EP0000092A1 - Method of preparing ascorbic acid and intermediates specially adapted for use therein - Google Patents
Method of preparing ascorbic acid and intermediates specially adapted for use therein Download PDFInfo
- Publication number
- EP0000092A1 EP0000092A1 EP78300014A EP78300014A EP0000092A1 EP 0000092 A1 EP0000092 A1 EP 0000092A1 EP 78300014 A EP78300014 A EP 78300014A EP 78300014 A EP78300014 A EP 78300014A EP 0000092 A1 EP0000092 A1 EP 0000092A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- lactone
- carbon atoms
- hydroxyl
- alkyl
- aldehyde
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 title claims abstract description 111
- 238000000034 method Methods 0.000 title claims abstract description 58
- 229960005070 ascorbic acid Drugs 0.000 title claims abstract description 56
- 235000010323 ascorbic acid Nutrition 0.000 title claims abstract description 35
- 239000011668 ascorbic acid Substances 0.000 title claims abstract description 35
- 239000000543 intermediate Substances 0.000 title abstract description 45
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 63
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 38
- 150000001875 compounds Chemical class 0.000 claims abstract description 19
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 5
- 125000004043 oxo group Chemical group O=* 0.000 claims abstract description 3
- -1 trialkylsilyl halide Chemical class 0.000 claims description 79
- 125000004432 carbon atom Chemical group C* 0.000 claims description 57
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 41
- 238000006243 chemical reaction Methods 0.000 claims description 36
- 125000000217 alkyl group Chemical group 0.000 claims description 32
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 claims description 23
- 125000003118 aryl group Chemical group 0.000 claims description 23
- 150000002596 lactones Chemical class 0.000 claims description 20
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical group O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims description 20
- SXZYCXMUPBBULW-SKNVOMKLSA-N L-gulono-1,4-lactone Chemical compound OC[C@H](O)[C@H]1OC(=O)[C@@H](O)[C@H]1O SXZYCXMUPBBULW-SKNVOMKLSA-N 0.000 claims description 19
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical group CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 11
- 125000001475 halogen functional group Chemical group 0.000 claims description 11
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 125000001424 substituent group Chemical group 0.000 claims description 11
- AMIMRNSIRUDHCM-UHFFFAOYSA-N Isopropylaldehyde Chemical group CC(C)C=O AMIMRNSIRUDHCM-UHFFFAOYSA-N 0.000 claims description 10
- PKZJLOCLABXVMC-UHFFFAOYSA-N 2-Methoxybenzaldehyde Chemical compound COC1=CC=CC=C1C=O PKZJLOCLABXVMC-UHFFFAOYSA-N 0.000 claims description 8
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical group CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 8
- 239000003377 acid catalyst Substances 0.000 claims description 8
- 239000007800 oxidant agent Substances 0.000 claims description 8
- 150000008064 anhydrides Chemical class 0.000 claims description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- 150000002576 ketones Chemical class 0.000 claims description 6
- BTFQKIATRPGRBS-UHFFFAOYSA-N o-tolualdehyde Chemical compound CC1=CC=CC=C1C=O BTFQKIATRPGRBS-UHFFFAOYSA-N 0.000 claims description 6
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- KJPRLNWUNMBNBZ-QPJJXVBHSA-N (E)-cinnamaldehyde Chemical group O=C\C=C\C1=CC=CC=C1 KJPRLNWUNMBNBZ-QPJJXVBHSA-N 0.000 claims description 4
- FPYUJUBAXZAQNL-UHFFFAOYSA-N 2-chlorobenzaldehyde Chemical compound ClC1=CC=CC=C1C=O FPYUJUBAXZAQNL-UHFFFAOYSA-N 0.000 claims description 4
- ZWUSBSHBFFPRNE-UHFFFAOYSA-N 3,4-dichlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C=C1Cl ZWUSBSHBFFPRNE-UHFFFAOYSA-N 0.000 claims description 4
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 claims description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 4
- 229940117916 cinnamic aldehyde Drugs 0.000 claims description 4
- KJPRLNWUNMBNBZ-UHFFFAOYSA-N cinnamic aldehyde Natural products O=CC=CC1=CC=CC=C1 KJPRLNWUNMBNBZ-UHFFFAOYSA-N 0.000 claims description 4
- 150000004820 halides Chemical class 0.000 claims description 4
- OVWYEQOVUDKZNU-UHFFFAOYSA-N m-tolualdehyde Chemical compound CC1=CC=CC(C=O)=C1 OVWYEQOVUDKZNU-UHFFFAOYSA-N 0.000 claims description 4
- 125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 claims description 4
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical group CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 3
- 239000012346 acetyl chloride Substances 0.000 claims description 3
- 125000003435 aroyl group Chemical group 0.000 claims description 3
- 125000005537 sulfoxonium group Chemical group 0.000 claims description 3
- IKHGUXGNUITLKF-XPULMUKRSA-N acetaldehyde Chemical compound [14CH]([14CH3])=O IKHGUXGNUITLKF-XPULMUKRSA-N 0.000 claims description 2
- FXXACINHVKSMDR-UHFFFAOYSA-N acetyl bromide Chemical compound CC(Br)=O FXXACINHVKSMDR-UHFFFAOYSA-N 0.000 claims description 2
- AQIHMSVIAGNIDM-UHFFFAOYSA-N benzoyl bromide Chemical compound BrC(=O)C1=CC=CC=C1 AQIHMSVIAGNIDM-UHFFFAOYSA-N 0.000 claims description 2
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical group ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 claims description 2
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N butyric aldehyde Natural products CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 claims description 2
- HUMNYLRZRPPJDN-KWCOIAHCSA-N benzaldehyde Chemical group O=[11CH]C1=CC=CC=C1 HUMNYLRZRPPJDN-KWCOIAHCSA-N 0.000 claims 1
- WTXGYGWMPUGBAL-MGCNEYSASA-N galactonolactone Chemical compound O[C@@H]1COC(=O)[C@H](O)[C@@H](O)[C@H]1O WTXGYGWMPUGBAL-MGCNEYSASA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 230000001590 oxidative effect Effects 0.000 abstract 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 52
- 239000011541 reaction mixture Substances 0.000 description 37
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 36
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 36
- 239000000243 solution Substances 0.000 description 36
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 35
- 239000007787 solid Substances 0.000 description 34
- 239000000463 material Substances 0.000 description 32
- 229910001868 water Inorganic materials 0.000 description 32
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 239000002904 solvent Substances 0.000 description 24
- 239000002211 L-ascorbic acid Substances 0.000 description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
- 238000007254 oxidation reaction Methods 0.000 description 20
- 235000000069 L-ascorbic acid Nutrition 0.000 description 19
- 239000000203 mixture Substances 0.000 description 19
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 230000003647 oxidation Effects 0.000 description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 17
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- 238000004458 analytical method Methods 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 238000001953 recrystallisation Methods 0.000 description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- SXZYCXMUPBBULW-LECHCGJUSA-N D-(-)-Gulono-gamma-lactone Chemical compound OC[C@@H](O)[C@@H]1OC(=O)[C@H](O)[C@@H]1O SXZYCXMUPBBULW-LECHCGJUSA-N 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 10
- 230000007062 hydrolysis Effects 0.000 description 10
- 238000006460 hydrolysis reaction Methods 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 150000001299 aldehydes Chemical class 0.000 description 8
- 239000012267 brine Substances 0.000 description 8
- 125000000468 ketone group Chemical group 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- 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 5
- CIWBSHSKHKDKBQ-MVHIGOERSA-N D-ascorbic acid Chemical compound OC[C@@H](O)[C@@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-MVHIGOERSA-N 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 150000001242 acetic acid derivatives Chemical class 0.000 description 5
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 239000003729 cation exchange resin Substances 0.000 description 4
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical group [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- SXZYCXMUPBBULW-NEEWWZBLSA-N L-galactono-1,4-lactone Chemical compound OC[C@H](O)[C@H]1OC(=O)[C@@H](O)[C@@H]1O SXZYCXMUPBBULW-NEEWWZBLSA-N 0.000 description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- 239000003456 ion exchange resin Substances 0.000 description 3
- 229920003303 ion-exchange polymer Polymers 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical group C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 3
- 238000001665 trituration Methods 0.000 description 3
- SXZYCXMUPBBULW-STGXQOJASA-N (3s,4s,5s)-5-[(1r)-1,2-dihydroxyethyl]-3,4-dihydroxyoxolan-2-one Chemical compound OC[C@@H](O)[C@@H]1OC(=O)[C@@H](O)[C@@H]1O SXZYCXMUPBBULW-STGXQOJASA-N 0.000 description 2
- DHKHKXVYLBGOIT-UHFFFAOYSA-N 1,1-Diethoxyethane Chemical compound CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 229930194542 Keto Natural products 0.000 description 2
- LKDRXBCSQODPBY-AMVSKUEXSA-N L-(-)-Sorbose Chemical compound OCC1(O)OC[C@H](O)[C@@H](O)[C@@H]1O LKDRXBCSQODPBY-AMVSKUEXSA-N 0.000 description 2
- 241000786363 Rhampholeon spectrum Species 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 150000001241 acetals Chemical class 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 244000309464 bull Species 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- QABCGOSYZHCPGN-UHFFFAOYSA-N chloro(dimethyl)silicon Chemical compound C[Si](C)Cl QABCGOSYZHCPGN-UHFFFAOYSA-N 0.000 description 2
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000012456 homogeneous solution Substances 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 239000012948 isocyanate Substances 0.000 description 2
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- KPHIBLNUVRGOGU-LMVFSUKVSA-N methyl (3s,4r,5s)-3,4,5,6-tetrahydroxy-2-oxohexanoate Chemical compound COC(=O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO KPHIBLNUVRGOGU-LMVFSUKVSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- 229910003446 platinum oxide Inorganic materials 0.000 description 2
- 229920000137 polyphosphoric acid Polymers 0.000 description 2
- 238000003822 preparative gas chromatography Methods 0.000 description 2
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- SXZYCXMUPBBULW-NRXMZTRTSA-N (3r,4r,5r)-5-[(1s)-1,2-dihydroxyethyl]-3,4-dihydroxyoxolan-2-one Chemical compound OC[C@H](O)[C@H]1OC(=O)[C@H](O)[C@H]1O SXZYCXMUPBBULW-NRXMZTRTSA-N 0.000 description 1
- SXZYCXMUPBBULW-QMKXCQHVSA-N (3r,4s,5r)-5-[(1s)-1,2-dihydroxyethyl]-3,4-dihydroxyoxolan-2-one Chemical compound OC[C@H](O)[C@H]1OC(=O)[C@H](O)[C@@H]1O SXZYCXMUPBBULW-QMKXCQHVSA-N 0.000 description 1
- SXZYCXMUPBBULW-MBMOQRBOSA-N (3s,4r,5s)-5-[(1r)-1,2-dihydroxyethyl]-3,4-dihydroxyoxolan-2-one Chemical compound OC[C@@H](O)[C@@H]1OC(=O)[C@@H](O)[C@H]1O SXZYCXMUPBBULW-MBMOQRBOSA-N 0.000 description 1
- KRGQEOSDQHTZMX-HXAZRIOBSA-N (4r,5s)-5-[(1r)-1,2-dihydroxyethyl]-4-hydroxyoxolane-2,3-dione Chemical compound OC[C@@H](O)[C@@H]1OC(=O)C(=O)[C@@H]1O KRGQEOSDQHTZMX-HXAZRIOBSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- FSGHEPDRMHVUCQ-UHFFFAOYSA-N 2-ethoxyprop-1-ene Chemical compound CCOC(C)=C FSGHEPDRMHVUCQ-UHFFFAOYSA-N 0.000 description 1
- 239000001431 2-methylbenzaldehyde Substances 0.000 description 1
- 125000006512 3,4-dichlorobenzyl group Chemical group [H]C1=C(Cl)C(Cl)=C([H])C(=C1[H])C([H])([H])* 0.000 description 1
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- AEMOLEFTQBMNLQ-DTEWXJGMSA-N D-Galacturonic acid Natural products O[C@@H]1O[C@H](C(O)=O)[C@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-DTEWXJGMSA-N 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- UYUXSRADSPPKRZ-UHFFFAOYSA-N D-glucuronic acid gamma-lactone Natural products O=CC(O)C1OC(=O)C(O)C1O UYUXSRADSPPKRZ-UHFFFAOYSA-N 0.000 description 1
- UYUXSRADSPPKRZ-SKNVOMKLSA-N D-glucurono-6,3-lactone Chemical compound O=C[C@H](O)[C@H]1OC(=O)[C@@H](O)[C@H]1O UYUXSRADSPPKRZ-SKNVOMKLSA-N 0.000 description 1
- RGHNJXZEOKUKBD-KKQCNMDGSA-N D-gulonic acid Chemical class OC[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-KKQCNMDGSA-N 0.000 description 1
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical class S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- 239000012028 Fenton's reagent Substances 0.000 description 1
- 244000182067 Fraxinus ornus Species 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound 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 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- DDWMFFZVZXMXCS-YVECIDJPSA-N [(2r)-2-acetyloxy-2-[(2s,3r,4r)-3,4-diacetyloxy-5-oxooxolan-2-yl]ethyl] acetate Chemical compound CC(=O)OC[C@@H](OC(C)=O)[C@@H]1OC(=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O DDWMFFZVZXMXCS-YVECIDJPSA-N 0.000 description 1
- MRAZLYJRXKMUIA-VJLHXPKFSA-N [(2r)-2-benzoyloxy-2-[(2s,3r,4r)-3,4-dibenzoyloxy-5-oxooxolan-2-yl]ethyl] benzoate Chemical compound O([C@H](COC(=O)C=1C=CC=CC=1)[C@H]1[C@H]([C@@H](OC(=O)C=2C=CC=CC=2)C(=O)O1)OC(=O)C=1C=CC=CC=1)C(=O)C1=CC=CC=C1 MRAZLYJRXKMUIA-VJLHXPKFSA-N 0.000 description 1
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N acetaldehyde dimethyl acetal Natural products COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 1
- XLUXHEZIGIDTCC-UHFFFAOYSA-N acetonitrile;ethyl acetate Chemical compound CC#N.CCOC(C)=O XLUXHEZIGIDTCC-UHFFFAOYSA-N 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- IAJILQKETJEXLJ-RSJOWCBRSA-N aldehydo-D-galacturonic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-RSJOWCBRSA-N 0.000 description 1
- 125000005233 alkylalcohol group Chemical group 0.000 description 1
- 239000012223 aqueous fraction Substances 0.000 description 1
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 1
- AEMOLEFTQBMNLQ-UHFFFAOYSA-N beta-D-galactopyranuronic acid Natural products OC1OC(C(O)=O)C(O)C(O)C1O AEMOLEFTQBMNLQ-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229920001429 chelating resin Polymers 0.000 description 1
- 239000002026 chloroform extract Substances 0.000 description 1
- UXTMROKLAAOEQO-UHFFFAOYSA-N chloroform;ethanol Chemical compound CCO.ClC(Cl)Cl UXTMROKLAAOEQO-UHFFFAOYSA-N 0.000 description 1
- SKCNIGRBPJIUBQ-UHFFFAOYSA-N chloroform;ethyl acetate Chemical compound ClC(Cl)Cl.CCOC(C)=O SKCNIGRBPJIUBQ-UHFFFAOYSA-N 0.000 description 1
- HYGYSIDIKIGPJA-UHFFFAOYSA-N chloroform;ethyl acetate;methanol Chemical compound OC.ClC(Cl)Cl.CCOC(C)=O HYGYSIDIKIGPJA-UHFFFAOYSA-N 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229950002441 glucurolactone Drugs 0.000 description 1
- 235000006486 human diet Nutrition 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- MGZTXXNFBIUONY-UHFFFAOYSA-N hydrogen peroxide;iron(2+);sulfuric acid Chemical compound [Fe+2].OO.OS(O)(=O)=O MGZTXXNFBIUONY-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 239000011968 lewis acid catalyst Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000000199 molecular distillation Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 238000007040 multi-step synthesis reaction Methods 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 239000012056 semi-solid material Substances 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011949 solid catalyst Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- FKHIFSZMMVMEQY-UHFFFAOYSA-N talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/32—Oxygen atoms
- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/62—Three oxygen atoms, e.g. ascorbic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
- C07H7/02—Acyclic radicals
- C07H7/027—Keto-aldonic acids
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the 3,5-adduct of formula IX can be used directly in the next step of the process i.e., the oxidation of the hydroxyl group to a keto group.
- the free hydroxyl at the 2- position may be selectively oxidized in preference to the other free hydroxyl at the 6- position of the lactone.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Biotechnology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Furan Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
- This invention relates to a novel process for preparing ascorbic acid. L-ascorbic acid, or Vitamin C, is required in the human diet and is widely sold in tablet form and as an additive in various foodstuffs to meet this need and also as an antioxidant. In all animals except primates and guinea pigs L-ascorbic acid is biosynthesised from D-glucose. The final step in this biosynthesis is the enzymatic conversion of L-gulono-1, 4-lactone to L-ascorbic acid. British Patent No. 763,055 discloses the conversion of L-gulono-1,4-lactone to L-ascorbic acid in about 40% yield by the use of an enzymatic oxidation system.
- Attempts to effect the direct conversion of L-gulono-1, 4-lactone to L-ascorbic acid by chemical means have been only partly successful, since over-oxidation and degradation reactions produce undesirable by-products. However, low yields of L-ascorbic acid have been produced. For example, Berends and Konings, Rec. Trav. Chem. des Pays-Bas, 74, 1365 (1955) disclose the use of Fentons reagent to give about a 10% yield of L-ascorbic acid. The most successful and common method of producing L-ascorbic acid is based on a multi-step synthesis from D-glucose going through sorbose and 2-keto-gulonic acid as intermediates. Many improvements in the original sorbose method of Reichstein and Grussner, Helv. Chim. Acta., 17, 311 (1934) have been made. D-ascorbic acid may be used as an antioxidant in foodstuffs.
- Derivatives of L-gulono-1,4-lactone are known in the art. For example, Matsui et al have prepared 2,3:5,6-di-O-iscpropyl- idene-L-gulono-1,4-lactone, 3,5-O-benzylidene-L-gulono-1,4-lactone, 2,6:3,5-di-O-benzylidene-L-gulono-1,4-lactone (Yakugaku Zasshi 86, 110 (1966)), and 2,3,5,6-tetrabenzoyl-L-gulono-1,4-lactone has been prepared by Kohn et al (J.A.C.S., 87, 5475 (1965)). Similar compounds derived from D-gulono-1,4-lactone are also known including 2,3:5,6-di-O-isopropylidene-D-gulono-1,4-lactone, 2,3-0-isopropylidene-D-gulono-1,4-lactone and 5,6-O-isopropylidene-D-gulono-1, 4-lactone (Hulyalkar et al, Can. J. Chem., 41, 1898 (1963)). Other compounds include 2,3,5,6-tetra-O-trimethylsilyl-D-gulono-1,4- lactone (Meguro et al, Agr. Bio Chem., 36, 2075 (1972)). 2,3,5,6-tetra-O-acetyl-D-gulono-1,4-lactone (Ness et al, J.A.C.S., 73, 4759 (1951)) and 2,3,5,6-tetra-O-benzoyl-D-gulono-1,4-lactone (Kohn et al, J.A.C.S., 86, 1457 (1964)). Similar derivatives of gulonic acid and gulonamide have been prepared. Similar derivatives of the other 1,4-lactones are also known. Prior to the present process, the oxidation cf partially protected 1,4-lactones is not known to have been described nor are such compounds known to have been employed as intermediates in the preparation of ascorbic acid.
- The present invention provides a novel process for the preparation of ascorbic acid from a 1,4-lactone selected from gulono-1,4-lactone, galactono-1,4-lactone, idono-1,4-lactone and talono-1,4-lactone. L-ascorbic acid is prepared from lactones of the L-series and D-ascorbic acid results from lactones of the D-series. The lactone is first reacted with a hydroxyl-protecting reagent to form a hydroxyl-protected intermediate wherein one of the hydroxyl groups located at the 2- and 3- positions of the ring is protected while the other remains as a free hydroxyl group.
- The free hydroxyl group at the 2- or 3- position of this protected intermediate is then oxidized to a keto group and the resulting compound subjected to hydrolysis until substantial conversion to ascorbic acid has occurred.
- Thus the invention provides a process for the preparation of ascorbic acid which is characterised by:
- (a) reacting gulono-, galactono-, idono- or talono-1,4-lactone with at least one hydroxyl-protecting reagent so as to protect the free hydroxyl groups in the 5-, 6- and either the 2- or 3- positions, or, reacting gulono- or idono-1,4-lactone with at least one hydroxyl-protecting reagent so as to protect the free hydroxyl groups in the 3-, 5- and optionally the 6- positions;
- (b) reacting the resulting intermediate having a free hydroxyl group at the 2- or 3- position with an oxidizing agent effective to convert said hydroxyl group to an oxo group; and
- (c) hydrolyzing the compound formed in step (b) until conversion to ascorbic acid is substantially complete.
- In one embodiment of this invention, this process may be effected by (a) contacting a 1,4-lactone selected from gulono-1, 4-lactone, galactono-1,4-lactone, idono-1,4-lactone and talono-1, 4-lactone with about three equivalents of a hydroxyl-protecting reagent per mole of 1,4-lactone; (b) contacting the resulting intermediate having a free hydroxyl group at the 2- or 3- position with an oxidizing agent effective to convert said hydroxyl group to a keto group and (c) hydrolyzing the compound formed in step (b) until conversion to ascorbic acid is substantially complete.
- Preferred hydroxyl-protecting reagents for this process include trialkylsilyl halides and dialkylsilyl halides, wherein each alkyl is of 1 to 6 carbon atoms; alkanoic anhydrides of 3 to 8 carbon atoms; alkanoyl halides of 2 to 6 carbon atoms; aroyl halides wherein said aroul is benzoyl, naphthoyl or mono-substituted benzoyl, wherein said substituents are alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halo or nitro; dialkyl ketones, wherein each alkyl is of 1 to 6 carbon atoms; alkyl aldehydes of 2 to 8 carbon atoms; and triphenylmethyl halides.
- Ascorbic acid may also be prepared by (a) contacting a 1,4-lactone selected from gulono-1,4-lactone and idono-1,4-lactone in the presence of an acid catalyst having a pK a of less than about 2.5 with at least about two equivalents of a hydroxyl-protecting reagent per mole of 1,4-lactone, said reagent being selected from an alkyl aldehyde of 2 LO 8 carbon atoms; an aryl aldehyde, an arylalkyl aldehyde and an arylalkenyl aldehyde, wherein said aryl is phenyl, mono-substituted or disubstituted phenyl, wherein said substituents are alkyl of 1 to 6 carbon atoms, alkoxy of one to six carbon atoms, halo or nitro, and said alkyl and alkenyl are each of 2 to 4 carbon atoms; (b) contacting the resulting intermediate having a free hydroxyl group at the 2- position with an oxidizing agent effective to convert said hydroxyl group to a keto group and (c) hydrolyzing the compound formed in step (b) until conversion to ascorbic acid is substantially complete.
- Preferred hydroxyl-protecting reagents for effecting this process include acetaldehyde, isobutyraldehyde, benzaldehyde, o-methylbenzaldehyde, m-methylbenzaldehyde, 3,4-dichlorobenzaldehyde, o-methoxybenzald&hyde, o-chlorobenzaldehyde and cinnamaldehyde.
- The present processfor the preparation of ascorbic acid utilizes as starting material a 1,4-lactone selected from gulono-1, 4-lactone, galactono-1,4-lactone, idono-1,4-lactone and talono-1, 4-lactone. These isomeric lactones differ in the stereochemistry of the hydroxyl groups at the 2- and 3- positions and may be represented by the formulae:
- The numbering of the lactone ring as used in the specification and claims herein is shown above in formula (I).
- The present process may be used to prepare either L-ascorbic acid or D-ascorbic, or mixtures of the two acids. L-ascorbic acid is derived from 1,4-lactones of the L-series, while D-ascorbic acid is prepared from the D-enantiomers. As used in the specification and claims hereof, reference to ascorbic acid, gulono-1,4-lactone, galactono-1,4-lactone, idono-1,4-lactone and talono-1,4-lactone and to intermediates derived therefrom is meant to include compounds of both the L-series and the D-series.
- The lactone starting materials are well known in the art and can be obtained commercially or synthesised. For example, L-gulono-1,4-lactone can be prepared by the hydrogenation of D-glucuronolactone. L-galactono-1,4-lactone may be prepared from pectin via D-galacturonic acid. D-gulono-1,4-lactone can be prepared from D-xylose. See, for example, Chem. Pharm. Bull. 13, 173 (1965), Helv. Chim. Acta. 21, 3 (1938); Bull Chem. Soc. Japan 13, 272 (1938); J.A.C.S. 49, 478 (1928); Helv. Chim. Acta 18, 482 (1938) and Organic Synthesis IV,. 506 (1963). Gulono-1,4-lactone is a preferred starting material.
- The first step in the present process is the formation of a protected intermediate, having an unprotected hydroxyl group remaining at either, but not both, the 2- or 3- position of the lactone ring. This may be effected in one embodiment of the invention by the reaction of the 1,4-lactone with about three equivalents of a hydroxyl-protecting reagent per mole of 1,4-lactone.
- As used in the specification and claims hereof, a hydroxyl-protecting reagent is considered to be. any compound that will react with the hydroxyl groups of the lactone, replacing the hydrogen atom with a radical derived from the reagent, which radical can in subsequent steps be removed by hydrolysis to regenerate the hydroxyl groups. By an equivalent of hydroxyl-protecting reagent is meant the stoichiometric amount required to react with one hydroxyl group. The hydroxyl-protecting reagent may be monofunctional, by which is meant that one molecule of reagent reacts with one hydroxyl group of the lactone. When such a reagent is used the hydroxyl groups at the 5- and 6- positions and one of the hydroxyl groups at the 2- or 3- position will be protected. Since only three equivalents are employed only one of the hydroxyl groups at the 2- and 3- positions will react and a free hydroxyl group will remain at the other position. The protected intermediates formed by this reaction are of the formulae:
- Many monofunctional hydroxyl-protecting reagents are known in the art including, but not limited to, trialkylsilyl halides, wherein each alkyl is of 1. to 6 carbon atoms;
- alkanoyl halides of 2 to 6 carbon atoms; aroyl halides, wherein aroyl is benzoyl, naphthoyl or mono-substituted benzoyl, wherein said substituents are alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halo or nitro; alkanoic anhydrides of 3 to 8 carbon atoms; alkyl vinyl ethers, wherein said alkyl is of 1 to 6 carbon atoms; alkyl mono- or di-substituted vinyl ethers, wherein said substituents are alkyl of 1 to 6 carbon atoms or halo; and triphenylmethyl halides. The choice of hydroxyl-protecting reagent is not critical and any compound which will allow formation of a protected intermediate which can be oxidized at the 2- or 3- position and the hydroxyl-protecting groups removed thereafter can be employed. A preferred class of monofunctional hydroxyl-protecting reagents is trialkylsilyl halides, wherein each alkyl is of 1 to 6 carbon atoms. Of these, trimethylsilyl halides and t-butyl-dimethylsilyl halides are especially preferred. Another preferred class of monofunctional reagents is alkanoic anhydrides of 3 to 8 carbon atoms; these are considered as monofunctional reagents for the purposes of this process, since the anhydride reacts dissociatively and each lactone hydroxyl reacted is esterified. A preferred alkanoic anhydride is acetic anhydride. Other preferred hydroxy-protecting reagents are alkanoyl halides of 2 to 6 carbon atoms; especially preferred are acetyl chloride and acetyl bromide. A further preferred class of hydroxyl-protecting reagents is aroyl halides, wherein said aroyl is benzoyl, naphthoyl or mono-substituted benzoyl, wherein said substituents are alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halo or nitro.
- Especially preferred are benzoyl chloride and benzoyl bromide. A preferred triphenylmethyl halide is triphenylchloromethane.
- In a further embodiment of this invention, difunctional hydroxyl-protecting reagents may be employed. By a difunctional hydroxyl-protecting reagent is meant a compound one molecule of which can react with two hydroxyl groups of the lactone to form a bridged intermediate. Thus, one mole of such a reagent provides two equivalents of hydroxyl-protecting reagent according to the definition used hPrein. The difunctional hydroxyl-protecting reagents may be effective to form two types of intermediates, depending on the choice of reagent employed. Difunctional reagents react to form a 5,6-bridged intermediate. Examples of difunctional hydroxyl-protecting reagents that can be employed in the formation of such an intermediate include, but are not limited to, dialkylsilyl halides, alkyl isocyanates, and alkyl haloformates, wherein each alkyl is of 1 to 6 carbon atoms; aryl isocyanates, wherein aryl is phenyl, monosubstituted or disubstituted phenyl, wherein the substituents are alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halo or nitro; and alkyl aldehydes of 2 to 8 carbon atoms. Choice of reagent is not critical. When a difunctional hydroxyl-protecting reagent is employed it is preferably used in the amount of about . two equivalents in conjunction with one equivalent of a monofunctional hydroxyl-protecting reagent, which reacts with one of the hydroxyl groups at the 2- or 3- position of the lactone, to form an intermediate of the type:
- A preferred class of difunctional hydroxyl-protecting reagents is dialkylsilyl halides, wherein each alkyl is of 1 to 6 carbon atoms. Another class of preferred hydroxyl-protecting reagents is dialkyl ketones, wherein each alkyl is of 1 to 6 carbon atoms; especially preferred are acetone, methyl ethyl ketone and methyl isobutyl ketone. A further class of preferred difunctional hydroxyl-protecting reagents Ls alkyl aldehydes of 2 to 8 carbon atoms; especially preferred compounds are acetaldehyde and propionaldehyde. The alkyl aldehydes may be used directly or in the form of dialkyl acetals and reference to such aldehydes in the specification and claims hereof is intended to include such acetals.
- Formation of the protected intermediates described above and represented by formulae V through VIII is generally conducted in non-hydroxylic organic solvents. Suitable solvents include, but are not limited to, dimethyl formamide, pyridine and dimethyl sulfoxide.
- It is not necessary, however, that the starting lactone be fully soluble in the organic medium and the protected intermediate can ' be prepared in a heterogeneous system where the lactone is dispersed in an inert organic diluent. The 1,4-lactone is contacted with the appropriate hydroxyl-protecting reagent at temperatures in the range of about -10°C to 150°C. Temperature is, however, not critical and usually the reaction can be most conveniently accomplished at room temperature. The hydroxyl-protecting reagent may be added to the solution of the 1,4-lactone either dropwise or in one batch. In either case, the mixture should be adequately stirred throughout the period of reaction. The time for complete reaction will, of course, vary with the temperature and concentration of reagents. In general, however, the reaction will be substantially complete in a period of about 30 minutes to about 15 hours. When alkyl aldehydes are employed in forming the protected intermediates described above, the reaction may be advantageously conducted in the presence of a weak Lewis acid catalyst, such as cupric sulfate or ferric chloride.
- A limited number of difunctional hydroxyl-protecting reagents have been found to form a 3,5-adduct of the type:
- Such intermediates are only formed with gulono-1,4- lactone and idono-1,4-lactone, in which the stereochemistry of the 3- amd 5-hydroxyl groups allows the formation of this bridged compound. The hydroxyl-protecting reagents that have been found to form this type of intermediate are aryl aldehydes, arylakyl aldehydes and arylalkenyl aldehydes, wherein aryl is phenyl, mono- substituted or disubstituted phenyl, wherein said substituents are alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halo or nitro, and alkyl and alkenyl are each of 2 to 4 carbon atoms; and alkyl aldehydes of 2 to 8 carbon atoms. Preferred alkyl aldehydes are acetaldehyde and isobutyraldehyde. Preferred aryl aldehydes include benzaldehyde, o-methylbenzaldehyde, m-methylbenzaldehyde, 3,4-dichlorobenzaldehyde, o-methoxybenzaldehyde and o-chlorobenzaldehyde. Benzaldehyde is an especially preferred reagent. Another especially preferred reagent is o-methoxybenzaldehyde. A preferred arylalkenyl aldehyde is cinnamaldehyde.
- Formation of the 3,5-protected intermediates described above and represented by formula IX is conducted in an organic solvent or diluent. Suitable solvents are non-hydroxylic organic compounds such as dimethyl formamide, pyridine and dimethyl sulfoxide. A particularly preferred process employs an excess of the aldehyde hydroxyl-protecting reagent as solvent or diluent. Since the intermediate is a 3,5-adduct, further reaction of the aldehyde with other hydroxyl groups of the same lactone ring does not occur. Thus, for example, the 1,4-lactone can be contacted with from about 3 to about 10 equivalents of the aldehyde hydroxyl-protecting reagent. Two equivalents of the aldehyde hydroxyl-protecting reagent are consumed by reaction with the 1,4-lactone to form the 3,5-adduct, while the remainder acts as solvent or diluent. The formation of the 3,5-adduct requires the presence of a strong acid catalyst having a pKa of less than about 2.5, generally added in an amount between about 0.05 and about 1.5 moles per mole of 1,4-lactone. Suitable acid catalysts include, but are not limited to, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, sulfonic ion exchange resins and polyphosphoric acid. Temperatures between about -100C and 150 C may be employed. Temperatures are not critical, however, and the reaction is usually conducted at about room temperature. The hydroxyl protecting reagent may be added to the solution of the 1,4-lactone either dropwise or in one batch while stirring the reaction mixture. The time for complete reaction will depend on the temperature and the concentration of the reagents. In general, however, the reaction will be substantially complete in a period of about 30 minutes to about 15 hours.
- The 3,5-adducts of formula IX may also be formed from 5, 6-adducts formed with alkyl aldehyde protecting groups by heating in the presence of a strong acid catalyst as described above.
- The 3,5-adduct of formula IX can be used directly in the next step of the process i.e., the oxidation of the hydroxyl group to a keto group. The free hydroxyl at the 2- position may be selectively oxidized in preference to the other free hydroxyl at the 6- position of the lactone. Thus, in this embodiment of the present invention, the first step in the process may be effected by contacting a 1,4-lactone selected from gulonolactone and idonolactone in the presence of an acid catalyst having a pKa of less than about 2.5 with at least about two equivalents of a hydroxyl-protecting reagent per mole of 1,4-lactone, said reagent being selected from an alkyl aldehyde of 2 to 8 carbon atoms; an aryl aldehyde, an arylalkyl aldehyde and an arylalkenyl aldehyde, wherein said aryl is phenyl, mono-substituted or disubstituted phenyl wherein said substituents are alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms halo or nitro, and said alkyl and alkenyl are each of 2 to 4 carbon atoms. This is a preferred embodiment of the present process.
- The above reactions can also be employed to form intermediates of the formula:
- A preferred monofunctional hydroxyl-protecting reagent for the formation of these intermediates is a triphenylmethyl halide, such triphenylchloromethane. Intermediates of formula X are suitable for oxidation of the 2-hydroxyl group to a keto group in the same way as other 3,5-adducts, as described hereinafter.
- In specifying the amount of hydroxyl-protecting reagent required to form the above protected intermediates, i. e. about three equivalents or about two equivalents per mole of 1,4-lactone, depending on the hydroxyl-protecting reagent employed, it will of course be recognised that lesser amounts of reagent can be used with corresponding lower yields of the intermediates. It is intended that the specification and claims hereof include a process where only a part of the 1,4-lactone starting material is reacted and unreacted 1,4-lactone may be subsequently recycled for further reaction. It is, of course, advantageous to avoid such recycle and the present process allows high yields in a single pass.
- The protected intermediates formed in the first step of the process as described above, may be used directly in the next step of the present process without further purification. If desired, however, the protected intermediates may be isolated and purified by recrystallisation or other means known in the art. Preferably, before use in the next step excess solvent is removed.
- The second step in the present process is the oxidation of the unprotected hydroxyl group, located at the 2- or 3- position of the protected lactone, to keto. This may be effected by methods known in the art for the oxidation of secondary alcohols to ketones. However, choice of oxidizing agents will be affected by the protecting groups employed and the type of intermediate formed in the first step of the process. For example, oxidation of the 3,5- protected intermediates and others having a free hydroxyl group at the 2- position of the lactone may conveniently be effected with manganese dioxide. In the case of the 3,5-intermodiates having a free hydrcxyl group at the 6- position of the lactone, as shown in formula IX, the hydroxyl group at the 2- position is oxidized preferentially by such use of manganese dioxide. Any of the intermediates formed in the first step of the process may be oxidized via a sulfoxonium salt. formed from a mixture of dimethyl sulfoxide and, for example, acetic anhydride or trifluoroacetic anhydride, or from a mixture of dimethylsulfide and N-chlorsuccinimide, in the presence of a base, such as triethylamine. Oxidation may also be effected catalytically using either pure oxygen or an oxygen- containing gas. A suitable catalyst is platinum. Oxidation may also be effected electrochemically. The oxidation is conducted in an organic solvent, which may be the same as that used in the first step of the process in forming the protected intermediate. However, other solvents may be used and in general, any organic solvent inert to oxidation conditions can be employed.
- Examples of suitable solvents include, but are not limited to, dimethyl formamide, pyridine, dimethyl sulfoxide, dichloromethane and acetone. It is not necessary that the intermediate be fully soluble in the organic medium. Temperatures suitable for the oxidation reaction will vary according to the type of oxidation employed. For example, in oxidation via sulfoxonium salts, the oxidation may be conducted at about -60°C to 100°C depending on the method used to generate the initial sulfonium salt. The reaction is preferably conducted at about 0°C to 50°C. Oxidation by manganese dioxide is conducted at about -10°C to about 75°C, preferably about 0°C to room temperature. Catalytic oxidation using platinum and oxygen may be conducted at about room temperature to about 100°C, preferably about 50°C to about 75°C. Before proceeding to the next step of the process the oxidized intermediate should be separated from any excess oxidizing agent, for example, by filtration of solid catalyst residues of by extraction or recrystallisation of the product. If desired, the oxidized intermediate can be isolated and purified by menas known in the art; however, this is not necessary. The oxidized intermediates may exist in the keto, enol or hydrated forms depending on the protecting groups employed. The 3,5-protected intermediates are generally isolated as the hydrated or keto form.
- The oxidized intermediates formed as described above are novel compounds. Particularly useful and preferred intermediates are those of the formula:
- The final step in the present process is the removal of the hydroxyl-protecting groups by hydrolysis and subsequent rearrangement to yield ascorbic acid. Hydrolysis may generally be effected under said acid conditions. Suitable acids for effecting removal of the hydroxyl-protecting groups include hydrochloric acid, sulfuric acid, acetic acid and other lower alkyl carboxylic acids and sulfonic ion exchange resins. Hydrolysis may be conducted in aqueous organic co-solvent mixtures, with methanol and other lower alkyl alcohols being suitable solvents. Another preferred hydrolysis medium is aqueous acetic acid.
- With some hydroxyl-protecting groups hydrolysis may also be effected under basic conditions, for example, where ester intermediates are employed. Suitable bases include sodium carbonate, sodium hydroxide and similar salts. The ascorbic acid is then obtained in the form of the sodium or other metal salt and can be converted to the free acid by treatment with a dilute acid, such as hydrochloric acid, or by ion exchange. Under either basic or acidic hydrolysis conditions temperatures are not critical, generally temperatures in the range of about 35°C to 100°C being suitable with temperatures of about 50°C to 750C being preferred. Under some strong acid or basic hydrolysis conditions the lactone ring may be opeened to form methyl 2-ketogulonate or 2-ketogulonic acid. These can be readily converted by further reaction to ascorbic acid by means known in the art and thus the formation of these intermediates is not detrimental to the present process. If desired, the methyl 2-ketogulonate or 2- ketogulonic acid may be isolated and purified. The ascorbic acid produced can be purified by means known in the art, for example by recrystallisation from methanol, methanol-water or other suitable solvents or solvent mixtures.
- The process of the present invention is further illustrated by the following Examples. It should be understood, however, that the invention is not limited to the specific details of these examples.
- To 50 ml of dry DMF was added 8.91 g (50 mmol) of L-gulono-1,4-lactone. To this homogeneous solution was added 24.04 g (395 rnmol) of imidazole and 23.27 g (156 mmol) of t-butyldimethylchlorosilane. The reaction was slightly exothermic initially and was stirred under nitrogen for 15 hours. At that time 350 ml of benzene was added and this solution was extracted 5 times with 50 ml of water, 2 times with brine, and then it was dried with anhydrous sodium sulfate. Removal of the solvent under vacuum afiorded 26.3 g (50.5 mmol, 100%) of a colourless oil which t.l.c. revealed contained two components. This material was chromatographed on 510 g of silica gel using 0.25% methanol-benzene to elute the faster moving component (16.2 g, 31.1 mmol, 62.2%) and then using 0.5% methanol-chloroform to 2% methanol-chloroform to elute the slower moving component (8.2 g, 15.9 mmol, 31.9%).
- The faster moving component was shown to be 2,5,6-tri-O-t-butyldimethylsilyl-L-gulono-1,4-lactone by n.m.r. decoupling experiments. An analytically pure sample was prepared by preparative gas chromatography on 10% SE 30 on A/W DMCS Chromosorb G: i.r. (neat) 3550, 1800 cm 1; n.m.r. (DMSO-d6)δH 0.08 (m, 18), 0.90 (m, 27), 3.57-4.40 (m, 5), 4.63 (d, 1, J = 4; -CHCO2), 5.12 (d, 1, J = 4, -OH); in benzene three different t-butyl groups can clearly be seen in the n.m.r.
- Analysis: Calculated for C24H52O6Si3: C, 55.33; H, 10.06.
- Found: C, 55.17; H, 9.79.
- The slower moving component was shown to be 3,5,6-Tri-O-t-butyl.dimethylsilyl-L-gulono-1,4-lactone by n.m.r. decoupling experiments. An analytically pure sample was prepared by preparative gas chromatography on 10% SE 30 on A/W DMCS Chromosorb G: i.r. (neat) 3400, 1790 cm-1; n.m.r. (DMSO-d6)δH 0.10 (m, 18), 0.93 (m, 27), 3.50-4.67 (m, 6), 6.03 (d, 1, -OH).
- Analysis: Calculated for C24H52O6Si3: C, 55.33; H, 10.06
- Found: C, 55.41; H, 9.93.
- To 120 ml of dry dichloromethane under nitrogen was added 4.2 ml (59 mmol) of dimethylsulfoxide. This solution was cooled to less than -550 and 8.0 ml (56.5 mmol) of trifluoroacetic anhydride was added. The resulting heterogeneous solution was stirred for 30 minutes below -50°. Then 15.0 g (28.1 mmol) of a mixture of 2,5, 6-tri-0-t-butyldimethylsilyl-L-gulono-1,4-lactone and 3,5,6-tri-O-t-butyldimethylsilyl-L-gulono-1,4-lactone in 50 ml of dry dichloromethane was added to the reaction mixture. The temperature during the addition was maintained below -55°. The reaction mixture was stirred at less than -55° for 30 minutes at which time 12 ml (86 mmol) of dry triethylamine was added. After stirring at -60° or below for 30 minutes, the reaction mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction was worked up by extracting with water, 1N hydrochloric acid, water, and then brine and finally drying with anhydrous sodium sulfate. Removal of the solvent afforded 12.6 g of material.
- To this material was added 50 ml of THF, 20 ml of water, and 50 ml of glacial acetic acid. This solution was heated at 75° for 24 hours and the solvent was then removed under vacuum. The resulting dark smi-solid (4.8 g) contained ascorbic acid which was identical to authentic ascorbic acid by g.l.p.c. and t.l.c. By iodine tritration the yield of ascorbic acid from the mixture of triprotected derivatives of L-gulono-1,4-lactone was 31%.
- To a dry flank under nitrogen containing 5 ml of dry dichloron.ethane was added 0.293 g (1.4 mmol) of trifluoroacetic anhydride. After cooling to -60°, 0.10 ml (1.4 mmol) of dry DMSO was added. After 30 minutes, 0.618 g (1.2 mmol) of 2,5,6-tri-O-t-butyldimethylsilyl-L-gulono-1,4-lactone in 2 ml of dry dichloromethane was added. The reaction mixture was stirred at less than -500 for 30 minut and then warmed to room temperature. When the temperature reached 10°, 0.2 ml (14.4 mmol) of triethylamine was added. After 45 minutes, 60 ml of dichloromethane was added. This solution was extracted with 1N hydrochloric acid, water and brine and then dried with sodium sulfate. Removal of the solvent afforded 0.533 g (1.03 mmol, 86%) of a clear semi-solid material whose i.r. and n.m.r. were consistent with those expected for 2,5, 6-tri-O-t-butyldimethylsilyl-L-ascorbic acid. This product may be hydrolysed to L-ascorbic acid by the procedure of Example 2.
- 3,5,6-Tri-O-t-butyidimethylsilyl-L-gulono-1,4-lactone was oxidized by a procedure identical to that described in Example 3 for the preparation of 2, 5, 6-tri-O-t-butyldimetnyl-L-asccrbic acid. From 0.53 g (1.02 mmol) of 3,5,6-tri-O-t-butyldimethylsilyl-L gulono-1,4-lactone was obtained a slightly yellow oil containing 3,5,. 6-tri-O-t-butyldimethylsilyl-L-ascorbic acid. This may be hydrolysed to L-ascorbic acid by the procedure of Example 2.
- To a dry 500 ml 3-neck flask fitted with a mechanical stirrer was added 68 ml (0.67 mol) of benzaldehyde. Hydrogen chloride gas was bubbled through the benzaldehyde for one minute and then 30.0 g (0.169 mmol) of L-gulono-1,4-lactone was added to the solution. The reaction mixture was stirred for several minutes and then 0.3 g of seed crystals of 3,5-O-benzylidene-L-gulono-1,4-lactone was added. (Seed crystals are obtained by prior reactions run without the addition of such seed crystals. Addition of seed crystals is not necessary but results in better yields). After approximately 1.5 hours, the reaction mixture became very thick and stirring was stopped. After standing overnight, the reaction mixture was triturated with ether and filtered. The solid was wahsed thoroughly with ether 3 times, with water 3 times, and then with ether an additional 2 times. After drying this afforded 33.3 g (0.125 mmol, 74%) of 3,5-O-benzylidene-L-gulono-1,4-lactone. Recrystallisation from absolute ethanol afforded pure material in 65% yield, m.p. 188-189°:
- This compounds was also prepared by the above procedure but employing one equivalent of concentrated hydrochoric acid as the acid catalyst.
- To 70 ml of acetone was added 3.32 g (20 mmol) of 3,5-O-benzylidene-L-gulono-1,4-lactone followed by 21.2 g (0.246 mmol) of manganese (IV) oxide. The reaction mixture was stirred at room temperature for 3 hours. After filtering the solvent was removed under vacuum to afford 4.42 g (15.7 mmol, 78%) of 3,5-0-benzylidene-L-xylo-hexulosono-1,4-lactone hydrate as a white amorphous solid which was analytically pure. This white solid was shown to be the hydrated form of the xylo-hexulosono-1,4-lactone by the i.r., 1H-n.m.r. and 13C-.n.m.r.: i.r. (KBr) 3472, 1812 cm-1; n.m.r. (DMSO--d6)δH 3.67 (broad t, 2, -CH2O-), 4.08-4.65 (m, 3), 5.02 (t, 1, J = 5, -CH2OH), 5.75 (s, 1, -OCHO-), 7.15 (s, 1, -OH), 7.52 (s, 6, aromatic and -OH); n.m.r. (DMSO-d6) δC 170.9 (-CO2-), 134.4, 129.1, 128.4, and 126.4 (aromatic), 98.1 and 97.2 (-OCHO- and -CH(OH)2), 93.8 (-OCH-C(OH)2), 76.2 and 70.8 (-OCH-), 60.0 (-CH2OH); exact mass (C13H12O6), 264.0637 (calculated 264.0640).
- Analysis: Calculated for C13H12O6·H2O: C, 55.32; H,.5.00
- Found: C, 55.05; H, 5.02.
- To 50 ml of 70% acetic acid-water under nitrogen was added 6.362 g (22.6 mmol) of 3,5-O-benzylidene-L-xylo-hexulosono-1,4- lactone.
- The heterogeneous reaction was heated to 70-75° and after 1 hour it was homogenequs. After 4 hours the reaction was worked up by removing the solvent in vacuo. To the residual solid was added 25 ml of chloroform and 25 ml of water. The layers were separated, the chloroform layer was washed with 10 ml of water, and the water laye weve combined and concentrated in vacuo affording 3.796 g (21.5 mmol) of an off-white solid. Iodine titration of 0.222 g of this material showed the yield of ascorbic acid to be 70%. Recrystallisation of the remaining solid from methanol-ethyl acetate afforded 0.550 g of ascorbic acid in the first crop, 1.399 g in the second crop, and 0.247 g in the third crop for a total of 2.196 g (12.5 mmol, 59%). This material was identical With authentic ascorbic acid by t.l.c., g.l.p.c., i.r. and n.m.r., m.p. 184-5° (authentic 185-6°): i.r. (KBr) 3497, 3378, 3268, 3165, 2976, 2688, 1751, 1653 cm-1, n.m.r. (D2O)δH 3.7-4.3 (m, 3), 4.75 (s, -OH), 5.02 (d, 1, J = 2, ring -CH).
- To a solution of 38 ml of acetone and 7 ml of water was added 2.39 g (9.0 mmol) of 3,5-0-benzylidene-L-gulono-l,4-lactone and 0.65 g of platinum oxide. The reaction was carried out in a resin flask and rapidly agitated with a Vibro mixer. Oxygen was bubbled through the solution at a rapid rate. The intial pH of the solution was 7.4 but it rapidly dropped to 4.3 and remained there during the 7 hours oxygen was passed through the solution. At the end of that period, the catalyst was removed by filtration and the soivent was removed under vacuum.
- The resulting solid was chromatographed on 100 g of silica gel.with ethyl acetate-chloroform-methanol (60:40:1). From the column was obtained 0.240 g (0.85 mmol, 9.5%) of3,5-O-benzylidene-L-xylo-hexulosono-1,4-lactone hydrate. This material was identical with that which had been previously obtained by oxidation with manganese dioxide. The product may be converted to L-ascorbic acid by the procedure of Example 5.
- To 2 ml of methanol and 1 ml of water was added 0.221 g (0.78 mmol) of 3,5-O-benzylidene-L-xylo-hexulosono-1,4-lactone hydrate followed by 0.16 g of IR-120 cation exchange resin. After stirring the reaction mixture at room temperature for 0.5 hours, it was warmed to 500C. After 1.25 hours, an additional 0.16 g of IR-120 cation exchange resin was added. The reaction was stirred overnight. The cation exchange resin was then filtered off, washed with water, and then the aqueous solution was extracted with chloroform. On removal of the solvent, 0.138 g of an off-white solid was isolated. The yield of ascorbic acid was 61% (determined by h.p.l.c.).
- 3.0 g (10.6 mmol) 0f 3,5-O-benzylidene-L-xylo-hexulosono-1,4-lactone hydrate was added to 45 ml of 33% water-methanol solution followed by 2.12 g of IR-120 cation exchange resin. The reaction mixture was heated at 50° for 16 hours and at 60° for 4 hours. The reaction mixture was then filtered, washed with chloroform, and concentrated to a viscous oil which was triturated with ethanol to afford 1.42 g of a white solid.
- A portion of this material was purified by chromatography on IR-45 weakly basic ion exchange resin. The column was initially eluted with water to elute non-acidic impurities and then with 0.5N nydrochloric acid to elute the L-ascorbic acid. After removing the water, the resulting solid was triturated with chloroform-ethanol and recrystallised from methanol. The i.r. and n.m.r. spectra of this material were identical with authentic ascorbic acid.
- Tnrough 25 ml of dry methanol was bubbled anhydrous hydrogen chloride for approximately 30 seconds. To this solution was added 2.60 g (12.8 mmol) of 3,5-0-benzylidene-L-xylo-hexulosono-1, 4-lactone hydrate. The reaction mixture was heated to 50° for 1 hour at which time the solvent was removed. The resulting solid was dissolved in water and this was extracted with ether. The ether layer was extracted with water and the combined aqueous fractions were concentrated to a tacky foam. By h.p.l.c. this material was essentially pure methyl 2-keto-L-gulonate. Recrystallisation from methanol afforded 0.602 g (2.80 mmol, 23%) of pure methyl 2-keto- gulonato, m.p. 158-162°. The n.m.r. and i.r. spectra were identical with the authentic methyl 2-keto-L-gulonate. The mixed mp of authentic material (157-160°) with the material isolated above was 158-162°. The methyl 2-ketogulonate may be converted to L-ascorbic acid by heating in solution in the presence of an acid or base catalyst.
- To a dry flask was added 1.78 g (10 mmol) of L-gulono-1,4-lactone, 4.83 ml (40 mmol) of 2-methoxybenzaldehyde, and 0.8 ml (9.7 mmol) of concentrated hydrochloric acid. After standing at room temperature overnight, the solid reaction mixture was worked up by washing with ether, water, and then ether. This afforded 2.70 g (9.1 mmol, 91%) of 3,5-O-(2-methoxybenzylidene)-L-gulono-1,4-lactone. Analytically pure material was obtained by recrystallisation from acetonitrile, m.p. 220-221°:
- Analysis: Calculated for C14H16O7: C, 56.75; H, 5.44
- Found: C, 56.92; H, 5.50.
- Following the procedure of Example 5, from 1.18 g (4 mmol) of 3,5-O-(2-methoxybenzylidene)-L-gulono-1,4-lactone was isolated 0.710 g (2.27 mmol, 47%) of 3,5-0-(2-methoxybenzylidene)-L-xylo-hexulosono-1,4-lactone hydrate as a white amorphous solid: i.r. (KBr) 3333, 1770 cm-1; n.m.r. (DMSO-d6)δH 3.47-4.83 (m, 5), 3.83 (s, 3, -OCH3), 5.0 (t, 1, J = 5, -CH2OH), 6.0 (s, 1, -OCHO-); 6.83-7.63 (m, 6, aromatic and -OH); exact mass (C14H1407) 294.0725 (calculated 294.0711).
- Analysis: Calculated for C14H14O7.0.5 H20: C, 55.44; H, 4.98
- Found: C, 55.30; H, 5.29.
- To 5.2 ml of 70% acetic acid-water was added 0.523 g (1.7 mmol) of 3,5-O-(2-methoxybenzylidene)-L-xylo-hexulosono-1,4- lactone hydrate. This heterogeneous solution was at 70° for 2 hours. The reaction mixture was transferred to a separatory funnel with water and extracted 2 times with dichloromethane. The aqueous solution was concentrated under vacuum and afforded a white foam, 0.397 g. This material was dissolved in deuterium oxide to which was added acetcnitrile as an internal n.m.r. standard. The n.m.r. spectrum of an aliquot of this material indicated that L-ascorbic acid had been formed in 49% yield.
- L-gulono-1,4-lactone (1.78 g, 10 mmol), 2-methylbenz- alhyde (3.1 ml, 40 mmol), and concentrated hydrochloric acid (0.81 ml, 9.7 mmol) were combined. After 0.75 hours the reaction mixture turned solid and after standing overnight the reaction was worked up as previously described in Example 5 to afford 2.32 g (8.3 mmol, 83%) of 3,5-0-(2-methylbenzylidene)-L-gulono-l,4-lactone. Analytically pure material was obtained by recrystallisation from acetonitrile, m.p. 208-210°:
- Analysis: Calculated for C14H15O6: C, 59.99; H, 5.75
- Found: C, 60.18; H, 5.75.
- Following the procedure of Example 5, 1.4 g (5 mmol) of 3,5-0-(2-methylbenzylidene)-L-gulono-1,4-lactone was converted to 1.12 g (3.78 mmol, 76%) of 3,5-O-(2-methyl-benzylidene-L-xylo-hexulosono-1,4-lactone hydrate as a white amorphous solid: i.r. (KBr) 3378, 1792 cm-1; n.m.r. (DMSO-d6) δH 2.38 (s, 3, -CH3), 3.25-4.75 (m, 5), 5.83 (d, 1, -OCHO-), 7.33 (m, 4, aromatic); ms 279 (10.1), 278 (77.5), 163 (40.2), 121 (100), 120 (32.3), 119 (66.2), 105 (87.8), 93 (36.8), 91 (71.3); exact mass (C14H14O6), 278.0802 (calculated 278.0812).
- The product may be converted to ascorbic acid by hydrolysis by the procedure of Example 5.
- 3,4-dichlorobenzaldehyde (14.0 g, 80 mmol), L-gulono-1, 4-lactone (3.56 g, 20 mmol), and 1.62 ml (19.5 mmol) of concentrated hydrochloric acid were combined. After 0.5 hours the reaction mixture turned solid. After standing overnight at room temperature, the reaction was worked up as previously described to afford 6.70 g (20 mmol, 100%) of 3,5-O-(3,4-dichlorobenzylidene)-L-gulono-1,4- lactone.. Analytically pure material was obtained by recrystallisation from ethyl acetate-acetonitrile, m.p. 230-232°:
- Analysis: Calculated for C13H12O6Cl2: C, 46.58; H, 3.61
- Found: C, 46.46; H, 3.64.
- Following the procedure of Example 5, from 2.01 g (6 mmol) of 3.5-O-(3,4-dichl-orobenzylidene)-L-gizlonolactone was isolated 1.28 g (3. 64 mmol, 61 %) of 3, 5-O- (3,4-dichlorobenzyl.idene)-L-xylo- hexulcsono-1,4-lactone hydrate as a white amorphous solid: i.r. (KBr) 3333, 1792 cm-1; n.m.r. (DMSO-d6)δH 3.55-4.70 (m, 5), 5.05 (t, 1, J = 5, -CH2OH), 5.8 (s, 1, -OCHO-), 7.2 (s, i, -OH), 7.37-7.97 (m, 4, aromatic and -OH); ms 334 (6.7), 332 (9.9), 177 (52.5), 175 (100), 173 (38.2), 147 (21.8), 113 (26.8), 111 (29.2), 85 (37.6) 84 (31.3), 75 (20.8), 74 (29.0), 57 (20.9), 56 (22.5) and 55 (27.0); exact mass (C13H10O6Cl2), 331.9860 (calculated 331.9866).
- Analysis: Calculated for C13H10O6Cl2.0.25 H2O: C, 46.24; H, 3.13
- Found: C, 46.50; H, 3.58.
- L-gulono-1,4-lactone (1.78 g, 10 mmol), 2-methylpropionaldehyde (3.68 ml, 40 mmol), and concentrated hydrochloric acid (0.81 ml, 9.7 mmol) were combined and stirred for 48 hours. The excess 2-methylpropionaldehyde was removed under vacuum. The resulting thick oil was triturated with ether and the resulting solid was collected to give 0.55 g, 24% of 3,5-0-(2-methylpropylidene)-L-gulono-1,4-lactone. Analytically pure material was obtained by recrystallisation from ethyl acetate, n.p. 165-1670:
-
- Analysis: Calculated for C10H16O6: C, 51.71; H, 6.94
- Found: C, 51.81; H, 6.94.
- Following the procedure of Example 5, from 0.696 g (3 mmol) of 3,5-O-(2-methylpropylidene)-L-gulono-1,4-lactone was obtained 0.537 g (2.17 mmol, 72%) of 3,5-O-(2-methylpyopylidene)-L-xylo-hexuloxono-1,4-lactone hydrate as a white amorphous solid, m.p. 179-183° (dec.): i.r. (KBr) 3378, 1779 cm-1; n.m.r. (DMSO-d6)δH 0.90 (d, 6, J = 6, -CH3), 1.67 (m, 1, -CH(CH3)2), 3.47-4.73 (m,6) 4.91 (t, J = 5, -CH2OH); ms 230 (4.8), 187 (58.2), 127 (23.8), 97 (20.3), 85 (38.8), 73 (52.2), 71 (23.2), 69 (29.8), 68 (20.3), 57 (53.1), 55 (64.3), 45 (28.3), 44 (39.9), 43 (100) and 41 (62.4); exact mass (C10H14O6) 230.0787 (calculated 230.0783).
- Analysis: Calculated for C10H14O6.O.5 H2O: C, 51.16; H, 6.22
- Found: C, 51.13; H, 6.34.
- 3,5-O-(2-Methylpropylidene)-L-xylo-hexulosono-1,4-lactone hydrate was also prepared as follows.
- To a mixture of 30 ml of dioxane and 4 ml of water was added 0.60 g (2.59 mmol) of 3,5-O-(2-methylpropylidine)-L-gulono-1,4-lactone followed by 0.64 g of prereduced platinum oxide. The reaction mixture was heated to 70° and oxygen was bubbled through the solution. After one hour most of the starting material was gone, the catalyst was removed by filtration, and the solution concentrated in vacuo. T.l.c. and n.m.r. confirmed the presence of 3,5-O-(2-methylpropyl- idine)-L-xylo-hexulosono-l,4-lactone.
- The product may be converted to L-ascorbic acid by the procedure of Example 5.
- To a dry 50 ml flask was added 3.56 g (20 mmol) of L-gulono-1,4-lactone, 9.0 ml (80 mmol) of 2-chlorobenzaldehyde, and 1.6 ml (19.2 mmol) of concentrated hydrochloric acid. The reaction mixture turned solid within 0.5 hours and after standing at room temperature overnight was worked up by washing with ether, saturated sodium bicarbonate, water and ether. This afforded 4.78 g (15.9 mmol, 80%) of 3,5-0-(2-chlorobenzylidene)-L-gulono-l,4-lactone which was pure by t.l.c. Analytically pure material was obtained by recrystallisation from acetonitrile, m.p. 208-211°:
- Analysis: Calculated for C13H13O6Cl: C, 51.92; H, 4.35
- Found: C, 51.84; H, 4.32.
- This product may be converted to L-ascorbic acid by the procedure of Example 5.
- To 9.4 ml (80 mmol) of 3-methylbenzaldehyde was added 3.56 g (20 mmol) of L-gulono-1,4-lactone. After stirring for several minutes, 1.62 ml (19.4 mmol) of concentrated hydrochloric acid was added. On stirring at room temperature for 20 hours the initially mobile slurry had turned solid. The reaction mixture was triturated with ether, filtered, washed three times with ether, one time with water, two times with saturated sodium bicarbonate, two times with water, and finally one time with ether. The white solid after drying weighed 2.91 g (10.4 mmol, 52%), m.p. 188-191° which was pure by t.l.c. Analytically pure 3,5-O-(3-methylbenzylidene)-L-gulono-1,4-lactone was obtained by recrystallisation from acetonitrile, m.p. 198-200°:
- Analysis: Calculated for C14H1606: C, 59.99; H, 5.75
- Found: C, 60.04; H, 5.82.
- To 100 ml of acetone was added 10.0 g (56.8 mmdl) of L-galactono-1,4-lactone and 4 ml of concentrated sulfuric acid. This solution was stirred at room temperature for 21 hours. Ammom was then bubbled through the solution until it was slightly basic. The white precipitate was filtered off and the solids washed twice with 50 ml of acetone. These washings were combined with the original filtrate and they were concentrated in vacuo to a yellow oil (12.0 g). This oil was chromatographed on 325 g of silica gel which was eluted.with 10% ethyl acetate-chloroform to ethyl acetate. This afforded an oil which was triturated with diethyl ether and a white solid was filtered off. The solvent was removed from the filtrate affording 2.436 g (11.2 mmol, 20%) of an oil, 5,6-isopropylidene-L-galacto-1,4-lactone.
- Alternatively 5,6-O-isopropylidene-L-galactono-1,4-lactone can be prepared by the following procedure: To 5 ml of dry dimethylformamide was added 2.10 g (11.8 mmol) of L-galactono-1,4-lactone 1.0 g (11.8 mmol) of ethyl isopropenyl ether and a catalytic amount of p-toluenesulfonic acid. The reaction mixture was stirred at 0° for one hour and at room temperature for 18 hours. A small amount of Amberlite A-21 weakly basic resin was added and the reaction mixture was stirred for several minutes, filtered, and then concentrated in vacuo to an oil in which crystals formed on standing. Chromatography on 60 g of silica gel using 1% methanol-ethyl acetate as solvent afforded 1.213 g (5.56 mmol, 47%) of a clear oil which was pure by g.l.p.c.:
- n.m.r. (DMSO-d6)δH 1.33 (s, 6, -CH3), 3.60-4.47 (m, 6), 5.90-6.22 (m, 2, -OH); n.m.r. (DMSO-d6)δC 174.2 (-CO2-), 108.9 (-OCO-), 79.2, 76.0, 73.8, 64.7 (-OCH-), 26.3, 25.6, (-CH3); exact mass (C9H1406) (P + H) 219.0858 (calculated 219.0847), (P-CH ) 203.0563 (calculated 203.0570).
- To 17.5 ml of chloroform was added 4.263 g (19.5 mmol) of 5,6-O-isopropylidene-L-galactono-1.4-lactone and 3.2 ml of dry pyridine. The reaction mixture was cooled to -60°, and 1.39 ml (19.5 mmol) of acetyl chloride was slowly added. The reaction was stirred at -600 or below for 2 hours, diluted with ethyl acetate and extracted with 1N hydrochloric acid two times, water two times, saturated sodium bicarbonate two times, and brine. The organic solution was dried with sodium sulfate, and concentrated in vacuo to an oil, 3.79 g (15.2 mmol, 78%). This material clearly was a mixture of isomers by 'H-n.m.r. with one isomer predominating. Analytically pure material was obtained by chromatography on silica gel (4% methanol-chloroform) followed by molecular distillation: n.m.r. (DMSO-d6)δH 1.31 (s, 6, -CH3), 2.17 (s, 3, -COCH3), 3.58-4.52 (m, 5), 5.65 (1, m, -CHOCOCH3), 6.22 (1, m, -OH).
- Analysis: Calculated for C11H16O7: C, 50.76; H, 6.19
- Found: C, 50.44; H, 6.11.
- The material obtained from the above chromatography was greater than 95% one isomer. The n.m.r. data suggests that it is 5,6-O-isopropylidene-3-O-acetyl-L-galactono-1,4-lactone.
- The above crude mixture of acetates was converted to ascorbic acid as follows: To 25 ml of dry dichloromethane was added 1.69 ml (12 mmol) of trifluoroacetic anhydride. After cooling to less than -50°, 0.85 ml (12 mmol) of dimethylsulfoxide was added. The resulting heterogeneous solution was stirred at -50° or below for 30 minutes. Then 15 ml of dichloromethane containing 1.49 g (6.0 mmol) of the mixture of acetates was added. The resulting solution was stirred at less than -50° for 40 minutes at which time 1.2 ml of triethylamine was added. After 25 minutes at -500 or lower, the reaction mixture was stirred at room temperature for 1 hour. Ethyl acetate (100 ml) was added and the resulting solution was extracted two times with 1N hydrochloric acid (50 ml), two times with water (50 ml), and two times with brine (100 ml). The organic layer was dried over sodium sulfate and concentrated in vacuo to an oil, 1.25 g (5.08 mmol, 85%).
- A portion of this oil (0.697 g, 2.7 mmol) was dissolved in 10 ml of 70% acetic acid-water and heat at 70° for 20 hours under nitrogen. The solvent was removed in vacuo affording 0.453 g of material. A portion was titrated with iodine and showerl that ascorbic acid was formed in 50% yield (42% from the mixture of acetates). This material by t.l.c. and g.l.p.c. was identical with authentic ascorbic acid.
- To a dry 500 ml flask fitted with a Dean-Stark trap was added 17.8 g (100 mmol) of L-gulono-l,4-lactone, 57 ml (400 mmol) of acetaldehyde diethyl acetal, 40 ml of dry dimethylformamide, 200 ml of benzene, and 0.2 g of p-toluenesulfonic acid. This reaction mixture was refluxed under nitrogen for 21 hours at which time a small amount of sodium bicarbonate was added. The solution was stirred for several minutes, cooled, and filtered. The solution was concentrated under vacuum to a light amber oil which was triturated with ether. The resulting solid, 5,6-0-ethylidene-L-gulono-,14-lactone (12.4 g, 60.8 mmol, 61%) which was pure by t.l.c. was recryst.allised from ethanol to afford 6.94 g (34 mmol, 34%) of a white crystalline solid, m.p. 153.5-158.5 . A second crop of crystals weighing 1.22 g (6.0 mmol, 6%) was obtained by concentrating the mother liquor. T.l.c. on silica gel using ethyl acetate revealed that this material was a diastereomcric mixture. Recrystallisation of this mixture from benzene afforded a crystalline product greatly enriched in one of the diastereomers, m.p. 164-165 . The spectral data below was obtained from a diastereomeric mixture: i.r. (KBr) 3448, 3279, 1783 cm-1; n.m.r. (DMSO-d6)δH 1.28 (two sets of d, 3, J = 5, -CH3), 3.48-4.58 (m, 6), 5.00 (two sets of q, 1, J = 5, -OCHO-), 5.48 (broad d, 1, J = 4, -OH), 5.88 (d, 1, J = 7, -OH); n.m.r. (DMSO-d6)δC 176.0.(s, 1, -CO2-), 81.6, 80.1; 75.6, 75.3; 70.5; 69.5, 69.0 (all d, 4), 65.4 (t, 1, -CH2O-), 101.7, 100.4 (each a d, -OCHO-), 20.0, 19.6 (each a q, -CH3); ms 203 (1.8), 189 (30.4), 125 (36.1), 87 (50.4), 69 (35.5), 60 (13.8), 59 (49.6), 58 (14.4), 57 (17.8), 55 (18.7), 45 (27.9), 44 (51.8), 43 (100), 42 (19.5), 41 (27.5).
- Analysis: Calculated for C8H12O6: C, 47.05; H, 5.92
- Found: C, 47.09; H, 5.77.
- To a solution of 3 ml of chloroform and 5 ml of dry pyridine under nitrogen was added 1.175 g (5.75 mmol) of 5,6-O-ethylidene-L-gulono-1,4-lactone. This solution was cooled to less than-50° and 0.57 ml (0.62 g, 6.05 mmol) of acetic anhydride was added. The reaction mixture was stirred at or below -50 for. 3 hours and then at room temperature for 16 hours. Chloroform (100 ml) was added and the reaction mixture was extracted with 30 ml of water, two times with 30 ml of 1N hydrochloric acid and brine. The organic solution was dried with sodium sulfate and the solvent was removed in vacuo affording 1.118 g (4.5 mmol, 78%) of an oil which crystallised on standing. The n.m.r. spectrum showed a mixture of the acetates.
- To a 200 ml round-bottom flask under nitrogen was added 30 ml of dry dichloromethane. After cooling to less than -50°, 1.4 ml (2.1 g, 10 mmol) of trifluoroacetic anhydride followed by 0.71 ml (10 mmol, 0.78 g) of dry dimethylsulfoxide was added. The resulting heterogeneous solution was stirred at less than -50° for 30 minutes at which time the above mixture of acetates (1.118 g, 4.5 mmol) in 30 ml of dry dichloromethane was added while maintaining the temperature below -50°. The resulting homogeneous solution was stirred for 40 minutes below -50° and then 2 ml of dry triethylamine was added. After 25 minutes at -50° or lower, the solution was allowed to warm to room temperature and stirred for 2 hours. At that time 70 ml of ethyl acetate was added to the reaction mixture which was then extracted two times with 40 ml of 1N hydrochloric acid, once with 40 ml of water and brine. The organic layer was dried with sodium sulfate and concentrated in vacuo affording 0.992 g of material to which was added 10 ml of 70% acetic acid-water. This solution was heated for 20 hours under nitrogen at 80° ± 5°. Removal of the solvent afforded material which by t.l.c. and g.l.p.c. was identical with authentic ascorbic acid.
- L-ascorbic acid may be prepared by the procedures of Examples 1 and 2 but cmploying each of L-galacto-1,4-lactone, L-talono-1,4-lactone and L-idono-1,4-lactone as starting materials.
- D-ascorbic acid may be prepared by the procedures of Examples 1 and 2 but employing each of D-gulono-1,4-lactone, D-galacto-14,-lactone, D-talono-1,4-lactone and D-idono-1,4-lactone as starting materials.
- D-ascorbic acid may be prepared by the procedure of Example 5 but employing each of D-gulono-1,4-lactone and D-idono-1,4-lactone as starting materials.
- To 9.41 g (52.9 mmol) of L-gulono-1,4-lactone was added 11.8 ml (0.211 mol) of acetaldehyde. Hydrogen chloride gas was bubbled through the reaction mixture which was then stirred at room temperature for 18 hours.
- The initially heterogeneous reaction mixture became a mobile liquid containing only a residual amount of solid.which was removed by adding acetone and filtering. The solution was concentrated to an oil from which a crystalline solid was obtained on trituration with ethyl acetate. The resulting solid was recrystallised from ethyl acetate to afford 2.68 g (13.1 mmol, 25%) of material which was further purified by crystallisation from ethanol, m.p. 158-60°. Analytically pure 3,5-O-ethylene-L-gulono-1,4-lactone was obtained by recrystallisation from acetone, m.p. 160-62°: i.r. (KBr) 3367, 3175, 1799, 1779 cm-1; n.m.r. (DMSO-d6) δH 1.53 (d, 3, J = 5, -CH3), 3.58 (m, 2, -CH2O-), 3.95 (m, 1), 4.17-5.17 (m, 5, -OH, -OCHO-, others), 5.87 (d, 1, J = 6, -OH); n.m.r. (DMSO-d6) δC 175.9 (-CO2-), 96.2 (-OCO-), 75.6, 74.3, 70.6, 69.3 (-CHO-), 59.8 (-CH2OH), 20.8 (-CH3); ms 204 (0.3), 203 (1.6), 160 (22.3), 99 (21.8), 85 (34.4), 83 (11.3), 73 (27.5), 72 (11.6), 71 (27.7), 69 (11.1), 57 (39.3), 45 .(100), 44 (11.3), 43 (50.7); exact mass (C8H1206), 204.0636 (calculated 204.0633).
- Analysis: Calculated for C8H1206: C, 47.06; H, 5.93
- Found: C, 47.44; H, 5.75.
- To 6 ml of acetone was added 0.210 g (1.03 mmol) of 3,5-O-ethylidene L-gulono-1,4-lactone followed by 1.08 g (12.5 mmol) of manganese dioxide. The reaction mixture was stirred under nitrogen at room temperature for 2.25 hours. Acetone was added and the reaction mixture was filtered through a pad to celite to remove the manganese dioxide.
- 0.169 g (0.77 mmol, 75%) of 3,5-O-ethylidene-L-xylo-hexulosono-1, 4-lactone hydrate was obtained on concentration of the acetone solution: i.r. (KBr) 3390, 1799 cm-1; n.m.r. (DMSO-d6)δH 1.25 (d, 3, J = 5, -CH3), 3.10-4.32 (m, 5), 4.43 (broad s, 1), 4.92 (m, 2, -OH and -CHCH3), 7.07 and 7.38 (-C(OH)2); exact mass (C8H10O6), 202.0439 (calculated 202.0477).
- This material may be converted to ascorbic acid using the hydrolysis conditions described in Example 5.
- To 8 ml of dry pyridine was added 1.254 g (4.71 mmol) of 3,5-O-benzylidene-L-gulono-1,4-lactone followed by 1.40 g (5.02 mmol) of triphenylchloromethane. The reaction was stirred at room temperature for 20 hours. Chloroform was added and the reaction mixture was extracted with water, 1N hydrochloric acid, saturated sodium bicarbonate, and brine. The chloroform extract was dried with sodium sulfate and concentrated affording an oil. Chromatography on florisil using 5% methanol-chloroform afforded 0.920 g (1.81 mmol, 38%) of 3,5-O-benzylidene-6-O-triphenylmethyl-L-gulono-1,4-lactone: i.r. (KBr) 3378, 1786 cm-1; n.m.r. (DMSO-d6)δH 3.20 (m, 2), 4.27-4.93 (m, 4), 5.77 (sm 1, -OCHO-), 5.83 (broad peak, 1, -OH), 7.40 (broad singlet, 20, aromatic); n.m.r. (DMSO-d6)δC 175.5 (-CO2-), 143.3, 137.5, 128.8, 128.2, 127.9, 127.8, 127.0, 126.2 (aromatic), 97.8 (-OCO-), 86.2, 74.7, 74.2, 70.6, 69.6 and 62.5 (-CO-); ms 508 (0.5), 259 (10.2), 258 (17.6), 249 (17.9), 244 (24.7), 243 (100), 165 (32.1), 107 (28.0), 105 (43.2), 79.0 (16.3), 77 (20.2); exact mass (C32H28O6), 508.1939 (calculated 508.1886).
- To 2 ml of acetone was added 0.071 g (0.14 mmol) of the above solid followed by 0.245 g (2.82 mmol) of manganese dioxide The reaction was stirred at room temperature for 2 hours. Acetone was added and the reaction mixture was filtered through a pad of celite to remove the manganese dioxide and concentrated (0.058 g, 0.11 mmol, 79%). To this material was added under nitrogen 2 ml of 70% acetic acid-water and the reaction mixture was heated to 70-75° for 4 hours. The solvent was removed and afforded material which was identical with authentic ascorbic acid by t.l.c. and g.l.p.c.
- To 50 ml of benzene and 7 ml of dimethylformamide was added 10 ml (80mmol) of cinnamaldehyde followed by two drops of polyphosphoric acid and 3.56 g (20 mmol) of L-gulono-1,4-lactone. The reaction mixture was refluxed and water removed via a Dean-Stark trap. After 5 hours this reaction mixture was filtered while hot. Sodium bicarbonate was added to the filtrate which was then refiltered. The solvent was removed under vacuum, the resulting oil triturated with ether and the solid formed was collected by filtration and dried to afford 2.44 g (8.4 mmol, 42%) of 3,5-0-cinnamylidene-L-gulono-1,4-lactone. Analytically pure material was obtained by trituration with hot benzene followed by recrystallisation from water acetone, m.p. 164-1670c. In an alternative procedure, the white solid resulting from ether trituration was purified by dissolving in tetrahydrofuran and washing the solution three times with. a saturated brine-sodium bicarbonate solution.
- The tetrahydrofuran was then concentrated and the resulting solid was recrystallised from acetone-water, m.p. 185-187°C,
- Analysis: Calculated for C15H16O6: C, 61.63; H, 5.51
- Found: C, 61.77; H, 5.52.
Claims (10)
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US803020 | 1977-06-03 | ||
US05/803,020 US4111958A (en) | 1977-06-03 | 1977-06-03 | Ascorbic acid synthesis |
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EP0000092A1 true EP0000092A1 (en) | 1978-12-20 |
EP0000092B1 EP0000092B1 (en) | 1981-04-29 |
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EP78300014A Expired EP0000092B1 (en) | 1977-06-03 | 1978-06-02 | Method of preparing ascorbic acid and intermediates specially adapted for use therein |
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US (1) | US4111958A (en) |
EP (1) | EP0000092B1 (en) |
JP (2) | JPS5845432B2 (en) |
DE (1) | DE2860636D1 (en) |
DK (1) | DK248178A (en) |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0295841A1 (en) * | 1987-06-15 | 1988-12-21 | Takeda Chemical Industries, Ltd. | New ascorbic acid ester |
WO2014014125A1 (en) * | 2012-07-20 | 2014-01-23 | Fujifilm Corporation | Etching method, and method of producing semiconductor substrate product and semiconductor device using the same |
Families Citing this family (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4283340A (en) * | 1977-06-13 | 1981-08-11 | Pfizer Inc. | Ascorbic acid intermediates |
US4232168A (en) * | 1977-06-13 | 1980-11-04 | Pfizer Inc. | Preparation of ascorbic acid intermediates |
US4421924A (en) * | 1980-05-05 | 1983-12-20 | Pfizer Inc. | Ascorbic acid intermediates and their preparation |
EP0057699A4 (en) * | 1980-08-14 | 1982-11-08 | Nat Foundation For Cancer Res | 5,6-o-isoalkylidene ascorbic acid derivatives. |
US4423236A (en) * | 1980-08-14 | 1983-12-27 | National Foundation For Cancer Research, Inc. | 5,6,-0-Isoalkylidene ascorbic acid derivatives |
US4552888A (en) * | 1982-01-15 | 1985-11-12 | Eli Lilly And Company | Ascorbic acid ethers in angiogene |
DK36784A (en) * | 1983-02-25 | 1984-08-26 | Hoffmann La Roche | PROCEDURE FOR PREPARING CHIRAL ALDEHYDES |
US4931558A (en) * | 1983-09-21 | 1990-06-05 | Eli Lilly And Company | Processes for preparing intermediates of picenadol |
JPS61192907U (en) * | 1985-05-24 | 1986-12-01 | ||
JPS6244712U (en) * | 1985-09-09 | 1987-03-18 | ||
JPS63114705U (en) * | 1987-01-20 | 1988-07-23 | ||
US5569875A (en) * | 1992-03-16 | 1996-10-29 | Legend Products Corporation | Methods of making explosive compositions, and the resulting products |
US5442079A (en) * | 1993-05-10 | 1995-08-15 | Virginia Polytechnic Institute And State University | Method for preparing erythruronolactone |
FR2761991B1 (en) | 1997-04-11 | 1999-06-25 | Ceca Sa | 5-6, O ALKYLIDENES GLUCONOLACTONES-1 (4) AND DERIVATIVES, METHODS OF PREPARATION AND USES |
US6610863B2 (en) | 2000-12-22 | 2003-08-26 | Eastman Chemical Company | Continuous process for producing L-ascorbic acid |
DE10231890B4 (en) * | 2002-07-12 | 2004-07-01 | Basf Ag | Process for the separation of ascorbic acid from a polar solvent containing ascorbic acid and 2-keto-L-gulonic acid |
-
1977
- 1977-06-03 US US05/803,020 patent/US4111958A/en not_active Expired - Lifetime
-
1978
- 1978-06-01 IE IE1103/78A patent/IE47102B1/en unknown
- 1978-06-02 IT IT7824178A patent/IT1098308B/en active
- 1978-06-02 DK DK248178A patent/DK248178A/en not_active Application Discontinuation
- 1978-06-02 EP EP78300014A patent/EP0000092B1/en not_active Expired
- 1978-06-02 DE DE7878300014T patent/DE2860636D1/en not_active Expired
- 1978-06-02 JP JP53066593A patent/JPS5845432B2/en not_active Expired
-
1980
- 1980-05-02 JP JP5934380A patent/JPS55149286A/en active Granted
Non-Patent Citations (2)
Title |
---|
CHEMICAL ABSTRACTS 70 (1969) 4455v. & Chem. Pharm Bull. (Tokyo), 1968, 16 (7), 1294-9 * |
CHEMICAL ABSTRACTS, 82 (1975), 73330k & Agrio. Biol. Chem. 1974, 38, (11) 2189-90. * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0295841A1 (en) * | 1987-06-15 | 1988-12-21 | Takeda Chemical Industries, Ltd. | New ascorbic acid ester |
US4845246A (en) * | 1987-06-15 | 1989-07-04 | Takeda Chemical Industries, Ltd. | Ascorbic acid ester |
WO2014014125A1 (en) * | 2012-07-20 | 2014-01-23 | Fujifilm Corporation | Etching method, and method of producing semiconductor substrate product and semiconductor device using the same |
Also Published As
Publication number | Publication date |
---|---|
DE2860636D1 (en) | 1981-08-06 |
DK248178A (en) | 1978-12-04 |
IE781103L (en) | 1978-12-03 |
IT1098308B (en) | 1985-09-07 |
EP0000092B1 (en) | 1981-04-29 |
IE47102B1 (en) | 1983-12-28 |
JPS5719117B2 (en) | 1982-04-20 |
US4111958A (en) | 1978-09-05 |
JPS543058A (en) | 1979-01-11 |
JPS5845432B2 (en) | 1983-10-08 |
IT7824178A0 (en) | 1978-06-02 |
JPS55149286A (en) | 1980-11-20 |
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