CN105601485B - A kind of preparation method of voglibose intermediate - Google Patents
A kind of preparation method of voglibose intermediate Download PDFInfo
- Publication number
- CN105601485B CN105601485B CN201510775975.6A CN201510775975A CN105601485B CN 105601485 B CN105601485 B CN 105601485B CN 201510775975 A CN201510775975 A CN 201510775975A CN 105601485 B CN105601485 B CN 105601485B
- Authority
- CN
- China
- Prior art keywords
- compound
- method described
- benzyloxy
- electrolyte
- reducing agent
- 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.)
- Active
Links
- 0 CO[C@](C1)[C@](*)[C@@](*)(C*)CC1=O Chemical compound CO[C@](C1)[C@](*)[C@@](*)(C*)CC1=O 0.000 description 2
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/65—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention provides one kind and prepares voglibose key intermediate (2R, 3S, 4S, 5S) 5 hydroxyl 2,3, the method of 4 three (benzyloxy) 5 [(benzyloxy) methyl] cyclohexanone, including by the hydroxyl 4 of 2,2 dichloro 3,5,6 trityloxy 3 [(benzyloxy) methyl] (3S, 4S, 5S, 6R,) cyclohexanone is in the presence of metal class reducing agent and electrolyte, in polar solvent, obtained at a temperature of 25~55 DEG C through reduction dechlorination.The method of the present invention reduces poisonous and expensive reagent use, improves yield, greatly reduces the cost of raw material, environment-friendly, industrialized production preferably.
Description
Technical field
The invention belongs to technical field of medicine synthesis, it is related to a kind of voglibose key intermediate --- (2R, 3S, 4S,
5S) -5- hydroxyls -2,3, the preparation technology of 4- tri- (benzyloxy) -5- [(benzyloxy) methyl]-cyclohexanone (compound ii), the change
Compound is the important intermediate of voglibose.
Background technology
Voglibose is developed for the military field pharmacy of Japan, is alpha-glucosidase inhibitor, can improve diabetes high blood after the meal
Sugar.The action intensity of voglibose is stronger than like product acarbose 190~270 times in curative effect, and to gastral
Alpha-glucosidase does not influence.On the other hand, the side effect of voglibose is relatively low, is typically not in hypoglycemia, also there are no
The report influenceed on Liver and kidney function, its side effect is that abdominal distension and exhaust increase, patient's better tolerance.
At present, by with the chloro-3-hydroxyls -4,5 of 2,2- bis-, 6- trityloxies -3- [(benzyloxy) methyl]-(3S, 4S,
5S, 6R)-cyclohexanone (chemical compounds I) prepares voglibose key intermediate (2R, 3S, 4S, 5S) -5- hydroxyls -2,3,4- three
The method of (benzyloxy) -5- [(benzyloxy) methyl]-cyclohexanone (compound ii) mainly has two kinds.By document
J.Org.Chem.1992,57,3642-3658 reports.
Method one：Chemical compounds I and tri-butyl tin hydride, azodiisobutyronitrile are stirred into 1h, generationization for 100 DEG C in toluene
Compound II.
Tri-butyl tin hydride and azodiisobutyronitrile are the method use, two kinds of materials are expensive, and toxicity is big, no
Beneficial to environmental protection, it is unfavorable for industrialized production.
Method two：By chemical compounds I and 5% Pd-BaSO4And sodium acetate is in tetrahydrofurfuryl carbinol mixed solution, 3~
3.5Kg/cm2Hydro-reduction under Hydrogen Vapor Pressure, room temperature reaction is stayed overnight, and generates compound ii.
This method is inflammable and explosive due to having used pressurized with hydrogen, dangerous high；It also using precious metal palladium, valency simultaneously
Lattice are expensive, and toxicity is larger, is I class heavy metal；This another technique productions cycle is long, and yield is low, is unfavorable for industrialized production.
In view of prior art employs the expensive and larger reagent of toxicity and precious metal and uses poisonous, inflammable and explosive,
Dangerous high hydrogen, and yield is low.Therefore, it is necessary to study the method for a more cost-effective suitable industrialized production.
The content of the invention
Object of the present invention is to provide a kind of voglibose key intermediate (2R, 3S, 4S, 5S) -5- hydroxyl -2,
The method of 3,4- tri- (benzyloxy) -5- [(benzyloxy) methyl]-cyclohexanone (i.e. compound II).The present inventor is in voglibose
During synthetic test, it is found that this method is used in the presence of metal class reducing agent and electrolyte, in polar solvent,
In 25~55 DEG C of temperature ranges, using compound I as raw material, target compound II is obtained after reduction dechlorination, reaction equation is as follows.This
Outside, the yield that method of the invention obtains product is 80%~90%, and 40%~70% compared with document report is significantly improved.With
Prior art is compared, and method of the invention reduces poisonous and expensive reagent use, improves yield, greatly reduces former material
Expect cost, environment-friendly, industrialized production preferably.
The present invention provides one kind and prepares voglibose key intermediate (2R, 3S, 4S, 5S) -5- hydroxyls -2,3,4- three
The method of (benzyloxy) -5- [(benzyloxy) methyl]-cyclohexanone (i.e. compound ii), including compound I is reduced in metal class
In the presence of agent and electrolyte, in polar solvent, target product chemical combination is obtained after reduction dechlorination at a temperature of 25~55 DEG C
Thing II.
The method of the invention described above, further comprises target product through suction filtration, concentration, refined, obtains compound II.
The method of the invention described above, the metal class reducing agent and compound I mol ratio are 10：1~50：1.The gold
Belong to class reducing agent for iron powder, zinc powder or copper powder, electrolyte and compound I mol ratio are 5：1~50：1, the electrolyte is
Ammonium chloride, ammonium sulfate, ammonium carbonate, ammonium oxalate, frerrous chloride or ferrous sulfate.It is preferred that reaction temperature be 30-40 DEG C.
The method of the invention described above, the polar solvent be selected from ethanol, acetonitrile, N, dinethylformamide, hydrous ethanol,
Containing water-acetonitrile and aqueous N, dinethylformamide, wherein, the hydrous ethanol, containing water-acetonitrile and aqueous N, N- dimethyl formyl
In amine, the percent by volume of its water content is 0.2~15%.
The method of the invention described above, it is described refined including the use of petroleum ether, octane, heptane, or hexane, or its mixed solvent
Dissolved compound II, mashing, is cooled to 0~30 DEG C, suction filtration is dried under reduced pressure.
In one embodiment, one kind of the invention prepares voglibose intermediate (2R, 3S, 4S, 5S) -5- hydroxyls
Base -2,3, the method for 4- tri- (benzyloxy) -5- [(benzyloxy) methyl]-cyclohexanone (compound ii), comprises the following steps：
A. in the presence of metal class reducing agent and electrolyte, in polar solvent, at 25~55 DEG C, preferred 30-40 temperature
In the range of degree, using chemical compounds I as raw material, target product i.e. compound ii is obtained after reduction dechlorination；
B. reaction solution step a obtained separates out crystal after refined, is filtrated to get compound through suction filtration, evaporated under reduced pressure
Ⅱ。
In the embodiment of the invention described above, described metal class reducing agent is iron powder, zinc powder, copper powder；Consumption is change
Compound I 10~50 equivalents (mol ratio), described electrolyte is ammonium chloride, ammonium sulfate, ammonium carbonate, ammonium oxalate, frerrous chloride,
Ferrous sulfate, preferably ammonium chloride, consumption are the equivalents of compound I 5~50 (mol ratio).
In the embodiment of the invention described above, the polar solvent is ethanol, acetonitrile, N, dinethylformamide；Contain
Water-ethanol (the volume % of water content 0.2~15 volume %), containing water-acetonitrile (the volume % of water content 0.2~15 volume %), aqueous N,
Dinethylformamide (the volume % of water content 0.2~15 volume %), consumption is 10~50 times of volumes of chemical compounds I.
In the embodiment of the invention described above, the process for purification is including the use of petroleum ether, octane, heptane, hexane, or
Its mixed solvent dissolved compound II, mashing, is cooled to 0~30 DEG C, crystallization, suction filtration is dried under reduced pressure.
The method beneficial outcomes of the present invention are：(the benzyls of (2R, 3S, 4S, 5S) -5- hydroxyls -2,3,4- three that the present invention is provided
Epoxide) -5- [(benzyloxy) methyl]-cyclohexanone (compound I) prepare method, reduce poisonous and expensive reagent use,
The inflammable and explosive technique of high-pressure hydrogenation has been got rid of, yield is improved, the cost of raw material is greatly reduced, it is environment-friendly, it is preferably
Industrialized production.Embodiment
Following examples are used for the essence for further understanding the present invention, the scope of but do not limit the invention in any way.
Embodiment 1 (2R, 3S, 4S, 5S) -5- hydroxyls -2,3,4- three (benzyloxy) -5- [(benzyloxy) methyl]-cyclohexanone
The preparation of (compound ii)
345g zinc powders, 94.6g ammonium chlorides, 510g acetonitriles and 15.3g water input 5L there-necked flasks are taken, stirring, water-bath liter is opened
Temperature starts that 110g compounds I acetonitrile solution 2000ml is added dropwise, 30~35 DEG C of temperature control, drop finishes, and reaction is complete to 30~35 DEG C
Afterwards, suction filtration, 40~45 DEG C of evaporated under reduced pressure, ethyl acetate 1500ml and 1000ml 2N salt acid extractions, 1000ml saturated aqueous common salts
Wash, anhydrous magnesium sulfate is dried, suction filtration, evaporated under reduced pressure, add 600ml n-hexanes, flow back 0.5h, is cooled to 0~10 DEG C, suction filtration,
50 DEG C are dried under reduced pressure and obtain 86.1g white solids, purity 97.86%, yield 88%.
The compound II of acquisition is tested with HPLC, and efficient liquid phase testing conditions are shown in Table 1, as a result such as table 2 below.
The efficient liquid phase testing conditions of table 1
The efficient liquid phase testing result of table 2
| Sequence number | Retention time min | Peak area | Area percentage % |
| 1 | 2.521 | 6639 | 0.054 |
| 2 | 2.703 | 25472 | 0.205 |
| 3 | 4.006 | 6434 | 0.052 |
| 4 | 5.426 | 8435 | 0.068 |
| 5 | 8.357 | 1243 | 0.010 |
| 6 | 9.303 | 8883 | 0.072 |
| 7 | 10.490 | 32971 | 0.266 |
| 8 | 11.336 | 61528 | 0.496 |
| 9 | 13.376 | 1156 | 0.009 |
| 10 | 18.283 | 35261 | 0.284 |
| 11 | 19.517 | 32023 | 0.258 |
| 12 | 21.192 | 3034 | 0.024 |
| 13 | 25.718 | 12143754 | 97.86 |
Embodiment 2 (2R, 3S, 4S, 5S) -5- hydroxyls -2,3,4- three (benzyloxy) -5- [(benzyloxy) methyl]-cyclohexanone
The preparation of (compound ii)
297.6g iron powders are taken, 189.5g ammonium chlorides, 400ml N, dinethylformamide put into 5L there-necked flasks, open and stir
Mix, warming-in-water starts that 110g compounds I acetonitrile solution 400ml is added dropwise, 35~40 DEG C of temperature control, drop finishes, instead to 35~40 DEG C
After answering completely, suction filtration, evaporated under reduced pressure, ethyl acetate 1500ml and 1000ml2N salt acid extraction, the washing of 1000ml saturated common salts, nothing
Water magnesium sulfate is dried, suction filtration, evaporated under reduced pressure, adds 600ml normal heptanes, and flow back 0.5h, is cooled to 0~5 DEG C, suction filtration, and 50 DEG C subtract
Pressure is dried to obtain 78.3g white solids, purity 97.90%, yield 80%.
Finally illustrate, the above embodiments are merely illustrative of the technical solutions of the present invention and it is unrestricted, although pass through ginseng
According to the preferred embodiments of the present invention, invention has been described, it should be appreciated by those of ordinary skill in the art that can
Using in the form and details to its as it is various change, without departing from appended claims limited it is of the invention
Spirit and scope.
Claims (7)
1. a kind of method for preparing voglibose intermediate compound II, including
Compound I compounds II
By compound I in the presence of metal class reducing agent and electrolyte, in polar solvent, through also at a temperature of 25~55 DEG C
Target product is obtained after former dechlorination, target product is further obtained into compound II through suction filtration, concentration, refined, wherein, it is described
Metal class reducing agent is iron powder, zinc powder or copper powder, and the electrolyte is ammonium chloride, ammonium sulfate, ammonium carbonate, ammonium oxalate, protochloride
Iron or ferrous sulfate.
2. according to the method described in claim 1, the metal class reducing agent and compound I mol ratio are 10：1~50：1.
3. according to the method described in claim 1, wherein, electrolyte and compound I mol ratio are 5：1~50：1.
4. according to the method described in claim 1, the temperature is 30-40 DEG C.
5. according to the method described in claim 1, the polar solvent be selected from ethanol, it is acetonitrile, N, dinethylformamide, aqueous
Ethanol, containing water-acetonitrile and aqueous N, dinethylformamide.
6. method according to claim 5, wherein, the hydrous ethanol, containing water-acetonitrile and aqueous N, N- dimethyl formyl
In amine, the percent by volume of its water content is 0.2~15%.
7. according to the method described in claim 1, wherein, it is described refined including the use of petroleum ether, octane, heptane, or hexane, or
Its blending ingredients is beaten, and is cooled to 0~30 DEG C, suction filtration is dried under reduced pressure.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510775975.6A CN105601485B (en) | 2015-11-11 | 2015-11-11 | A kind of preparation method of voglibose intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510775975.6A CN105601485B (en) | 2015-11-11 | 2015-11-11 | A kind of preparation method of voglibose intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105601485A CN105601485A (en) | 2016-05-25 |
| CN105601485B true CN105601485B (en) | 2017-11-07 |
Family
ID=55981914
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510775975.6A Active CN105601485B (en) | 2015-11-11 | 2015-11-11 | A kind of preparation method of voglibose intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105601485B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4898986A (en) * | 1986-09-09 | 1990-02-06 | Takeda Chemical Industries, Ltd. | Inosose derivatives, production and use thereof |
| CN104098458A (en) * | 2014-08-07 | 2014-10-15 | 重庆植恩药业有限公司 | Preparation method of voglibose intermediate |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005049547A1 (en) * | 2003-11-21 | 2005-06-02 | Ranbaxy Laboratories Limited | Process for the preparation of 1,2,3,4-cyclohexanetetrol derivatives |
-
2015
- 2015-11-11 CN CN201510775975.6A patent/CN105601485B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4898986A (en) * | 1986-09-09 | 1990-02-06 | Takeda Chemical Industries, Ltd. | Inosose derivatives, production and use thereof |
| CN104098458A (en) * | 2014-08-07 | 2014-10-15 | 重庆植恩药业有限公司 | Preparation method of voglibose intermediate |
Non-Patent Citations (2)
| Title |
|---|
| 2,3,4,6-四-O-苄基井冈霉烯胺的合成;杨光丽等;《化学研究与应用》;20090531;第21卷(第5期);730-733 * |
| Synthesis of a Branched-Chain Inosose Derivative, a Versatile Synthon of N-Substituted Valiolamine Derivatives from D-Glucose;Hiroshi Fukase et al.;《J.Org.Chem.》;19921231;第57卷(第13期);3642-3650 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105601485A (en) | 2016-05-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2014170759A8 (en) | Process of producing 1,4-butanediol | |
| Dulcevscaia et al. | New copper (II) complexes with isoconazole: Synthesis, structures and biological properties | |
| Pellei et al. | Syntheses and biological studies of nitroimidazole conjugated heteroscorpionate ligands and related Cu (I) and Cu (II) complexes | |
| CN105601485B (en) | A kind of preparation method of voglibose intermediate | |
| Yang et al. | Progress in the synthesis of analogues of bistetrahdro-isoquinoline antitumor alkaloids | |
| Siddiqi et al. | Enhanced production of ginsenoside Rh2 (S) from PPD-type major ginsenosides using BglSk cloned from Saccharibacillus kuerlensis together with two glycosidase in series | |
| CN105130999B (en) | A kind of synthetic method of Xi Gelieting impurity | |
| CN105315332A (en) | CIPPC-AA-OBzl, and preparation, nano structure, activity and application thereof | |
| CN102249987B (en) | Combretastatin compound and preparation method and application thereof | |
| CN105239130A (en) | High-antiseptic aluminum alloy anode oxide film non-nickel sealant and preparation method thereof | |
| CN107163166A (en) | A kind of preparation method of chitosan tartaric acid rare earth complex | |
| CN104447394A (en) | Novel synthesis process of ubenimex | |
| CN105111155B (en) | A kind of synthetic method of 4,7- diaza spiro [2.5] octane -7- t-butyl formate | |
| CN109516951B (en) | Preparation method of nicorandil trimer | |
| CN103880708A (en) | Improved catalytic synthesis method of malononitrile | |
| CN105175400B (en) | A kind of preparation method of afatinib intermediate | |
| CN104447787B (en) | The method of separation and purification two kinds of sesquiterpene lactones compounds and application from artemisiifolia | |
| CN106995467A (en) | A kind of method that microwave catalysis synthesizes bicycloplatin | |
| CN104961851B (en) | Inner salt compound formed by two types of polymers, and preparation method and application of inner salt compound | |
| CN102631918B (en) | Nano ruthenium-rhodium catalyst, preparation of catalyst and application of catalyst in hydrogenation reaction process | |
| CN106519071A (en) | Synthetic method of antitumor drug 6-hydroxy seleninic acid esterification chitosan copper | |
| CN106542973A (en) | Ta Simeiqiong intermediates and preparation method thereof | |
| CN105200489A (en) | Heat-resistant aluminum alloy anode oxide film nickel-free hole sealing agent and preparation method thereof | |
| CN101508719A (en) | 11-deoxidized glycyrrhetinic acid-3-0-succinic acid half ester rare earth salt and synthetic method thereof | |
| CN109071481A (en) | Method for generating maltol Fe composition by elemental iron |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CP03 | Change of name, title or address |
Address after: 401328 No.1-6 standard workshop, Jinfeng biomedical industrial park, 28 Gaoxin Avenue, Jiulongpo District, Chongqing Patentee after: Zhien Biotechnology Co.,Ltd. Address before: 400039 Jiulongpo District of Chongqing Science Park Road No. 73 of 25 layers Patentee before: Chongqing Zen Pharmaceutical Co.,Ltd. |
|
| CP03 | Change of name, title or address |