CN107325070B - Preparation method of 2,3, 4-tri-O-benzyl-6-deoxy-D-glucopyranose-1, 5-lactone - Google Patents
Preparation method of 2,3, 4-tri-O-benzyl-6-deoxy-D-glucopyranose-1, 5-lactone Download PDFInfo
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- CN107325070B CN107325070B CN201710621433.2A CN201710621433A CN107325070B CN 107325070 B CN107325070 B CN 107325070B CN 201710621433 A CN201710621433 A CN 201710621433A CN 107325070 B CN107325070 B CN 107325070B
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- 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 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 66
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 48
- 238000006243 chemical reaction Methods 0.000 claims description 40
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 37
- 238000001914 filtration Methods 0.000 claims description 30
- 239000003960 organic solvent Substances 0.000 claims description 28
- 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
- 239000003054 catalyst Substances 0.000 claims description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 20
- 238000001816 cooling Methods 0.000 claims description 20
- 238000003756 stirring Methods 0.000 claims description 20
- 238000010438 heat treatment Methods 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 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-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
- 239000012043 crude product Substances 0.000 claims description 15
- 238000010992 reflux Methods 0.000 claims description 14
- 238000005406 washing Methods 0.000 claims description 12
- RMTFNDVZYPHUEF-XZBKPIIZSA-N 3-O-methyl-D-glucose Chemical compound O=C[C@H](O)[C@@H](OC)[C@H](O)[C@H](O)CO RMTFNDVZYPHUEF-XZBKPIIZSA-N 0.000 claims description 10
- 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
- 239000007788 liquid Substances 0.000 claims description 10
- 238000002425 crystallisation Methods 0.000 claims description 9
- 230000008025 crystallization Effects 0.000 claims description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 9
- 238000006467 substitution reaction Methods 0.000 claims description 9
- 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 description 8
- 239000002253 acid Substances 0.000 claims description 8
- HOVAGTYPODGVJG-UHFFFAOYSA-N methyl beta-galactoside Natural products COC1OC(CO)C(O)C(O)C1O HOVAGTYPODGVJG-UHFFFAOYSA-N 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical group C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 7
- 239000013078 crystal Substances 0.000 claims description 6
- 238000004458 analytical method Methods 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 5
- 239000007791 liquid phase Substances 0.000 claims description 5
- 230000003472 neutralizing effect Effects 0.000 claims description 5
- XWIJIXWOZCRYEL-UHFFFAOYSA-M potassium;methanesulfonate Chemical compound [K+].CS([O-])(=O)=O XWIJIXWOZCRYEL-UHFFFAOYSA-M 0.000 claims description 5
- 239000011780 sodium chloride Substances 0.000 claims description 5
- 239000007790 solid phase Substances 0.000 claims 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 claims description 4
- 238000010520 demethylation reaction Methods 0.000 claims description 4
- 239000008103 glucose Substances 0.000 claims description 4
- 238000007254 oxidation reaction Methods 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 238000004587 chromatography analysis Methods 0.000 claims description 3
- PHOQVHQSTUBQQK-SQOUGZDYSA-N D-glucono-1,5-lactone Chemical compound OC[C@H]1OC(=O)[C@H](O)[C@@H](O)[C@@H]1O PHOQVHQSTUBQQK-SQOUGZDYSA-N 0.000 claims description 2
- 238000005831 deiodination reaction Methods 0.000 claims description 2
- 238000001704 evaporation Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 8
- 238000009776 industrial production Methods 0.000 abstract description 2
- -1 2,3, 4-tri-O-benzyl-D-glucopyranose-6-methyl sulfonate Chemical compound 0.000 abstract 2
- 239000000047 product Substances 0.000 description 8
- 239000012634 fragment Substances 0.000 description 7
- 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 4
- 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 4
- 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 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 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 3
- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 description 3
- 229960003834 dapagliflozin Drugs 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 150000002611 lead compounds Chemical class 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000005556 structure-activity relationship Methods 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 108091006269 SLC5A2 Proteins 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 241000486679 Antitype Species 0.000 description 1
- 102000058081 Sodium-Glucose Transporter 2 Human genes 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
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 125000003118 aryl group Chemical group 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
- 230000000052 comparative effect Effects 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
- 230000029142 excretion Effects 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
- 239000012535 impurity Substances 0.000 description 1
- 238000000338 in vitro Methods 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
- 239000003446 ligand Substances 0.000 description 1
- 229950004397 luseogliflozin Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 description 1
- 229960001674 tegafur Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229950006667 tofogliflozin Drugs 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 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 invention relates to a preparation method of 2,3, 4-tri-O-benzyl-6-deoxidization-D-glucopyranose-1, 5-lactone, which comprises the steps of preparing 2,3, 4-tri-O-benzyl-D-glucopyranose-6-methyl sulfonate, preparing 2,3, 4-tri-O-benzyl-6-iodo-D-glucopyranose, further preparing 2,3, 4-tri-O-benzyl-6-deoxidization-D-glucopyranose, and finally preparing the 2,3, 4-tri-O-benzyl-6-deoxidization-D-glucopyranose-1, 5-lactone. When the preparation method is used for realizing kilogram-level preparation, the yield and purity of the 2,3, 4-tri-O-benzyl-6-deoxidization-D-glucopyranose-1, 5-lactone are still high, and the method is suitable for industrial production.
Description
Technical Field
The invention relates to a preparation method of 2,3, 4-tri-O-benzyl-6-deoxidization-D-glucopyranose acid-1, 5-lactone.
Background
At present, the molecular structure of the SGLT2 inhibitor which is marketed and in clinical stages of each period is analyzed in the current state of research on anti-type 2 diabetes drugs in the global scope, and most of the current SGLT2 inhibitors are structurally modified by taking dapaglifflon as a lead compound. Canagliflozin, ipragliflozin and empagliflozin take dapagliflozin as a template, keep the sugar ring fragment structure unchanged, and change the aglycone aromatic ring fragment of the glycoside; LX4211 and PF-04971729 keep the aglycone diphenylmethane structure unchanged, and the sugar ring fragment is slightly modified; tofogliflozin and TS-071 have been engineered to varying degrees for both the sugar ring fragment and the aglycone, but still follow the structural similarity of the sugar ring fragment and the aromaticity of the ligand moiety, i.e. remain lipophilic. The three general classes of SGLT2 inhibitors described above were all designed starting from dapagliflzin around which the aglycone or/and sugar ring moiety was altered, and none of them elucidated the role of the hydroxyl groups of the sugar ring fragments in the drug structure-activity relationship.
The Tianjin pharmaceutical institute selects dapaglilozin as a lead compound, and gradually single deoxidizes and combined deoxidizes four hydroxyl groups of the sugar ring segment of the dapaglilozin, so as to further determine the influence of the hydroxyl groups on the pharmaceutical structure-activity relationship. The effect of the four hydroxyl groups of the dapagliflozin sugar ring fragment on the drug structure-activity relationship was clarified by evaluation of the biological activities (in vitro activity evaluation and in vivo activity evaluation) of the deoxygenated products D6 (6-deoxydapagliflozin), D4 (4-deoxydapagliflozin), D3 (3-deoxydapagliflozin) and D2 (2-deoxydapagliflozin). The presence of 6-0H instead reduces the biological activity of the lead compound dapaglifflozin. The binding force between the 6-OH deoxidized product D6 and the receptor SGLT2 transporter is enhanced compared with dapagliflozin, so that the capability of SGLT2 to couple glucose is reduced, the reabsorption of glucose in the kidney is reduced, and the excretion of urine sugar is increased.
2,3, 4-tri-O-benzyl-6-deoxy-D-glucopyranose-1, 5-lactone is a key raw material of the hypoglycemic drug, namely, the tegafur, which enters the clinical test period, so that the preparation of the 2,3, 4-tri-O-benzyl-6-deoxy-D-glucopyranose-1, 5-lactone with high kilogram level, high yield and high purity is very important.
Disclosure of Invention
The invention aims to solve the technical problem of providing a preparation method of 2,3, 4-tri-O-benzyl-6-deoxy-D-glucopyranose-1, 5-lactone with high yield and high purity.
In order to achieve the above purpose, the invention adopts the following technical scheme:
an object of the present invention is to provide a method for preparing 2,3, 4-tri-O-benzyl-6-deoxy-D-glucopyranose-1, 5-lactone, comprising the steps of:
step (1), carrying out substitution reaction on 2,3, 4-tri-O-benzyl-D-pyran methyl glucoside-6-methanesulfonate and potassium iodide in the presence of an organic solvent to obtain 2,3, 4-tri-O-benzyl-6-iodo-D-pyran methyl glucoside;
step (2), carrying out deiodination reaction on the 2,3, 4-tri-O-benzyl-6-iodo-D-methyl glucopyranoside prepared in the step (1), potassium carbonate and hydrogen in the presence of a catalyst and an organic solvent to prepare the 2,3, 4-tri-O-benzyl-6-deoxy-D-methyl glucopyranoside;
step (3), carrying out demethylation reaction on the 2,3, 4-tri-O-benzyl-6-deoxidization-D-pyran methyl glucoside prepared in the step (2) in the presence of an organic solvent and acid to prepare 2,3, 4-tri-O-benzyl-6-deoxidization-D-pyran methyl glucose;
and (4) carrying out oxidation reaction on the 2,3, 4-tri-O-benzyl-6-deoxidization-D-pyran methyl glucose, dimethyl sulfoxide and acetic anhydride obtained in the step (3) to obtain the 2,3, 4-tri-O-benzyl-6-deoxidization-D-pyran glucono-1, 5-lactone.
Preferably, the organic solvent in step (1) is N, N-dimethylformamide.
Preferably, the organic solvent in the step (2) is ethanol with the mass concentration of 90% -98%.
Preferably, the catalyst in step (2) is a palladium on carbon catalyst.
Preferably, the organic solvent in step (3) is ethanol.
Preferably, the acid in the step (3) is hydrochloric acid with the mass concentration of 10% -20%.
Preferably, the substitution reaction described in step (1) is carried out under reflux conditions.
Preferably, in the step (1), the feeding mass ratio of the 2,3, 4-tri-O-benzyl-D-methyl glucopyranoside-6-methane sulfonate to the potassium iodide to the organic solvent is 2.5-3: 1:5 to 10.
Preferably, in the step (2), the feeding mass ratio of the 2,3, 4-tri-O-benzyl-6-iodo-D-methyl glucopyranoside, the potassium carbonate, the catalyst and the organic solvent is 1:0.9 to 1.1:0.05 to 0.2:3 to 10.
Preferably, the demethylation reaction in step (3) is carried out under reflux conditions.
Preferably, in the step (3), the feeding mass ratio of the 2,3, 4-tri-O-benzyl-6-deoxy-D-methyl glucopyranoside, the organic solvent and the acid is 1:1 to 5:1 to 5.
Preferably, the temperature at which the oxidation reaction is carried out in step (4) is from 20 to 30 ℃.
Preferably, in the step (4), the feeding mass ratio of the 2,3, 4-tri-O-benzyl-6-deoxy-D-methyl glucopyranose, the dimethyl sulfoxide and the acetic anhydride is 1:1.5 to 5:0.9 to 2.
Preferably, the specific implementation mode of the preparation method is as follows:
step (1), adding the 2,3, 4-tri-O-benzyl-D-pyran methyl glucoside-6-methanesulfonate into a reaction kettle, heating the potassium iodide and the organic solvent to reflux under the stirring condition, carrying out chromatographic tracking until the reaction is finished, filtering, removing the potassium methanesulfonate, heating and recovering the organic solvent until the organic solvent is nearly dry, adding ethanol, stirring, cooling and crystallizing, and filtering to obtain the 2,3, 4-tri-O-benzyl-6-iodo-D-pyran methyl glucoside;
step (2), adding the 2,3, 4-tri-O-benzyl-6-iodo-D-methyl glucopyranoside prepared in the step (1), the potassium carbonate, the catalyst and the organic solvent into a reaction kettle, introducing the hydrogen at 0-40 ℃ under the condition of stirring, carrying out chromatographic tracking analysis, judging the end point, ending the reaction, filtering, and removing the organic solvent from the liquid phase to obtain the 2,3, 4-tri-O-benzyl-6-deoxidization-D-methyl glucopyranoside; washing the solid phase with water fully, reusing insoluble matter as the catalyst, evaporating water from the washing liquid, concentrating and crystallizing to obtain potassium iodide, and using the potassium iodide in the substitution reaction in the step (1);
step (3), adding the 2,3, 4-tri-O-benzyl-6-deoxidization-D-methyl glucopyranoside into a reaction kettle, adding the acid after dissolving, refluxing for reaction, tracking to a reaction end point by chromatography, cooling for crystallization, filtering, and washing with water to obtain a crude product of the 2,3, 4-tri-O-benzyl-6-deoxidization-D-methyl glucopyranose; neutralizing the filtrate with sodium hydroxide, separating methanol, ethanol and water in a rectifying tower, and crystallizing the tower bottom liquid to obtain sodium chloride crystal; recrystallizing the 2,3, 4-tri-O-benzyl-6-deoxidization-D-pyran methyl glucose crude product with ethanol to obtain the 2,3, 4-tri-O-benzyl-6-deoxidization-D-pyran methyl glucose;
step (4), adding the 2,3, 4-tri-O-benzyl-6-deoxidization-D-methyl glucopyranose into a reaction kettle, dropwise adding the dimethyl sulfoxide into the acetic anhydride at the temperature of 20-30 ℃, carrying out chromatographic tracking to a reaction end point, adding water, heating and decompressing to recover dimethyl sulfide, acetic acid and DMSO until no distillate exists, cooling to 45-55 ℃, adding an ethanol aqueous solution with the mass concentration of 40-60%, stirring, cooling and filtering to obtain a crude product of the 2,3, 4-tri-O-benzyl-6-deoxidization-D-glucopyranose-1, 5-lactone, recrystallizing with ethanol, filtering and drying to obtain the 2,3, 4-tri-O-benzyl-6-deoxidization-D-glucopyranose-1, 5-lactone.
In the invention, the synthetic route of the 2,3, 4-tri-O-benzyl-6-deoxidization-D-glucopyranose acid-1, 5-lactone is as follows:
due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:
the invention optimizes the synthetic route and the process conditions, etc., so that the yield and the purity of the 2,3, 4-tri-O-benzyl-6-deoxidization-D-glucopyranose-1, 5-lactone are still high when the preparation of kilogram-level 2,3, 4-tri-O-benzyl-6-deoxidization-D-glucopyranose-1, 5-lactone is realized, and the invention is suitable for industrial production.
Detailed Description
The present application is described in detail below with reference to examples, but the present application is not limited to these examples. Unless otherwise specified herein, "%" represents mass%.
Example 1
(1) Adding 568kg (1048 mol) of 2,3, 4-tri-O-benzyl-D-pyran methyl glucoside-6-methane sulfonate into a 2000L reaction kettle, stirring 210kg (1265 mol) of potassium iodide, 1200kg of N, N-Dimethylformamide (DMF), heating to reflux, reacting for 3h, tracking the chromatograph until the reaction is finished, filtering, removing potassium methane sulfonate, heating to recover DMF until the DMF is nearly dry, adding 1500kg of ethanol, stirring, cooling and crystallizing, filtering to obtain 300kg of 2,3, 4-tri-O-benzyl-6-iodo-D-pyran methyl glucoside, and obtaining the product with the yield of 50% and the purity of 99%.
(2) Adding 300kg (523 mol) of the product 2,3, 4-tri-O-benzyl-6-iodo-D-methyl glucopyranoside obtained in the previous step into a 2000L reaction kettle, 300kg (2171 mol) of potassium carbonate, 30kg of palladium-carbon catalyst, 1200kg of 95% ethanol, stirring, introducing hydrogen at room temperature and normal pressure, reacting for 6h, carrying out chromatographic tracking analysis, judging the end point, filtering, removing the solvent from the liquid phase to obtain 223kg of 2,3, 4-tri-O-benzyl-6-deoxy-D-methyl glucopyranoside with the yield of 95% and the purity of 99%; the solid phase is fully washed by water, insoluble matters are palladium-carbon catalyst, the catalyst is recycled, the washing liquid evaporates water, and potassium iodide is obtained by concentration and crystallization and is used for the previous substitution reaction.
(3) Adding 223kg (498 mol) of 2,3, 4-tri-O-benzyl-6-deoxidization-D-methyl glucopyranoside into a 1000L reaction kettle, heating and dissolving 380kg of ethanol, adding 500kg of 15% hydrochloric acid, refluxing for 3-4h, tracking to the reaction end point by chromatography, cooling to 0 ℃ for crystallization, filtering, and washing with a small amount of water to obtain a crude product of 2,3, 4-tri-O-benzyl-6-deoxidization-D-methyl glucopyranose; neutralizing the filtrate with sodium hydroxide to pH 7.0, separating methanol, ethanol and water in a rectifying tower, and crystallizing the tower bottom liquid to obtain sodium chloride crystal; the crude product is recrystallized by 750kg of ethanol to obtain 205kg of 2,3, 4-tri-O-benzyl-6-deoxidization-D-pyran methyl glucose with the yield of 95 percent and the purity of 99 percent.
(4) Adding 205kg (472 mol) of 2,3, 4-tri-O-benzyl-6-deoxidization-D-methyl glucopyranose into a 1000L reaction kettle, adding 460kg (5888 mol) of dimethyl sulfoxide (DMSO), dropwise adding 230kg (2253 mol) of acetic anhydride at a temperature of 20-30 ℃ for reacting for 10 hours, tracking the chromatograph to the end point of the reaction, adding a small amount of water, heating and decompressing to recover dimethyl sulfide, acetic acid and DMSO until no distillate exists, cooling to 50 ℃, adding 300kg of 50% ethanol water solution, fully stirring, cooling and filtering to obtain a crude product of 2,3, 4-tri-O-benzyl-6-deoxidization-D-glucopyranose acid-1, 5-lactone, recrystallizing with 690kg of ethanol, filtering and drying to obtain 204kg of 2,3, 4-tri-O-benzyl-6-deoxidization-D-glucopyranose acid-1, 5-lactone, wherein the yield is 100%, and the purity is 99.5%.
2,3, 4-tri-O-benzyl-6-deoxy-D-glucopyranoside-1, 5-lactone of formula: c (C) 27 H 28 O 5 The method comprises the steps of carrying out a first treatment on the surface of the Molecular weight: 432.51;
structural formula:
the quality criteria are shown in Table 1.
TABLE 1
| Index name | Unit (B) | Index (I) |
| Appearance of | -- | White crystals |
| Content of | ％ | ≥99.5 |
| Volatile component | ％ | ≤0.5 |
| Burning residues | ％ | ≤0.02 |
| Single impurity | ％ | ≤0.1 |
| Heavy metal limit check | ppb | ≤20 |
Example 2
(1) Adding 568kg (1048 mol) of 2,3, 4-tri-O-benzyl-D-pyran methyl glucoside-6-methane sulfonate into a 2000L reaction kettle, stirring 210kg (1265 mol) of potassium iodide, 1200kg of N, N-Dimethylformamide (DMF), heating to reflux, reacting for 3h, tracking the chromatograph until the reaction is finished, filtering, removing potassium methane sulfonate, heating to recover DMF until the DMF is nearly dry, adding 1500kg of ethanol, stirring, cooling and crystallizing, filtering to obtain 300kg of 2,3, 4-tri-O-benzyl-6-iodo-D-pyran methyl glucoside, and obtaining the product with the yield of 50% and the purity of 99%.
(2) Adding 300kg (523 mol) of the product 2,3, 4-tri-O-benzyl-6-iodo-D-methyl glucopyranoside obtained in the previous step into a 2000L reaction kettle, 300kg (2171 mol) of potassium carbonate, 30kg of palladium-carbon catalyst, 1200kg of 95% ethanol, stirring, introducing hydrogen at room temperature and normal pressure, reacting for 6h, carrying out chromatographic tracking analysis, judging the end point, filtering, removing the solvent from the liquid phase to obtain 223kg of 2,3, 4-tri-O-benzyl-6-deoxy-D-methyl glucopyranoside with the yield of 95% and the purity of 99%; the solid phase is fully washed by water, insoluble matters are palladium-carbon catalyst, the catalyst is recycled, the washing liquid evaporates water, and potassium iodide is obtained by concentration and crystallization and is used for the previous substitution reaction.
(3) Adding 223kg (498 mol) of 2,3, 4-tri-O-benzyl-6-deoxidization-D-methyl glucopyranoside into a 1000L reaction kettle, heating and dissolving 223kg of ethanol, adding 250kg of 15% hydrochloric acid, refluxing for 3-4 hours, tracking the chromatograph to the reaction end point, cooling to 0 ℃ for crystallization, filtering, and washing with a small amount of water to obtain a crude product of 2,3, 4-tri-O-benzyl-6-deoxidization-D-methyl glucopyranose; neutralizing the filtrate with sodium hydroxide to pH 7.0, separating methanol, ethanol and water in a rectifying tower, and crystallizing the tower bottom liquid to obtain sodium chloride crystal; the crude product is recrystallized by 750kg of ethanol to obtain 183kg of 2,3, 4-tri-O-benzyl-6-deoxidization-D-pyran methyl glucose with the yield of 85 percent and the purity of 99 percent.
(4) Adding 183kg (422 mol) of 2,3, 4-tri-O-benzyl-6-deoxy-D-methyl glucopyranose into a 1000L reaction kettle, adding 460kg (5888 mol) of dimethyl sulfoxide (DMSO), dropwise adding 230kg (2253 mol) of acetic anhydride at a temperature of 20-30 ℃ for reaction for 10 hours, carrying out chromatographic tracking to the end point of the reaction, adding a small amount of water, heating and decompressing to recover dimethyl sulfide, acetic acid and DMSO until no distillate exists, cooling to 50 ℃, adding 300kg of 50% ethanol water solution, fully stirring, cooling and filtering to obtain a crude product of 2,3, 4-tri-O-benzyl-6-deoxy-D-glucopyranose-1, 5-lactone, recrystallizing with 690kg of ethanol, filtering and drying to obtain 183kg of 2,3, 4-tri-O-benzyl-6-deoxy-D-glucopyranose-1, 5-lactone, wherein the yield is 100%, and the purity is 99.5%.
Comparative example 1
(1) Adding 568kg (1048 mol) of 2,3, 4-tri-O-benzyl-D-methyl glucopyranoside-6-methyl sulfonate into a 2000L reaction kettle, stirring 250kg of potassium iodide, 1200kg of dimethyl sulfoxide, heating to reflux, reacting for 3h, tracking the chromatograph to the end of the reaction, filtering, removing potassium methanesulfonate, heating to recover DMF until the DMF is nearly dry, adding 1500kg of ethanol, stirring, cooling for crystallization, filtering to obtain 60kg of 2,3, 4-tri-O-benzyl-6-iodo-D-methyl glucopyranoside with the yield of 10 percent and the purity of 80 percent.
(2) Adding 60kg (105 mol) of the product 2,3, 4-tri-O-benzyl-6-iodo-D-methyl glucopyranoside obtained in the previous step into a 2000L reaction kettle, 90kg (651 mol) of potassium carbonate, 8kg of palladium-carbon catalyst, 1200kg of 75% ethanol, starting stirring, introducing hydrogen at room temperature and normal pressure, reacting for 6h, carrying out chromatographic tracking analysis, judging the end point, filtering, removing the solvent from the liquid phase to obtain 24kg of 2,3, 4-tri-O-benzyl-6-deoxy-D-methyl glucopyranoside, and obtaining the product with the yield of 50% and the purity of 85%; the solid phase is fully washed by water, insoluble matters are palladium-carbon catalyst, the catalyst is recycled, the washing liquid evaporates water, and potassium iodide is obtained by concentration and crystallization and is used for the previous substitution reaction.
(3) Adding 24kg (54 mol) of 2,3, 4-tri-O-benzyl-6-deoxidization-D-methyl glucopyranoside into a 1000L reaction kettle, heating and dissolving 144kg of ethanol, adding 144kg of 30% hydrochloric acid, refluxing for 3-4h, tracking the chromatograph to the reaction end point, cooling to 0 ℃ for crystallization, filtering, and washing with a small amount of water to obtain a crude product of 2,3, 4-tri-O-benzyl-6-deoxidization-D-methyl glucopyranose; neutralizing the filtrate with sodium hydroxide to pH 7.0, separating methanol, ethanol and water in a rectifying tower, and crystallizing the tower bottom liquid to obtain sodium chloride crystal; the crude product is recrystallized by 750kg of ethanol to obtain 9.4kg of 2,3, 4-tri-O-benzyl-6-deoxidization-D-pyranomethyl glucose with the yield of 40 percent and the purity of 70 percent.
(4) Adding 9.4kg (22 mol) of 2,3, 4-tri-O-benzyl-6-deoxidization-D-methyl glucopyranose into a 1000L reaction kettle, dropwise adding 28kg of acetic anhydride into 56kg of dimethyl sulfoxide (DMSO) at a temperature of 40 ℃ for reacting for 10 hours, tracking the chromatograph to the reaction end point, adding a small amount of water, heating and decompressing to recover dimethyl sulfide, acetic acid and DMSO until no distillate exists, cooling to 50 ℃, adding 300kg of 50% ethanol aqueous solution, fully stirring, cooling and filtering to obtain a crude product of 2,3, 4-tri-O-benzyl-6-deoxidization-D-glucopyranose-1, 5-lactone, recrystallizing with 690kg of ethanol, filtering and drying to obtain 6.7kg of 2,3, 4-tri-O-benzyl-6-deoxidization-D-glucopyranose-1, 5-lactone, wherein the yield is 70% and the purity is 80%.
The above embodiments are only for illustrating the technical concept and features of the present invention, and are intended to enable those skilled in the art to understand the present invention and to implement the same, but are not intended to limit the scope of the present invention, and all equivalent changes or modifications made according to the spirit of the present invention should be included in the scope of the present invention.
Claims (9)
1. A preparation method of 2,3, 4-tri-O-benzyl-6-deoxidization-D-glucopyranose acid-1, 5-lactone is characterized in that: the method comprises the following steps:
step (1), carrying out substitution reaction on 2,3, 4-tri-O-benzyl-D-pyran methyl glucoside-6-methanesulfonate and potassium iodide in the presence of an organic solvent to obtain 2,3, 4-tri-O-benzyl-6-iodo-D-pyran methyl glucoside;
step (2), carrying out deiodination reaction on the 2,3, 4-tri-O-benzyl-6-iodo-D-methyl glucopyranoside prepared in the step (1), potassium carbonate and hydrogen in the presence of a catalyst and an organic solvent to prepare the 2,3, 4-tri-O-benzyl-6-deoxy-D-methyl glucopyranoside;
step (3), carrying out demethylation reaction on the 2,3, 4-tri-O-benzyl-6-deoxidization-D-pyran methyl glucoside prepared in the step (2) in the presence of an organic solvent and acid to prepare 2,3, 4-tri-O-benzyl-6-deoxidization-D-pyran methyl glucose;
step (4), carrying out oxidation reaction on the 2,3, 4-tri-O-benzyl-6-deoxidization-D-pyran methyl glucose, dimethyl sulfoxide and acetic anhydride obtained in the step (3) to obtain the 2,3, 4-tri-O-benzyl-6-deoxidization-D-pyran glucono-1, 5-lactone;
the organic solvent in the step (1) is N, N-dimethylformamide; the organic solvent in the step (2) is ethanol with the mass concentration of 90% -98%, and the catalyst is palladium-carbon catalyst; the organic solvent in the step (3) is ethanol, and the acid is hydrochloric acid with the mass concentration of 10-20%.
2. The method for producing 2,3, 4-tri-O-benzyl-6-deoxy-D-glucopyranose-1, 5-lactone according to claim 1, wherein: the substitution reaction described in step (1) is carried out under reflux conditions.
3. The method for producing 2,3, 4-tri-O-benzyl-6-deoxy-D-glucopyranose-1, 5-lactone according to claim 1, wherein: in the step (1), the feeding mass ratio of the 2,3, 4-tri-O-benzyl-D-methyl glucopyranoside-6-methane sulfonate to the potassium iodide to the organic solvent is 2.5-3: 1:5 to 10.
4. The method for producing 2,3, 4-tri-O-benzyl-6-deoxy-D-glucopyranose-1, 5-lactone according to claim 1, wherein: in the step (2), the feeding mass ratio of the 2,3, 4-tri-O-benzyl-6-iodo-D-methyl glucopyranoside to the potassium carbonate to the catalyst to the organic solvent is 1:0.9 to 1.1:0.05 to 0.2:3 to 10.
5. The method for producing 2,3, 4-tri-O-benzyl-6-deoxy-D-glucopyranose-1, 5-lactone according to claim 1, wherein: the demethylation reaction in step (3) is carried out under reflux conditions.
6. The method for producing 2,3, 4-tri-O-benzyl-6-deoxy-D-glucopyranose-1, 5-lactone according to claim 1, wherein: in the step (3), the feeding mass ratio of the 2,3, 4-tri-O-benzyl-6-deoxidization-D-methyl glucopyranoside to the organic solvent to the acid is 1:1 to 5:1 to 5.
7. The method for producing 2,3, 4-tri-O-benzyl-6-deoxy-D-glucopyranose-1, 5-lactone according to claim 1, wherein: the temperature at which the oxidation reaction is carried out in the step (4) is 20-30 ℃.
8. The method for producing 2,3, 4-tri-O-benzyl-6-deoxy-D-glucopyranose-1, 5-lactone according to claim 1, wherein: in the step (4), the feeding mass ratio of the 2,3, 4-tri-O-benzyl-6-deoxidization-D-pyranomethyl glucose, the dimethyl sulfoxide and the acetic anhydride is 1:1.5 to 5:0.9 to 2.
9. The method for producing 2,3, 4-tri-O-benzyl-6-deoxy-D-glucopyranose-1, 5-lactone according to any one of claims 1 to 8, characterized in that: the specific implementation mode of the preparation method is as follows:
step (1), adding the 2,3, 4-tri-O-benzyl-D-pyran methyl glucoside-6-methanesulfonate into a reaction kettle, heating the potassium iodide and the organic solvent to reflux under the stirring condition, carrying out chromatographic tracking until the reaction is finished, filtering, removing the potassium methanesulfonate, heating and recovering the organic solvent until the organic solvent is nearly dry, adding ethanol, stirring, cooling and crystallizing, and filtering to obtain the 2,3, 4-tri-O-benzyl-6-iodo-D-pyran methyl glucoside;
step (2), adding the 2,3, 4-tri-O-benzyl-6-iodo-D-methyl glucopyranoside prepared in the step (1), the potassium carbonate, the catalyst and the organic solvent into a reaction kettle, introducing the hydrogen at 0-40 ℃ under the condition of stirring, carrying out chromatographic tracking analysis, judging the end point, ending the reaction, filtering, and removing the organic solvent from the liquid phase to obtain the 2,3, 4-tri-O-benzyl-6-deoxidization-D-methyl glucopyranoside; washing the solid phase with water fully, reusing insoluble matter as the catalyst, evaporating water from the washing liquid, concentrating and crystallizing to obtain potassium iodide, and using the potassium iodide in the substitution reaction in the step (1);
step (3), adding the 2,3, 4-tri-O-benzyl-6-deoxidization-D-methyl glucopyranoside into a reaction kettle, adding the acid after dissolving, refluxing for reaction, tracking to a reaction end point by chromatography, cooling for crystallization, filtering, and washing with water to obtain a crude product of the 2,3, 4-tri-O-benzyl-6-deoxidization-D-methyl glucopyranose; neutralizing the filtrate with sodium hydroxide, separating methanol, ethanol and water in a rectifying tower, and crystallizing the tower bottom liquid to obtain sodium chloride crystal; recrystallizing the 2,3, 4-tri-O-benzyl-6-deoxidization-D-pyran methyl glucose crude product with ethanol to obtain the 2,3, 4-tri-O-benzyl-6-deoxidization-D-pyran methyl glucose;
step (4), adding the 2,3, 4-tri-O-benzyl-6-deoxidization-D-methyl glucopyranose into a reaction kettle, dropwise adding the dimethyl sulfoxide into the acetic anhydride at the temperature of 20-30 ℃, carrying out chromatographic tracking to a reaction end point, adding water, heating and decompressing to recover dimethyl sulfide, acetic acid and DMSO until no distillate exists, cooling to 45-55 ℃, adding an ethanol aqueous solution with the mass concentration of 40-60%, stirring, cooling and filtering to obtain a crude product of the 2,3, 4-tri-O-benzyl-6-deoxidization-D-glucopyranose-1, 5-lactone, recrystallizing with ethanol, filtering and drying to obtain the 2,3, 4-tri-O-benzyl-6-deoxidization-D-glucopyranose-1, 5-lactone.
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