CN107325070A - A kind of preparation method of the lactone of 2,3,4 three O benzyls, 6 deoxidation D glucopyras saccharic acid 1,5 - Google Patents
A kind of preparation method of the lactone of 2,3,4 three O benzyls, 6 deoxidation D glucopyras saccharic acid 1,5 Download PDFInfo
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- CN107325070A CN107325070A CN201710621433.2A CN201710621433A CN107325070A CN 107325070 A CN107325070 A CN 107325070A CN 201710621433 A CN201710621433 A CN 201710621433A CN 107325070 A CN107325070 A CN 107325070A
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- tri
- benzyl
- deoxidation
- pyrans
- organic solvent
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- NAOLWIGVYRIGTP-UHFFFAOYSA-N 1,3,5-trihydroxyanthracene-9,10-dione Chemical compound C1=CC(O)=C2C(=O)C3=CC(O)=CC(O)=C3C(=O)C2=C1 NAOLWIGVYRIGTP-UHFFFAOYSA-N 0.000 title claims abstract description 32
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 title abstract description 9
- 150000002596 lactones Chemical class 0.000 title abstract description 7
- 229930182478 glucoside Natural products 0.000 claims abstract description 41
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- HOVAGTYPODGVJG-UVSYOFPXSA-N (3s,5r)-2-(hydroxymethyl)-6-methoxyoxane-3,4,5-triol Chemical compound COC1OC(CO)[C@@H](O)C(O)[C@H]1O HOVAGTYPODGVJG-UVSYOFPXSA-N 0.000 claims abstract description 26
- HOVAGTYPODGVJG-UHFFFAOYSA-N methyl beta-galactoside Natural products COC1OC(CO)C(O)C(O)C1O HOVAGTYPODGVJG-UHFFFAOYSA-N 0.000 claims abstract description 26
- -1 pyrans methyl glucosides Chemical class 0.000 claims abstract description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 79
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 37
- 235000019441 ethanol Nutrition 0.000 claims description 31
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- 239000003960 organic solvent Substances 0.000 claims description 24
- 239000003054 catalyst Substances 0.000 claims description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 15
- 238000001914 filtration Methods 0.000 claims description 14
- 238000010438 heat treatment Methods 0.000 claims description 14
- 239000012043 crude product Substances 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 10
- 238000002425 crystallisation Methods 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- 238000001953 recrystallisation Methods 0.000 claims description 10
- 238000006467 substitution reaction Methods 0.000 claims description 9
- BUBVLQDEIIUIQG-UHFFFAOYSA-N 3,4,5-tris(phenylmethoxy)-6-(phenylmethoxymethyl)oxan-2-one Chemical compound C=1C=CC=CC=1COC1C(OCC=2C=CC=CC=2)C(OCC=2C=CC=CC=2)C(=O)OC1COCC1=CC=CC=C1 BUBVLQDEIIUIQG-UHFFFAOYSA-N 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 8
- 235000001727 glucose Nutrition 0.000 claims description 8
- 150000008131 glucosides Chemical class 0.000 claims description 8
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical group C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000013078 crystal Substances 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 claims description 5
- 238000004458 analytical method Methods 0.000 claims description 5
- 238000004140 cleaning Methods 0.000 claims description 5
- 239000007791 liquid phase Substances 0.000 claims description 5
- MMDSSERULWYGSW-UHFFFAOYSA-N methanesulfonic acid;potassium Chemical compound [K].CS(O)(=O)=O MMDSSERULWYGSW-UHFFFAOYSA-N 0.000 claims description 5
- 238000011084 recovery Methods 0.000 claims description 5
- 238000000926 separation method Methods 0.000 claims description 5
- 239000011780 sodium chloride Substances 0.000 claims description 5
- 239000007790 solid phase Substances 0.000 claims description 5
- 230000001335 demethylating effect Effects 0.000 claims description 4
- 238000001704 evaporation Methods 0.000 claims description 4
- 230000008020 evaporation Effects 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 238000007254 oxidation reaction Methods 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 150000007513 acids Chemical class 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- 238000010792 warming Methods 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 235000000346 sugar Nutrition 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 abstract description 4
- 210000003746 feather Anatomy 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 125000002346 iodo group Chemical group I* 0.000 abstract 1
- 150000004880 oxines Chemical class 0.000 abstract 1
- 239000000047 product Substances 0.000 description 8
- JVHXJTBJCFBINQ-ADAARDCZSA-N Dapagliflozin Chemical compound C1=CC(OCC)=CC=C1CC1=CC([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)=CC=C1Cl JVHXJTBJCFBINQ-ADAARDCZSA-N 0.000 description 6
- 229960003834 dapagliflozin Drugs 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 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 4
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- TWCMVXMQHSVIOJ-UHFFFAOYSA-N Aglycone of yadanzioside D Natural products COC(=O)C12OCC34C(CC5C(=CC(O)C(O)C5(C)C3C(O)C1O)C)OC(=O)C(OC(=O)C)C24 TWCMVXMQHSVIOJ-UHFFFAOYSA-N 0.000 description 3
- PLMKQQMDOMTZGG-UHFFFAOYSA-N Astrantiagenin E-methylester Natural products CC12CCC(O)C(C)(CO)C1CCC1(C)C2CC=C2C3CC(C)(C)CCC3(C(=O)OC)CCC21C PLMKQQMDOMTZGG-UHFFFAOYSA-N 0.000 description 3
- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- PFOARMALXZGCHY-UHFFFAOYSA-N homoegonol Natural products C1=C(OC)C(OC)=CC=C1C1=CC2=CC(CCCO)=CC(OC)=C2O1 PFOARMALXZGCHY-UHFFFAOYSA-N 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 238000005556 structure-activity relationship Methods 0.000 description 3
- 108091006269 SLC5A2 Proteins 0.000 description 2
- 102000058081 Sodium-Glucose Transporter 2 Human genes 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 150000002611 lead compounds Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 241000255964 Pieridae Species 0.000 description 1
- ZXOCGDDVNPDRIW-NHFZGCSJSA-N Tofogliflozin Chemical compound O.C1=CC(CC)=CC=C1CC1=CC=C(CO[C@@]23[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)O)C2=C1 ZXOCGDDVNPDRIW-NHFZGCSJSA-N 0.000 description 1
- 238000012925 biological evaluation Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229960001713 canagliflozin Drugs 0.000 description 1
- VHOFTEAWFCUTOS-TUGBYPPCSA-N canagliflozin hydrate Chemical compound O.CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1.CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1 VHOFTEAWFCUTOS-TUGBYPPCSA-N 0.000 description 1
- QNEFNFIKZWUAEQ-UHFFFAOYSA-N carbonic acid;potassium Chemical compound [K].OC(O)=O QNEFNFIKZWUAEQ-UHFFFAOYSA-N 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 125000006840 diphenylmethane group Chemical group 0.000 description 1
- 229960003345 empagliflozin Drugs 0.000 description 1
- OBWASQILIWPZMG-QZMOQZSNSA-N empagliflozin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=CC=C(Cl)C(CC=2C=CC(O[C@@H]3COCC3)=CC=2)=C1 OBWASQILIWPZMG-QZMOQZSNSA-N 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229950000991 ipragliflozin Drugs 0.000 description 1
- AHFWIQIYAXSLBA-RQXATKFSSA-N ipragliflozin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=CC=C(F)C(CC=2SC3=CC=CC=C3C=2)=C1 AHFWIQIYAXSLBA-RQXATKFSSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 229950004397 luseogliflozin Drugs 0.000 description 1
- 239000002398 materia medica Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229950006667 tofogliflozin Drugs 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/16—Heterocyclic compounds containing six-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
- C07D309/28—Heterocyclic compounds containing six-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
- C07D309/30—Oxygen atoms, e.g. delta-lactones
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Saccharide Compounds (AREA)
Abstract
The present invention relates to one kind 2,3, the preparation method of the lactone of 4 three O benzyls, 6 deoxidation D glucopyras saccharic acid 1,5, by 2,3, the iodo D pyrans methyl glucosides of 2,3,4 three O benzyls 6 are made in the reaction of the methanesulfonates of 4 three O benzyl D pyrans methyl glucoside 6, further reaction is made 2, the deoxidation D pyrans methyl glucosides of 3,4 three O benzyls 6, further react and are made 2,3, the deoxidation D pyrans methyl glucosides of 4 three O benzyls 6, final reaction is made described 2,3, the lactone of 4 three O benzyls, 6 deoxidation D glucopyras saccharic acid 1,5.The present invention is when realizing prepared by feather weight, and the yield and purity of the lactone of 2,3,4 three O benzyls, 6 deoxidation D glucopyras saccharic acid 1,5 are still very high, is adapted to industrialized production.
Description
Technical field
The present invention relates to a kind of preparation side of-O- benzyl -6- deoxidation-D- glucopyra saccharic acid -1,5- lactones of 2,3,4- tri-
Method.
Background technology
Anti- diabetes B drug research present situation in current global range, to having listed and being in each phase clinical stage
SGLT2 inhibitor molecular structure dissected, find the current SGLT2 inhibitor overwhelming majority using dapagliflozin as
Lead compound carries out structural modification.Canagliflozin, ipragliflozin and empagliflozin with
Dapagliflozin is template, keeps sugared ring plate segment structure constant, changes the aglucon aromatic rings fragment of glucosides；LX4211 and PF-
04971729 keeps aglycone diphenyl-methane structure constant, and trickle change has been done to sugared ring plate section；tofogliflozin
Then sugared ring plate section and aglycone are made and transformed to some extent with TS-071, but still follows sugared ring plate segment structure phase
It is to keep lipophilicity suitable like property and aglucon partial aromatic.The starting point of above-mentioned three major types SGLT2 inhibitor design is all enclosed
Around dapagliflzin, make the change of aglycone or/and sugared loop section, all do not illustrate the hydroxyl of sugared ring plate section for
The role of medicine structure-activity relationship.
Tianjin Inst. of Materia Medica selects dapagliflozin as lead compound, to four hydroxyls of its sugared ring plate section
Carry out gradually single deoxidation and combination deoxidation, and then influence of the clear and definite hydroxyl to medicine structure-activity relationship.By to deoxidation products D6
(6-deoxydapagliflozin), D4 (4-deoxydapagliflozin), D3 (3-deoxydapagliflozin) and D2
The biological evaluation (external activity evaluation and activity in vivo evaluation) of (2-deoxydapagliflozin), specify that
Influence of four hydroxyls of dapagliflozin sugar ring plate sections to medicine structure-activity relationship.6-0H presence reduces guide on the contrary
Compound dapagliflozin bioactivity.The adhesion of 6-OH deoxidation products D6 and acceptor SGLT2 transport proteins compared with
Dapagliflozin strengthens, and then causes SGLT2 to couple the ability reduction of glucose, reduces again suction of the glucose in kidney
Receive and add the excretion of glucose in urine.
- O- benzyl -6- deoxidation-D- glucopyra saccharic acid -1,5- the lactones of 2,3,4- tri- are to have been enter into clinical test phase hypoglycemic
Medicine Tag arranges net critical materials, therefore, carry out feather weight and yield is high, purity is high 2,3,4- tri--O- benzyl -6- deoxidations -
Preparing for D- glucopyra saccharic acid -1,5- lactones is extremely important.
The content of the invention
The technical problems to be solved by the invention are to provide the-O- benzyls -6- of 2,3,4- tri- that a kind of yield is high, purity is high and taken off
The preparation method of oxygen-D- glucopyra saccharic acid -1,5- lactones.
To reach above-mentioned purpose, the technical solution adopted by the present invention is：
It is an object of the present invention to provide a kind of-O- benzyl -6- deoxidation-D- glucopyra saccharic acids -1,5- of 2,3,4- tri-
The preparation method of lactone, it comprises the following steps：
Step (1), by the-O- benzyls-D- pyrans methyl glucoside -6- methanesulfonates of 2,3,4- tri- and KI organic
Substitution reaction is carried out in the presence of solvent-O- benzyl -6- iodo-D- pyrans the methyl glucosides of 2,3,4- tri- are made；
Step (2), by the-O- benzyl -6- iodo-D- pyrans methyl glucosides of 2,3,4- made from step (1) tri-, carbonic acid
Potassium and hydrogen carry out de- Iod R in the presence of catalyst and organic solvent and the-O- benzyl -6- deoxidation-D- pyrroles of 2,3,4- tri- are made
Furfuryl glucoside；
Step (3),-O- benzyl -6- deoxidation-D- pyrans methyl glucosides of 2,3,4- made from step (2) tri- are being had
Demethylating reaction is carried out in the presence of machine solvent and acid, and-O- benzyl -6- deoxidation-D- pyrans the methyl glucosides of 2,3,4- tri- are made；
It is step (4),-O- benzyl -6- deoxidation-D- pyrans methyl glucosides of 2,3,4- made from step (3) tri-, diformazan is sub-
Sulfone and acetic anhydride carry out oxidation reaction and are made in the described-O- benzyl -6- deoxidation-D- glucopyra saccharic acids -1,5- of 2,3,4- tri-
Ester.
Preferably, the organic solvent in step (1) is DMF.
Preferably, the organic solvent in step (2) is the ethanol that mass concentration is 90%~98%.
Preferably, the catalyst described in step (2) is palladium-carbon catalyst.
Preferably, the organic solvent described in step (3) is ethanol.
Preferably, the acid described in step (3) is the hydrochloric acid that mass concentration is 10%~20%.
Preferably, the substitution reaction described in step (1) is carried out under reflux conditions.
Preferably, in step (1), described 2,3,4- tri--O- benzyl-D- pyrans methyl glucoside -6- methanesulfonates,
The mass ratio that feeds intake of described KI and described organic solvent is 2.5~3：1：5~10.
Preferably, it is described 2,3,4- tri--O- benzyl -6- iodo-D- pyrans methyl glucosides, described in step (2)
Potassium carbonate, described catalyst, the mass ratio that feeds intake of described organic solvent is 1：0.9~1.1：0.05~0.2：3~10.
Preferably, the described demethylating reaction in step (3) is carried out under reflux conditions.
Preferably, it is described 2,3,4- tri--O- benzyl -6- deoxidation-D- pyrans methyl glucosides, described in step (3)
Organic solvent and the described sour mass ratio that feeds intake be 1：1~5：1~5.
Preferably, the temperature that described oxidation reaction is carried out in step (4) is 20~30 DEG C.
Preferably, it is described 2,3,4- tri--O- benzyl -6- deoxidation-D- pyrans methyl glucosides, described in step (4)
The mass ratio that feeds intake of dimethyl sulfoxide and described acetic anhydride is 1：1.5~5：0.9~2.
Preferably, the embodiment of described preparation method is：
Step (1), the described-O- benzyl-D- pyrans methyl glucoside -6- first sulphurs of 2,3,4- tri- are added in a kettle.
Acid esters, described KI, described organic solvent under conditions of stirring, is warming up to backflow, and chromatogram tracking is to reacting knot
Beam, filtering removes methanesulfonic acid potassium, and the organic solvent described in heating recovery adds ethanol near dry, stirs crystallisation by cooling, filtering
Obtain the described-O- benzyl -6- iodo-D- pyrans methyl glucosides of 2,3,4- tri-；
Described-O- benzyl -6- iodo-D- the pyrroles of 2,3,4- tri- made from step (2), in a kettle. addition step (1)
Furfuryl glucoside, described potassium carbonate, described catalyst, described organic solvent, under conditions of stirring, 0~
Described hydrogen is passed through at 40 DEG C, chromatogram tracking analysis judges terminal, reaction terminates, filtered, liquid phase take off described in it is organic molten
Agent, obtains 2,3,4- tri- described-O- benzyl -6- deoxidation-D- pyrans methyl glucosides；Solid phase is fully washed with water, insoluble matter
For described catalyst, reuse, cleaning solution evaporation water, condensing crystallizing obtains KI, the substitution reaction for step (1)；
Step (3), the described-O- benzyl -6- deoxidation-D- pyrans methyl glucosides of 2,3,4- tri- are added in a kettle.
Glycosides, described organic solvent after dissolving, adds described acid, back flow reaction, chromatogram tracking to reaction end, crystallisation by cooling, mistake
Filter, is washed with water, obtains 2,3,4- tri--O- benzyl -6- deoxidation-D- pyrans methyl glucoside crude products；Filtrate is neutralized with sodium hydroxide,
Into rectifying column separation methanol, ethanol, water, tower bottoms crystallizes to obtain sodium chloride crystal；Described-O- benzyls-the 6- of 2,3,4- tri- take off
Oxygen-D- pyrans methyl glucoside crude products obtain the described-O- benzyl -6- deoxidation-D- pyrans first of 2,3,4- tri- with ethyl alcohol recrystallization
Base glucose；
Step (4), 2,3,4- tri- described-O- benzyl -6- deoxidation-D- pyrans methyl glucosides are added in a kettle.,
Described dimethyl sulfoxide, 20~30 DEG C of control temperature instills described acetic anhydride, and chromatogram tracking to reaction end adds water, risen
Dimethyl sulphide, acetic acid, DMSO is recovered under reduced pressure to without distillate, being cooled to 45~55 DEG C in temperature, and it is 40~60% to add mass concentration
Ethanol water, stirring, cold filtration obtains 2,3,4- tri--O- benzyl -6- deoxidation-D- glucopyra saccharic acid -1,5- lactones thick
Product, then with ethyl alcohol recrystallization, filter, be dried to obtain 2,3,4- tri- described-O- benzyl -6- deoxidation-D- glucopyras saccharic acid -1,
5- lactones.
In the present invention, the synthesis road of described 2,3,4- tri--O- benzyl -6- deoxidation-D- glucopyra saccharic acid -1,5- lactones
Line is：
Because above-mentioned technical proposal is used, the present invention has following advantages compared with prior art：
The present invention passes through the optimization to synthetic route and process conditions etc. so that realizing-O- the benzyls of feather weight 2,3,4- tri-
During the preparation of base -6- deoxidation-D- glucopyra saccharic acid -1,5- lactones, 2,3,4- tri--O- benzyl -6- deoxidation-D- glucopyranoses
The yield and purity of acid -1,5- lactones are still very high, are adapted to industrialized production.
Embodiment
The application is described in detail with reference to embodiment, but the application is not limited to these embodiments.If not special herein
Illustrate, " % " representation quality percentage.
Embodiment 1
(1)-O- benzyl-D- pyrans methyl glucoside -6- the methanesulfonates of 2,3,4- tri-, is added in 2000L reactors
568kg (1048mol), KI 210kg (1265mol), DMF (DMF) 1200kg open stirring, heating
To flowing back, 3h is reacted, chromatogram tracking to reaction terminates, filtered, remove methanesulfonic acid potassium, heating recovery DMF is added near dry
1500kg ethanol, stirs crystallisation by cooling, filters to obtain 2,3,4- tri--O- benzyl -6- iodo-D- pyrans methyl glucoside 300kg,
Yield 50%, purity 99%.
(2)-O- benzyl -6- iodo-D- pyrans the methyl glucoses of step product 2,3,4- tri-, are added in 2000L reactors
Glucosides 300kg (523mol), potassium carbonate 300kg (2171mol), palladium-carbon catalyst 30kg, 95% ethanol 1200kg, unlatching are stirred
Mix, room temperature, normal pressure are passed through hydrogen, react 6h, chromatogram tracking analysis judges terminal, reaction terminates, filtered, liquid phase takes off solvent,
Obtain 2,3,4- tri--O- benzyl -6- deoxidation-D- pyrans methyl glucoside 223kg, yield 95%, purity 99%；Solid phase is filled with water
Divide washing, insoluble matter is palladium-carbon catalyst, and reuse, cleaning solution evaporation water, condensing crystallizing obtains KI, anti-for the substitution of upper step
Should.
(3)-O- benzyl -6- deoxidation-D- pyrans methyl glucosides the 223kg of 2,3,4- tri-, are added in 1000L reactors
(498mol), ethanol 380kg is dissolved by heating, and adds 15% hydrochloric acid 500kg, and flow back 3-4h, and chromatogram tracking is cold to reaction end
But to 0 DEG C of crystallization, filtering, a small amount of water washing obtains 2,3,4- tri--O- benzyl -6- deoxidation-D- pyrans methyl glucoside crude products；Filter
Liquid is neutralized to pH 7.0 with sodium hydroxide, and into rectifying column separation methanol, ethanol, water, tower bottoms crystallizes to obtain sodium chloride crystal；Slightly
Product obtain 2,3,4- tri--O- benzyl -6- deoxidation-D- pyrans methyl glucoside 205kg with 750kg ethyl alcohol recrystallizations, yield 95%,
Purity 99%.
(4)-O- benzyl -6- deoxidation-D- pyrans methyl glucosides the 205kg of 2,3,4- tri-, are added in 1000L reactors
(472mol), dimethyl sulfoxide (DMSO) 460kg (5888mol), 20-30 DEG C of control temperature instills acetic anhydride 230kg
(2253mol), reacts 10h, chromatogram tracking to reaction end, adds a small amount of water, heating be recovered under reduced pressure dimethyl sulphide, acetic acid,
DMSO adds 50% ethanol water 300kg, is sufficiently stirred for, cold filtration obtains 2,3,4- to without distillate, being cooled to 50 DEG C
Three-O- benzyl -6- deoxidation-D- glucopyra saccharic acid -1,5- lactone crude products, then use 690kg ethyl alcohol recrystallizations, it is filtering, dry
To 2,3,4- tri--O- benzyl -6- deoxidation-D- glucopyra saccharic acid -1,5- lactone 204kg, yield is 100%, and purity is
99.5%.
The molecular formula of-O- benzyl -6- deoxidation-D- glucopyra saccharic acid -1,5- the lactones of 2,3,4- tri-：C27H28O5；Molecular weight：
432.51；
Structural formula：
Quality standard such as table 1.
Table 1
| Index name | Unit | Index |
| Outward appearance | -- | White crystal |
| Content | % | ≥99.5 |
| Volatile matter | % | ≤0.5 |
| Ignition residue | % | ≤0.02 |
| Single contaminant | % | ≤0.1 |
| Heavy metal limit is checked | ppb | ≤20 |
Embodiment 2
(1)-O- benzyl-D- pyrans methyl glucoside -6- the methanesulfonates of 2,3,4- tri-, is added in 2000L reactors
568kg (1048mol), KI 210kg (1265mol), DMF (DMF) 1200kg open stirring, heating
To flowing back, 3h is reacted, chromatogram tracking to reaction terminates, filtered, remove methanesulfonic acid potassium, heating recovery DMF is added near dry
1500kg ethanol, stirs crystallisation by cooling, filters to obtain 2,3,4- tri--O- benzyl -6- iodo-D- pyrans methyl glucoside 300kg,
Yield 50%, purity 99%.
(2)-O- benzyl -6- iodo-D- pyrans the methyl glucoses of step product 2,3,4- tri-, are added in 2000L reactors
Glucosides 300kg (523mol), potassium carbonate 300kg (2171mol), palladium-carbon catalyst 30kg, 95% ethanol 1200kg, unlatching are stirred
Mix, room temperature, normal pressure are passed through hydrogen, react 6h, chromatogram tracking analysis judges terminal, reaction terminates, filtered, liquid phase takes off solvent,
Obtain 2,3,4- tri--O- benzyl -6- deoxidation-D- pyrans methyl glucoside 223kg, yield 95%, purity 99%；Solid phase is filled with water
Divide washing, insoluble matter is palladium-carbon catalyst, and reuse, cleaning solution evaporation water, condensing crystallizing obtains KI, anti-for the substitution of upper step
Should.
(3)-O- benzyl -6- deoxidation-D- pyrans methyl glucosides the 223kg of 2,3,4- tri-, are added in 1000L reactors
(498mol), ethanol 223kg is dissolved by heating, and adds 15% hydrochloric acid 250kg, and flow back 3-4h, and chromatogram tracking is cold to reaction end
But to 0 DEG C of crystallization, filtering, a small amount of water washing obtains 2,3,4- tri--O- benzyl -6- deoxidation-D- pyrans methyl glucoside crude products；Filter
Liquid is neutralized to pH 7.0 with sodium hydroxide, and into rectifying column separation methanol, ethanol, water, tower bottoms crystallizes to obtain sodium chloride crystal；Slightly
Product obtain 2,3,4- tri--O- benzyl -6- deoxidation-D- pyrans methyl glucoside 183kg with 750kg ethyl alcohol recrystallizations, yield 85%,
Purity 99%.
(4)-O- benzyl -6- deoxidation-D- pyrans methyl glucosides the 183kg of 2,3,4- tri-, are added in 1000L reactors
(422mol), dimethyl sulfoxide (DMSO) 460kg (5888mol), 20-30 DEG C of control temperature instills acetic anhydride 230kg
(2253mol), reacts 10h, chromatogram tracking to reaction end, adds a small amount of water, heating be recovered under reduced pressure dimethyl sulphide, acetic acid,
DMSO adds 50% ethanol water 300kg, is sufficiently stirred for, cold filtration obtains 2,3,4- to without distillate, being cooled to 50 DEG C
Three-O- benzyl -6- deoxidation-D- glucopyra saccharic acid -1,5- lactone crude products, then use 690kg ethyl alcohol recrystallizations, it is filtering, dry
To 2,3,4- tri--O- benzyl -6- deoxidation-D- glucopyra saccharic acid -1,5- lactone 183kg, yield is 100%, and purity is
99.5%.
Comparative example 1
(1)-O- benzyl-D- pyrans methyl glucoside -6- the methanesulfonates of 2,3,4- tri-, is added in 2000L reactors
568kg (1048mol), KI 250kg, dimethyl sulfoxide (DMSO) 1200kg, open stirring, are warming up to backflow, reaction 3h, chromatogram with
Track to reaction terminates, filtering, removes methanesulfonic acid potassium, and heating recovery DMF adds 1500kg ethanol near dry, stirs crystallisation by cooling,
Filter to obtain 2,3,4- tri--O- benzyl -6- iodo-D- pyrans methyl glucoside 60kg, yield 10%, purity 80%.
(2)-O- benzyl -6- iodo-D- pyrans the methyl glucoses of step product 2,3,4- tri-, are added in 2000L reactors
Glucosides 60kg (105mol), potassium carbonate 90kg (651mol), palladium-carbon catalyst 8kg, 75% ethanol 1200kg open stirring, room
Temperature, normal pressure are passed through hydrogen, react 6h, and chromatogram tracking analysis judges terminal, reaction terminates, filtered, liquid phase takes off solvent, obtains 2,
3,4- tri--O- benzyl -6- deoxidation-D- pyrans methyl glucoside 24kg, yield 50%, purity 85%；Solid phase is fully washed with water
Wash, insoluble matter is palladium-carbon catalyst, reuse, cleaning solution evaporates water, and condensing crystallizing obtains KI, for upper step substitution reaction.
(3)-O- benzyl -6- deoxidation-D- pyrans methyl glucosides the 24kg of 2,3,4- tri-, are added in 1000L reactors
(54mol), ethanol 144kg is dissolved by heating, and adds 30% hydrochloric acid 144kg, and flow back 3-4h, chromatogram tracking to reaction end, cooling
To 0 DEG C of crystallization, filtering, a small amount of water washing obtains 2,3,4- tri--O- benzyl -6- deoxidation-D- pyrans methyl glucoside crude products；Filtrate
PH 7.0 is neutralized to sodium hydroxide, into rectifying column separation methanol, ethanol, water, tower bottoms crystallizes to obtain sodium chloride crystal；Crude product
2,3,4- tri--O- benzyl -6- deoxidation-D- pyrans methyl glucoside 9.4kg are obtained with 750kg ethyl alcohol recrystallizations, yield 40% is pure
Degree 70%.
(4)-O- benzyl -6- deoxidation-D- pyrans methyl glucosides the 9.4kg of 2,3,4- tri-, are added in 1000L reactors
(22mol), dimethyl sulfoxide (DMSO) 56kg, 40 DEG C of instillation acetic anhydride 28kg of control temperature, reacts 10h, chromatogram tracking to reaction
Terminal, adds a small amount of water, and heating is recovered under reduced pressure dimethyl sulphide, acetic acid, DMSO to without distillate, being cooled to 50 DEG C, adds 50%
Ethanol water 300kg, is sufficiently stirred for, cold filtration, obtains 2,3,4- tri--O- benzyl -6- deoxidation-D- glucopyras saccharic acid -1,
5- lactone crude products, then 690kg ethyl alcohol recrystallizations are used, filter, be dried to obtain 2,3,4- tri--O- benzyl -6- deoxidation-D- glucopyras
Saccharic acid -1,5- lactone 6.7kg, yield is 70%, and purity is 80%.
The above embodiments merely illustrate the technical concept and features of the present invention, and its object is to allow person skilled in the art
Scholar can understand present disclosure and implement according to this, and it is not intended to limit the scope of the present invention, all according to the present invention
The equivalent change or modification that Spirit Essence is made, should all be included within the scope of the present invention.
Claims (10)
1. one kind 2,3, the preparation method of-O- benzyl -6- deoxidation-D- glucopyra saccharic acid -1, the 5- lactones of 4- tri-, its feature exists
In：It comprises the following steps：
Step (1), by the-O- benzyls-D- pyrans methyl glucoside -6- methanesulfonates of 2,3,4- tri- and KI in organic solvent
In the presence of carry out substitution reaction 2,3,4- tri--O- benzyl -6- iodo-D- pyrans methyl glucosides be made；
Step (2), by the-O- benzyl -6- iodo-D- pyrans methyl glucosides of 2,3,4- made from step (1) tri-, potassium carbonate and
Hydrogen carries out de- Iod R in the presence of catalyst and organic solvent and the-O- benzyl -6- deoxidation-D- pyrans first of 2,3,4- tri- is made
Base glucoside；
Step (3), by the-O- benzyl -6- deoxidation-D- pyrans methyl glucosides of 2,3,4- made from step (2) tri- organic molten
Demethylating reaction is carried out in the presence of agent and acid, and-O- benzyl -6- deoxidation-D- pyrans the methyl glucosides of 2,3,4- tri- are made；
Step (4), by the-O- benzyl -6- deoxidation-D- pyrans methyl glucosides of 2,3,4- made from step (3) tri-, dimethyl sulfoxide and
Acetic anhydride carries out the-O- benzyl -6- deoxidation-D- glucopyra saccharic acid -1,5- lactones of 2,3,4- tri- that oxidation reaction is made described.
2. the preparation of-O- benzyl -6- deoxidation-D- glucopyra saccharic acid -1,5- lactones of 2,3,4- tri- according to claim 1
Method, it is characterised in that：Organic solvent in step (1) is N,N-dimethylformamide；Organic solvent in step (2) is matter
The ethanol that concentration is 90%~98% is measured, described catalyst is palladium-carbon catalyst；Organic solvent described in step (3) is second
Alcohol, described acid is the hydrochloric acid that mass concentration is 10%~20%.
3. the preparation of-O- benzyl -6- deoxidation-D- glucopyra saccharic acid -1,5- lactones of 2,3,4- tri- according to claim 1
Method, it is characterised in that：Substitution reaction described in step (1) is carried out under reflux conditions.
4. the preparation of-O- benzyl -6- deoxidation-D- glucopyra saccharic acid -1,5- lactones of 2,3,4- tri- according to claim 1
Method, it is characterised in that：In step (1), described 2,3,4- tri--O- benzyl-D- pyrans methyl glucoside -6- methanesulfonic acids
The mass ratio that feeds intake of ester, described KI and described organic solvent is 2.5~3：1：5~10.
5. the preparation of-O- benzyl -6- deoxidation-D- glucopyra saccharic acid -1,5- lactones of 2,3,4- tri- according to claim 1
Method, it is characterised in that：In step (2), described 2,3,4- tri--O- benzyl -6- iodo-D- pyrans methyl glucosides, institute
Potassium carbonate, described catalyst, the mass ratio that feeds intake of described organic solvent stated are 1：0.9~1.1：0.05~0.2：3~
10。
6. the preparation of-O- benzyl -6- deoxidation-D- glucopyra saccharic acid -1,5- lactones of 2,3,4- tri- according to claim 1
Method, it is characterised in that：Described demethylating reaction in step (3) is carried out under reflux conditions.
7. the preparation of-O- benzyl -6- deoxidation-D- glucopyra saccharic acid -1,5- lactones of 2,3,4- tri- according to claim 1
Method, it is characterised in that：In step (3), described 2,3,4- tri--O- benzyl -6- deoxidation-D- pyrans methyl glucosides, institute
The organic solvent and the described sour mass ratio that feeds intake stated are 1：1~5：1~5.
8. the preparation of-O- benzyl -6- deoxidation-D- glucopyra saccharic acid -1,5- lactones of 2,3,4- tri- according to claim 1
Method, it is characterised in that：The temperature that described oxidation reaction is carried out in step (4) is 20~30 DEG C.
9. the preparation of-O- benzyl -6- deoxidation-D- glucopyra saccharic acid -1,5- lactones of 2,3,4- tri- according to claim 1
Method, it is characterised in that：It is described 2,3,4- tri--O- benzyl -6- deoxidation-D- pyrans methyl glucosides, described in step (4)
Dimethyl sulfoxide and the mass ratio that feeds intake of described acetic anhydride be 1：1.5~5：0.9~2.
10.-O- benzyl -6- deoxidation-D- glucopyras saccharic acid -1 of 2,3,4- tri- according to any one of claim 1 to 9,
The preparation method of 5- lactones, it is characterised in that：The embodiment of described preparation method is：
Step (1), the described-O- benzyl-D- pyrans methyl glucoside -6- methanesulfonic acids of 2,3,4- tri- are added in a kettle.
Ester, described KI, described organic solvent under conditions of stirring, is warming up to backflow, chromatogram tracking to reaction terminates,
Filtering, removes methanesulfonic acid potassium, and the organic solvent described in heating recovery adds ethanol near dry, stirs crystallisation by cooling, filters to obtain institute
- O- benzyl -6- iodo-D- pyrans the methyl glucosides of 2,3,4- tri- stated；
Described-O- benzyl -6- iodo-D- pyrans the first of 2,3,4- tri- made from step (2), in a kettle. addition step (1)
Base glucoside, described potassium carbonate, described catalyst, described organic solvent, under conditions of stirring, at 0~40 DEG C
Under be passed through described hydrogen, chromatogram tracking analysis judges terminal, reaction terminates, filtered, liquid phase take off described in organic solvent,
Obtain the described-O- benzyl -6- deoxidation-D- pyrans methyl glucosides of 2,3,4- tri-；Solid phase is fully washed with water, and insoluble matter is institute
The catalyst stated, reuse, cleaning solution evaporation water, condensing crystallizing obtains KI, the substitution reaction for step (1)；
Step (3), 2,3,4- tri- described-O- benzyl -6- deoxidation-D- pyrans methyl glucosides, institute are added in a kettle.
The organic solvent stated, after dissolving, adds described acid, back flow reaction, chromatogram tracking to reaction end, crystallisation by cooling is filtered, used
Water washing, obtains 2,3,4- tri--O- benzyl -6- deoxidation-D- pyrans methyl glucoside crude products；Filtrate is neutralized with sodium hydroxide, is entered
Rectifying column separation methanol, ethanol, water, tower bottoms crystallize to obtain sodium chloride crystal；Described-O- benzyl -6- deoxidations-the D- of 2,3,4- tri-
Pyrans methyl glucoside crude product obtains the described-O- benzyl -6- deoxidation-D- pyrans methyl glucoses of 2,3,4- tri- with ethyl alcohol recrystallization
Sugar；
Step (4), 2,3,4- tri- described-O- benzyl -6- deoxidation-D- pyrans methyl glucosides are added in a kettle., it is described
Dimethyl sulfoxide, 20~30 DEG C of temperature of control instills described acetic anhydride, and chromatogram tracking to reaction end adds water, and heating subtracts
Receipts dimethyl sulphide, acetic acid, DMSO are pushed back to without distillate, being cooled to 45~55 DEG C, the second that mass concentration is 40~60% is added
Alcohol solution, stirring, cold filtration obtains 2,3,4- tri--O- benzyl -6- deoxidation-D- glucopyra saccharic acid -1,5- lactone crude products,
Ethyl alcohol recrystallization is used again, is filtered, is dried to obtain 2,3,4- tri- described-O- benzyl -6- deoxidation-D- glucopyra saccharic acids -1,5-
Lactone.
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