CN104098458B - A kind of preparation method of voglibose intermediate - Google Patents
A kind of preparation method of voglibose intermediate Download PDFInfo
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- CN104098458B CN104098458B CN201410384897.2A CN201410384897A CN104098458B CN 104098458 B CN104098458 B CN 104098458B CN 201410384897 A CN201410384897 A CN 201410384897A CN 104098458 B CN104098458 B CN 104098458B
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Abstract
The invention discloses a kind of voglibose intermediate (2R, 3S, 4S, 5S)-5-hydroxyl-2, 3, the preparation method of 4-tri-(benzyloxy)-5-[(benzyloxy) methyl]-pimelinketone, this preparation method comprises: with 2, 2-bis-chloro-3-hydroxyl-4, 5, 6-trityloxy-3-[(benzyloxy) methyl]-(3S, 4S, 5S, 6R, )-pimelinketone is raw material, at initiator, under reductive agent exists, in low polar aprotic solvent, react in certain temperature range, after reaction solution is cooled to certain temperature, direct precipitation product, filtration obtains high purity (2R, 3S, 4S, 5S)-5-hydroxyl-2, 3, 4-tri-(benzyloxy)-5-[(benzyloxy) methyl]-pimelinketone.The whole synthesis technique of the present invention, has the advantages such as solvent toxicity is low, post-processing operation is simple, the reaction times is short, with low cost, product yield high quality is good, is applicable to suitability for industrialized production.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, relate to a kind of voglibose intermediate (2R, 3S, 4S, 5S)-5-hydroxyl-2, the preparation technology of 3,4-tri-(benzyloxy)-5-[(benzyloxy) methyl]-pimelinketone (Compound I), this compound is the important intermediates of voglibose.
Background technology
In ofhypoglycemic medicine, alpha-glucosidase inhibitor has unique effect to controlling postprandial blood sugar, alpha-glucosidase inhibitor has acarbose (Acarbose), voglibose (Voglibose) etc., to alpha-glycosidase, there is competitive inhibition at small intestine site, thus reach and fall hypoglycemic effect.Acarbose and voglibose not only to reduction on an empty stomach and postprandial blood sugar, HbAlc have obvious curative effects, also have obvious reducing effect to cholesterol, but body weight, Regular Insulin, triacylglycerol, high density lipoprotein cholesterol had no significant effect.The acarbose difference main with voglibose is that the zymogram suppressed is different, acarbose main competitive inhibition small intestine epithelium brush border glucoamylase, sucrase and pancreatic alpha-amylase, stop the hydrolysis of Isosorbide-5-Nitrae-glycosidic link, delay digesting and assimilating of starch and sucrose.Voglibose mainly suppresses maltin and sucrase, in the final step of carbohydrate digestion, suppresses disaccharide to be degraded to monose, thus slows down the formation of glucose, less to the restraining effect of starch.In curative effect, the action intensity of voglibose is stronger than acarbose 190 ~ 270 times, and does not affect gastral alpha-glycosidase.On the other hand, the side effect of voglibose is low compared with the side effect of acarbose, generally there will not be hypoglycemia, also there are no the report affected Liver and kidney function, its side effect is only that abdominal distension and exhaust increase, but low far beyond the incidence of acarbose, is only 10%, symptom is very low, and patient generally can tolerate well.
At present, the preparation method of voglibose mainly contains two kinds, is that fermentable adds semi-synthesis method and chemical method is complete synthesis respectively.
The fermentable that European patent EP 0477160 is reported adds semi-synthesis method and prepares voglibose, when utilizing validamycin producing strains to ferment, directly separation key intermediate Valiolamine from fermentating metabolism thing Validamycin, then obtain voglibose by chemical synthesis process:
It is loaded down with trivial details to there is separation purifying technique in the standby intermediate Valiolamine of this legal system, and the problems such as purity is not high, exist considerable influence to the quality condition of the finished product voglibose.
The complete synthesis route that Japanese Patent JP2007277238 reports is that key intermediate prepares voglibose with Compound I.
The advantage of this complete synthesis route is in synthetic compound I process, and without very low temperature reaction, reaction conditions is relatively gentle, but weak point is its trimethyl aluminium extremely unstable used, explosive, and during suitability for industrialized production, security risk is very big, is not suitable for large-scale production.
European patent EP 0260121 is reported, obtains voglibose from intermediate tetra-O-benzyl glucopyranose lactone.Use tri-butyl tin hydride and AIBN to cause dechlorination to Compound II per in this route, do solvent reaction with toluene, need after reaction to carry out to extract, wash, dry, distillation, cross the operations such as post, can obtain Compound I, the method complex operation, yield is low, be only 71%, be not suitable for suitability for industrialized production.
Summary of the invention
The object of this invention is to provide a kind of for the preparation of voglibose intermediate (2R, 3S, 4S, 5S) the novel method of-5-hydroxyl-2,3,4-tri-(benzyloxy)-5-[(benzyloxy) methyl]-pimelinketone, the method significantly simplifies postprocessing working procedures, shorten the production cycle, reduce material cost, suitability for industrialized production preferably.Reaction involved in the present invention, can state with following equation:
Specifically, the invention provides one for the preparation of voglibose intermediate (2R, 3S, 4S, 5S)-5-hydroxyl-2,3, the novel method of 4-tri-(benzyloxy)-5-[(benzyloxy) methyl]-pimelinketone (i.e. Compound I), it comprises the following steps:
A. under the existence of organic tin compound class reductive agent, azo type free radical initiator, at low polar aprotic C
1-C
8in one or more component solvent of alkane, at 85 DEG C ~ 110 DEG C, be more preferably in 90 ~ 95 DEG C of temperature ranges, with following Compound II per for raw material, be obtained by reacting target compound I;
II
B. the reaction solution that step a obtains is cooled to-20 ~ 65 DEG C, more preferably after 0 ~ 10 DEG C of temperature, crystallize out, filters and obtain Compound I;
Wherein, in Compound I or Compound II per, Bn represents benzyl.
In embodiments of the invention, one provided by the invention is for the preparation of voglibose intermediate (2R, 3S, 4S, 5S)-5-hydroxyl-2,3, the novel method of 4-tri-(benzyloxy)-5-[(benzyloxy) methyl]-pimelinketone (i.e. Compound I), wherein, described organic tin compound class reductive agent is tri-butyl tin hydride, triphenyl tin hydride or trimethyl hydrogenated tin, is more preferably tri-butyl tin hydride.
In embodiments of the invention, one provided by the invention is for the preparation of voglibose intermediate (2R, 3S, 4S, 5S)-5-hydroxyl-2,3, the novel method of 4-tri-(benzyloxy)-5-[(benzyloxy) methyl]-pimelinketone (i.e. Compound I), wherein, described azo type free radical initiator is Diisopropyl azodicarboxylate, 2,2'-Azobis(2,4-dimethylvaleronitrile) or azo-bis-iso-dimethyl, is more preferably Diisopropyl azodicarboxylate.
In embodiments of the invention, one provided by the invention is for the preparation of voglibose intermediate (2R, 3S, 4S, 5S) the novel method of-5-hydroxyl-2,3,4-tri-(benzyloxy)-5-[(benzyloxy) methyl]-pimelinketone (i.e. Compound I), wherein, described C
1-C
8one or more components of alkane are sherwood oil (such as specification is 30 ~ 60 DEG C, or 60 ~ 90 DEG C), octane, heptane, hexane, or its mixture, are more preferably normal heptane.
In embodiments of the invention, one provided by the invention is for the preparation of voglibose intermediate (2R, 3S, 4S, 5S)-5-hydroxyl-2,3, the novel method of 4-tri-(benzyloxy)-5-[(benzyloxy) methyl]-pimelinketone (i.e. Compound I), wherein, described azo type free radical initiator, its consumption is 0.5 ~ 20.0%(molar fraction of Compound I), be more preferably 4.0 ~ 6.0%.
In embodiments of the invention, one provided by the invention is for the preparation of voglibose intermediate (2R, 3S, 4S, 5S)-5-hydroxyl-2,3, the novel method of 4-tri-(benzyloxy)-5-[(benzyloxy) methyl]-pimelinketone (i.e. Compound I), wherein, described organic tin compound class reductive agent, its consumption is 2.0 ~ 3.5 equivalents (mol ratio) of Compound I, is more preferably 2.8 ~ 3.0 equivalents.
In embodiments of the invention, one provided by the invention is for the preparation of voglibose intermediate (2R, 3S, 4S, 5S)-5-hydroxyl-2, the novel method of 3,4-tri-(benzyloxy)-5-[(benzyloxy) methyl]-pimelinketone (i.e. Compound I), wherein, described low polar aprotic solvent, its consumption is 3 ~ 20 times (volume mass ratios, unit is ml/g) of Compound I, is more preferably 5 ~ 6 times.
Beneficial outcomes of the present invention is: (2R, 3S, 4S provided by the invention, 5S)-5-hydroxyl-2,3,4-tri-(benzyloxy)-5-[(benzyloxy) methyl] method prepared by-pimelinketone (Compound I), significantly simplifies postprocessing working procedures, shorten the production cycle, reduce material cost, be more suitable for suitability for industrialized production, products obtained therefrom purity is greater than 97%, after refining further, purity can be greater than 99%.
The present invention adopts the C1-C8 alkane of low polar aprotic as solvent, reacts complete, suction filtration after cooling reaction solution, target compound I, products obtained therefrom purity is greater than 97%, and after further refining, purity can be greater than 99%.In addition, the present invention only need at naturally cooling crystallization after completion of the reaction, filter and obtain target product Compound I, and overcome numerous and diverse aftertreatment of prior art such as European patent EP 0260121, thus substantially reduce the production cycle, reduce material cost, suitability for industrialized production preferably.
Accompanying drawing explanation
The purity of what Fig. 1 represented is embodiment 1 product
Detected result
| Sequence number | Retention time min | Peak area mAU*s | Area percentage % |
| 1 | 2.599 | 112.894 | 0.1281 |
| 2 | 3.744 | 34.298 | 0.0389 |
| 3 | 4.166 | 16.931 | 0.0192 |
| 4 | 4.883 | 44.661 | 0.0507 |
| 5 | 5.431 | 33.902 | 0.0385 |
| 6 | 6.981 | 14.000 | 0.0159 |
| 7 | 8.136 | 78.696 | 0.0893 |
| 8 | 9.849 | 257.757 | 0.2926 |
| 9 | 10.530 | 27.698 | 0.0314 |
| 10 | 16.614 | 374.310 | 0.4249 |
| 11 | 17.397 | 25.451 | 0.0289 |
| 12 | 21.374 | 8.67137e4 | 98.4223 |
| 13 | 23.644 | 369.427 | 0.4193 |
The hydrogen spectrum of what Fig. 2 represented is embodiment 1 product;
The carbon spectrum of what Fig. 3 represented is embodiment 1 product.
Embodiment
Embodiment of the present invention are specifically described below by the embodiment of the present invention.
embodiment 1the preparation of (2R, 3S, 4S, 5S)-5-hydroxyl-2,3,4-tri-(benzyloxy)-5-[(benzyloxy) methyl]-pimelinketone (Compound I)
Get 31.3g (50.4mmol) 2, 2-bis-chloro-3-hydroxyl-4, 5, 6-trityloxy-3-[(benzyloxy) methyl]-(3S, 4S, 5S, 6R, )-pimelinketone (Compound II per), 1.6g Diisopropyl azodicarboxylate (AIBN), 315ml normal heptane, 41.0g(140.9mmol) tri-butyl tin hydride drops into there-necked flask, 90 ~ 95 DEG C are heated under stirring, react 50 ~ 55 minutes, control in TLC, raw material point disappears, be cooled to 0 ~ 10 DEG C to stir 1 hour, suction filtration, filter cake 50 DEG C of decompression dryings, obtain 23.9g off-white powder, yield 86%, purity 98.4%(accompanying drawing 1, 2, 3).
High performance liquid phase testing conditions
| Chromatographic column | Agilent ZORBAX Extend-C18 4.6×250mm 5μm |
| Moving phase | 0.05mol/L ammonium dibasic phosphate solution: acetonitrile=30:70 |
| Flow velocity | 1.0ml/min |
| Determined wavelength | 210nm |
| Sample size | 20μl |
| Solvent | Acetonitrile |
embodiment 2(Compound I) preparation
Get 31.3g (50.4mmol) 2, 2-bis-chloro-3-hydroxyl-4, 5, 6-trityloxy-3-[(benzyloxy) methyl]-(3S, 4S, 5S, 6R, )-pimelinketone (Compound II per), 0.8g azo-bis-iso-dimethyl (AIBME), 190ml normal heptane, 41.0g(140.9mmol) tri-butyl tin hydride drops into there-necked flask, 90 ~ 95 DEG C are heated under stirring, react 30 ~ 35 minutes, control in TLC, raw material point disappears, be cooled to 0 ~ 10 DEG C to stir 1.5 hours, suction filtration, filter cake 50 DEG C of decompression dryings, obtain 23.1g off-white powder, yield 83%, purity 97.8%.
embodiment 3(Compound I) preparation
Get 31.3g (50.4mmol) 2, 2-bis-chloro-3-hydroxyl-4, 5, 6-trityloxy-3-[(benzyloxy) methyl]-(3S, 4S, 5S, 6R, )-pimelinketone (Compound II per), 1.6g Diisopropyl azodicarboxylate (AIBN), 150ml normal heptane, 150ml octane, 41.0g(140.9mmol) tri-butyl tin hydride drops into there-necked flask, 100 ~ 105 DEG C are heated under stirring, react 15 ~ 10 minutes, control in TLC, raw material point disappears, be cooled to-20 ~-10 DEG C to stir 1 hour, suction filtration, filter cake 50 DEG C of decompression dryings, obtain 22.2g off-white powder, yield 80%, purity 98.3%.
What finally illustrate is, above embodiment is only in order to illustrate technical scheme of the present invention and unrestricted, although by referring to the preferred embodiments of the present invention, invention has been described, but those of ordinary skill in the art is to be understood that, can in the form and details to it as various change, and do not depart from the spirit and scope of the present invention that claims limit.
Claims (13)
1., for the preparation of the method for voglibose intermediate (2R, 3S, 4S, 5S)-5-hydroxyl-2,3,4-tri-(benzyloxy)-5-[(benzyloxy) methyl]-pimelinketone, it comprises the following steps:
A., under the existence of organic tin compound class reductive agent, azo type free radical initiator, in low polar aprotic solvent, in 85 DEG C ~ 110 DEG C temperature ranges, with following Compound II per for raw material, target compound I is obtained by reacting;
B., after the reaction solution that step a obtains being cooled to 0 ~ 10 DEG C or-20 ~-10 DEG C of temperature, crystallize out, filters and obtains Compound I;
Here, in Compound I and Compound II per, Bn is benzyl;
Described low polar aprotic solvent is C
1-C
8one or more components of alkane, are selected from sherwood oil, octane, heptane, hexane, or its blending ingredients.
2. preparation method according to claim 1, wherein, described azo type free radical initiator is Diisopropyl azodicarboxylate, 2,2'-Azobis(2,4-dimethylvaleronitrile) or azo-bis-iso-dimethyl.
3. preparation method according to claim 2, wherein, described azo type free radical initiator is Diisopropyl azodicarboxylate.
4. preparation method according to claim 1, wherein, described azo type free radical initiator, its mole dosage is 0.5 ~ 20.0% of the mole dosage of Compound II per.
5. preparation method according to claim 4, wherein, described azo type free radical initiator, its mole dosage is 4.0 ~ 6.0% of the mole dosage of Compound II per.
6. preparation method according to claim 1, wherein, described organic tin compound class reductive agent is tri-butyl tin hydride, triphenyl tin hydride or trimethyl hydrogenated tin.
7. preparation method according to claim 6, wherein, described organic tin compound class reductive agent is tri-butyl tin hydride.
8. preparation method according to claim 1, wherein, described organic tin compound class reductive agent, its consumption is 2.0 ~ 3.5 equivalents of Compound II per.
9. preparation method according to claim 8, wherein, described organic tin compound class reductive agent, its consumption is 2.8 ~ 3.0 equivalents of Compound II per.
10. preparation method according to claim 1, wherein, described low polar aprotic solvent is normal heptane, or the mixture of normal heptane and octane.
11. preparation methods according to claim 1, wherein, described low polar aprotic solvent, its consumption is 3 ~ 20 with the volume mass ratio of Compound II per.
12. preparation methods according to claim 1, wherein, described low polar aprotic solvent, its consumption is 5 ~ 6 with the volume mass ratio of Compound II per.
13. preparation methods according to claim 1, wherein, temperature of reaction is 90 ~ 95 DEG C.
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Address after: Room 1-6, Jinfeng biomedical industrial park, No. 28, Gaoxin Avenue, Jiulongpo District, Chongqing Patentee after: Zhien Biotechnology Co.,Ltd. Address before: 400039 10th floor, building B3, Erlang liuchuang Park, Jiulongpo District, Chongqing Patentee before: Chongqing Zen Pharmaceutical Co.,Ltd. |