.
The present process thus enables the regioselective and stereoselective reduction of a 2,5-diketogluconate by reaction with an amine-borane. The reaction product is predominantly a 2-ketogulonate, with only minor amounts, about 2 to 12%, of a 2-ketogluconate beinq,formed. The reaction product is therefore suitable for the preparation of ascorbic acid by means known in the art, for example the base catalyzed lactonization of the lower alkyl esters of 2-ketogulonic acid. If desired, the minor amounts of 2-ketogluconic acid present in the reaction product may be converted to erythorbic acid by similar methods, either separately or concurrently with the conversion of the 2-ketogulonate to ascorbic acid.
The 2,5-diketogluconate used as the starting material in the present invention may be either 2,5-diketogluconic acid or salts of the acid. Suitable salts include those having as counterions on alkali metal, an alkaline earth metal, ammonium and tetra-alkylammonium where the alkyl groups have from 1 to 4 carbon atoms. Also useful as starting materials for the present process are the normal alkyl esters of 2,5-diketogluconic acid wherein the alkyl group is of 1 to 4 carbon atoms. As used in the specification and claims hereof, the terms 2,5-diketogluconate, 2-ketogulonate and 2-ketogluconate include the free acids and suitable alkyl esters and salts thereof as previously described. The 2,5-diketogluconic acid and salts thereof may be produced by any means known in the art.Generally, the 2,5-diketogluconate is produced as the calcium salt is aqueous solution by fermentation using methods well known in the fermentation industry and may be used directly in this form as the starting material for the present process. The 2,5-diketogluconate can also be produced by fermentation in the presence of other ions such as sodium and the resulting sodium 2,5-diketogluconate may likewise be used directly in the present process. In an alternative method, the 2,5-diketogluconate is prepared in the conventional way as the calcium 2,5-diketogluconate and converted to the desired compound by addition of a salt effective to precipitate calcium and leave the 2,5-diketogluconate in solution with the desired counterion.Thus for example sodium or ammonium 2,5-diketogluconate can be produced by addition of sodium or ammonium carbonate, respectively, to a solution of calcium 2,5-diketogluconate produced by fermentation. Calcium is precipitated as calcium carbonate leaving the 2,5-diketogluconate in solution with sodium or ammonium counterions. The free acid may also be neutralized with an appropriate hydroxide or other salt. If desired, the 2,5-diketogluconate can be isolated, purified and redissolved.
The normal alkyl esters of 2,5-diketogluconic acid wherein alkyl is of 1 to 4 carbon atoms may 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 1000C in the presence of a catalytic amount of a strong acid, such as concentrated sulfuric acid, hydrochloric acid, p-toluene sulfonic acid and the like, to form the corresponding alkyl 2,5-diketogluconate5,5-dialkyl acetal. Salts of 2,5-diketogluconic acid suitable for preparation of the esters by this means include the alkali metal, alkaline earth metal, ammonium and tetraalkyl ammonium salts, wherein each alkyl group of the tetraalkyl ammonium ion has from 1 to 4 carbon atoms.The acetal is then hydrolyzed with aqueous acid at a temperature between about -10"C and 30"C to afford 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.
When an alkali metal 2,5-diketogluconate is utilized as the starting material in the present amine-borane reduction process the sodium salt is preferred. A preferred alkaline earth 2,5-diketogluconate is the calcium salt. When tetraalkyi ammonium salts are employed, the tetramethylammonium salt is preferred. A preferred alkyl ester starting material is methyl 2,5-diketogluconate.
The reduction of the 2,5-diketogluconate is effected by contacting a solution of the 2,5-diketogluconate with an effective amount of an amine-borane of the formula R1R2HN.BH3wherein R1 and R2 are as previously defined, or with pyridine-borane. Preferably, the reaction is effected in aqueous solution, optionally containing organic cosolvents such as, but not limited to, alkanols of 1 to 4 carbon atoms, alkanedoils of 2 to 4 carbon atoms, and the like. Methanol is a preferred cosolvent. The concentration of the 2,5-diketogluconate is not critical but is preferably between about 5 and 20 weight percent. The concentration of the 2,5-diketogluconate formed by fermentation is generally within this range and thereby provides a suitable aqueous solution of the starting material for use in the present process.When an alkyl ester is utilized as starting material the reaction may be conducted in anhydrous solvents, such as alkanols, especially methanol. in all cases, it is not necessary that all the 2,5-diketogluconate be dissolved in the solvent, provided a substantial part of the material of the starting material is in solution.
The amine-boranes useful as reducing agents in the present process are well known in the art and are generally commercially available, see for example C. F. Lane, Aldrichimica 6, 51(1973). If desired, they can be prepared by known methods, for example by the reaction of diborane with an appropriate amine of the formula R1R2NH to form the amine-borane R1R2NH.BH3, the reaction generally being conducted at temperatures of about 0 C or below.
The amount of amine-borane employed in the reduction reaction will determine the amount of 2,5-diketogluconate starting material present in the reaction mixture that will be converted to the desired reaction product. Preferably, sufficient amine-borane will be employed to convert all of the 2,5diketogluconate starting material present in the reaction mixture, since this will give optimum yields of the desired 2-ketogulonate suitable for subsequent conversion to ascorbic acid. However, if desired lesser amounts of the amine-borane reducing agent can be used to achieve lower conversions i.e. reduction of only a part of the 2,5-diketogluconate present in the reaction mixtue. Unreacted 2,5-diketogluconate may then be recycled and subjected to further reduction reactions.It is intended that the specification and claims hereof be understood to include the above methods of practicing the present invention, as well as other procedures for carrying out the reduction which will be evident to those skilled in the art such as, but not limited to, conducting the reduction as either a batch or continuous process.
It will be understood that one mole of an amine-borane contains three equivalents of hydride ion. Thus, high yields of the desired 2-ketogulonate can be formed by employing between about 0.30 to about 0.40 moles, preferably about 0.33 moles, of an amine-borane per mole of 2,5-diketogluconate starting material present in the reaction mixture. However, since the 2-keto group of the product 2-ketogulonate is only very slowly reduced by excess amine-borane reducing agent, especially when R1 and R2 are both other than hydrogen, higher rates of reduction of the 5-keto group can be achieved, if desired, by use of relatively larger amounts of reducing agent, for example up to about 2 to 3 moles of amine-borane per mole of 2,5-diketogluconate and the use of such an excess ensures complete conversion of the 2,5-diketogluconate starting material in the reaction mixture.The amine-borane reducing agent can be added to the solution of the 2,5-diketogluconate either in one batch at the start of the reaction or in portions during the course of the reaction and may be added either as a solid or as a solution.
During the reduction of the 2,5-diketogluconate with the amine-boranethe pH of the solution should be maintained at between about 2 and 7, preferably between about 4 and 6. To maintain the pH in the above range, an acid such as a mineral acid, for example hydrochloric acid, sulfuric acid, phosphoric acid and the like, or an organic acid such as a lower alkyl carboxylic acid, for example a C1 to C5 alkyl carboxylic acid, may be added to the reaction mixture. The pH of an aqueous solution of sodium or calcium 2,5-diketogluconate produced by fermentation is usually lower than 5 and such a solution is therefore suitable for use in the present reduction process.
The time necessary to complete the reduction will depend on the temperature and the amounts of reagents employed. However, generally reaction times will be relatively short with the reaction being substantially complete in periods of about 15 minutes to about 3 hours. On completion of the selective reduction any unreacted 2,5-diketogluconate can be recycled for further reaction or it can be effectively
removed from the reaction mixture by heating with an acid or base followed by filtration.
The 2-ketogulonate formed in the above process can be isolated, together with lesser amounts of the 2-ketogluconate, by filtering the reaction mixture and adjusting the filtrate to a pH between about 1.5 and 2 by addition of an acid such as concentrated sulfuric acid and filtering off and discarding any precipitate that is formed. The desired product can be collected by removing the water or water-organic cosolvent, for example by freeze drying or heating under reduced pressure. The ratio of 2-ketogulonic acid to 2-ketogluconic acid in the mixture can be determined by gas-liquid chromatography of the pertrimethylsilylated methyl esters using a five foot OV-210 (Ohio Valley Specialty Co.) column at 1 350C. However, other methods of analysis, for example liquid chromatography or thin layer chromatography, may be employed.
The 2-ketogulonic acid formed in the present reduction process can readily be converted to ascorbic acid by means known in the art. The small amounts of 2-ketogluconate in the reactionFmixture may be separated, for example by chromatography, and the 2-ketogulonate converted to ascorbic acid. However, the mixture of 2-ketogulonate containing small amounts of 2-ketogluconate can be used directly in the subsequent reaction, the 2-ketogluconate being converted to erythorbic acid, which cambe separated from the ascorbic acid formed. Thus for example, the mixture of the 2-keto acids can be 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 about 3 to 24 hours. Other esters can be formed in this manner 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 is then refluxed in methanol in the presence of a base, such as sodium bicarbonate, in an inert atmosphere. On cooling, sodium ascorbate and sodium erythorbate precipitate out. The crude salts are collected by filtration, mixed with water and deionized with a cation exchange resin such as Dowex (Registered Trade Mark) 50 (Dow Chemical Co.). The water is removed and ascorbic acid and erythrobic acid are recrystallized from methanol-water to give ascorbic acid containing small amounts of erythorbic acid. If desired, ascorbic acid may be obtained by recrystallization from, for example, a 4:1 methanol-water solution. Other suitable solvents or cosolvents can be employed if desired.If desired, the methyl esters of 2-ketogulonic acid and 2-ketogiuconic acid can be separated and converted to ascorbic acid and erythorbic acid respectively using the same conditions as described above for the mixture of esters.
Ascorbic acid can also be prepared selectively from the 2-ketogulonate containing small amounts of the 2-ketogluconate obtained by the present reduction process by heating in a suitable organic solvent, such as benzene, toluene, xylene and the like, at about 50"C to 1 30 C, preferably 60"C to 90"C, in the presence of an acid selected from hydrochloric acid, hydrobromic acid, sulfuric acid and sulfonic ion exchange resins, although other similar acids may be used. A preferred acid is hydrochloric acid. After heating for a period of about 3 to 12 hours, depending on the reaction employed, lactonization of the 2-ketogulonate to ascorbic acid is substantially complete.In this process, erythorbic acid is not produced from the small amounts of 2-ketogluconate present and this method thereby affords a simple method of selectively forming ascorbic acid from the reaction product of the present amine-borane reduction.
The present invention is illustrated by the following examples. It should be understood, however, that the invention is not limited to the specific details of these examples.
Example 1
To 100 ml of a 15% (w/v) aqueous solution of 2,5-diketogluconic acid at a temperature of 6-8"C and pH 3.0 was added 4.6 g (1.07 mole) of borane-dimethylamine complex. After 1 hour h.p.l.c. analysis (Aminex A-21 resin in formate form, ammonium formate buffer atipH 5.0) indicated complete reduction had occurred, whereupon 30 ml of acetone was added and the solution slowly poured into a slurry of 150 ml of Dowex 50 ion exchange resin (hydrogen form). After hydrogen evolution had ceased, the resin was removed by filtration, solvent removed via rotary evaporation and the residue placed in 200 ml of anhydrous methanol.
Amberlyst 15 ion exchange resin catalyst (20 ml, hydrogen form) was added and the methanol trimethylborate azeotrope was distilled off at atmospheric pressure with concomitant esterification of the 2-ketogulonic acid. The methanol solution was filtered and reduced to 30 ml whereupon crystallization proceeded affording on isolation 6.9 g of methyl 2-ketogulonate (mp 152-154"C, lit 153-154"C). The mother liquor was evaporated in vacuo to a solid containing 3.5 g of methyl-2-ketogulonate and methyl-2ketogluconate in a ratio of 77:23 (by glpc analysis of the per-silylated methyl esters on a 5 ft OV-210 column at 135"C), corresponding to an overall reduction stereoselectivity of 92:8,2-ketogulonic: 2-ketogluconic acids.
Example 2
The procedure of Example 1 was repeated maintaining the pH at 3.5 with 6N HC1. Analysis by hlpc (Dowex 50 ion exchange resin in the calcium form, 0.01 M CaC12 buffer 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 1 affording after esterification a 96.4 mixture (by glpc analysis) of methyl 2-ketogulonate and methyl 2-ketogluconate.
Example 3-23
The reduction of sodium 2,5-diketogluconate was effected with a number of amine-boranes, under different temperature and pH conditions, by the following procedure: To a stirred solution of 10.5% (w/v) sodium 2,5-diketogluconate at specified temperature and pH is added the solid amine-borane in one portion.
Reactions are followed for completeness by hplc analysis (Aminex-25 resin in formate form, ammonium formate buffer at pH 5.3) and yields determined by hplc analysis with internal standard based on hydride equivalents used. Ratios of 2-ketogulonic and 2-ketogluconic acids in Examples 3 through 20 were determined by conversion as descibed in Example 1 to the corresponding methyl esters and glpc analysis of their corresponding pertrimethylsilylated methyl esters (5 ft OV-210 column at 135"C). Ratios of 2-ketogulonic and 2-ketogluconic acids in Examples 21 through 23 were determined by conversion to ascorbic and erythorbic acids and analysis of their corresponding pertrimethylsilylated methyl esters by glpc analysis as previously described.
The results obtained were as follows:
Example Amine- Temp Time (a)Reactant % (b)Ratio of
No. Borane pC pH (Hr) Ratio Yield 2-keto acids 3 (CH3)2NH.BH3 0 5.0 1 0.33 59 4 C5H5N.BH3 0 5.0 0.5 0.33 76 5 (CH3)3CNH2.BH3 0 5.0 1.0 0.33 61 6 C5H5N.BH3 0 5.0 0.5 0.33 76 88:12 7 C5H5N.BH3 30 5.0 - 0.33 70 8 C5H5N.BH3 70 5.0 - 0.33 59 9 (CH3)2NH.BH3 0 5.0 1 0.33 59 10 (CH3)2NH.BH3 0 5.0 - 0.33 62 86:14 11 (CH3)2NH.BH3 0 5.0 1 0.28 94 12 (CH3)2NH.BH3 0 3.9 0.75 0.28 84 92:8 13 (CH3)2NH.BH3 0 2.0 2.0 1.00 - 90:10 14 (CH3)2NH.BH3 0 3.0 2.0 1.00 - 87.13 15 (CH3)2NH.BH3 0 4.0 2.0 1.00 - 87:15 16 (CH3)2NH.BH3 0 5.0 2.0 1.00 - 87:13
17 (CH3)2NH.BH3 0 5.0 2.0 0.50 - 86:14
18 (CH3)2NH.BH3 0 5.0 2.0 0.33 - 86:14
19 C5H5N.BH3 0 5.0 2.0 1.00 - 88:12 20 (CH3)CNH2.BH3 0 5.0 2.0 1.00 - 88:12 21 C5H5N.BH3 0 5.0 5.5 0.33 79 92:8 22 (CH3)2NH.BH3 0 5.0 2.5 0.33 83 92: :8 23 (CH3)2NH.BH3 0 5.0 1.5 0.33 84 89:11
(a) Reactant ratio = moles of amine borane/moles of 2,5-diketogluconate
(b) Ratio of 2-keto acids = moles of 2-ketogulonate:moles of 2-ketogluconate
Claims (17)
1. A process for the preparation of a 2-ketogulonate which comprises reducing a 2,5-diketogluconate with an amine-borane of the formula R1R2HN.BH3 or pyridineijorane in solution at a pH between 2 and 7 at a temperature between -20" to 700C, wherein R1 and R2, are each hydrogen or alkyl of 1 to 4 carbon atoms; and
said 2,5-diketogluconate is 2,5-diketogluconic acid, a normal alkyl ester of said acid wherein said alkyl group
is of 1 to 4 carbon atoms, or a salt of said acid having as counterion an alkali metal, an alkaline earth metal,
ammonkum ortetraalkyl-ammonium having from 1 to 4 carbon atoms in each alkyl group.
2. A process according to claim 1 wherein said amine-borane is ammonia-borane.
3. A process according to claim 1, wherein said amine-borane is methylamine-borane.
4. A process according to claim 1, wherein said amine-borane is dimethylamine borane.
5. A process according to claim 1, wherein said amine-borane is t-butylamine borane.
6. A process according to claim 1, wherein said amine-borane is pyridine-borane.
7. A process as claimed in any one of claims 1 to 6 wherein the temperature is between 0 to 25"C.
8. A process as claimed in any preceding claim wherein between 0.30 and 0.40 moles of said
amine-borane is employed.
9. A process as claimed in any preceding claim wherein the pH is between 4 and 6.
10. A process as claimed in any preceding claim wherein the 2,5-diketogluconate is sodium
2,5-diketogluconate.
11. A process as claimed in any one of claims 1 to 9 wherein the 2,5-diketogluconate is calcium
2,5-diketogluconate.
12. A process as claimed in any one of claims 1 to 9 wherein the 2,5-diketogluconate is methyl
2,5-diketogluconate.
13. A process as claimed in any preceding claim wherein the reduction is effected in aqueous solution.
14. A process as claimed in claim 13 wherein said aqueous solution contains a co-solvent selected from an alkanol of 1 to 4 carbon atoms and an alkanediol of 2 to 4 carbon atoms.
15. A process as claimed in claim 14 wherein said co-solvent is methanol.
16. A process as claimed in claim 15 wherein the solution contains between about 5 and 20 weight percent of the 2,5-diketogluconate.
17. A process as claimed in claim 1 substantially as hereinbefore described with reference to any of the
Examples.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US96562678A | 1978-12-01 | 1978-12-01 | |
US06/024,284 US4212988A (en) | 1979-03-26 | 1979-03-26 | Preparation of 2-ketogulonic acid |
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GB2036740A true GB2036740A (en) | 1980-07-02 |
GB2036740B GB2036740B (en) | 1983-01-19 |
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Application Number | Title | Priority Date | Filing Date |
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GB7940847A Expired GB2036740B (en) | 1978-12-01 | 1979-11-27 | Process for the preparation of 2-ketogulonic acid |
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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) |
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MX4533E (en) * | 1976-12-10 | 1982-06-03 | Pfizer | PROCEDURE FOR PREPARING A MIXTURE OF 2-KETOGULONATE AND 2-KETOGLUCONATE |
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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 CH CH1063179A patent/CH641472A5/en not_active IP Right Cessation
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- 1979-11-29 CA CA000340867A patent/CA1140147A/en not_active Expired
- 1979-11-29 LU LU81936A patent/LU81936A1/en unknown
- 1979-11-30 FR FR7929467A patent/FR2442855A1/en active Granted
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NL7908678A (en) | 1980-06-03 |
NL177313B (en) | 1985-04-01 |
LU81936A1 (en) | 1980-06-05 |
CA1140147A (en) | 1983-01-25 |
FR2442855B1 (en) | 1983-02-25 |
FR2442855A1 (en) | 1980-06-27 |
DK470179A (en) | 1980-06-02 |
IE49219B1 (en) | 1985-08-21 |
DE2947741A1 (en) | 1980-06-04 |
GB2036740B (en) | 1983-01-19 |
DK154649C (en) | 1989-05-08 |
DE2947741C2 (en) | 1982-07-01 |
IT1126454B (en) | 1986-05-21 |
DK154649B (en) | 1988-12-05 |
IT7927761A0 (en) | 1979-11-30 |
CH641472A5 (en) | 1984-02-29 |
NL177313C (en) | 1985-09-02 |
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