CN103524469A - (1S)-1,6-dideoxygenated-1-[4-hydroxy-3-(trans-4-substituted cyclohexyl)methyl phenyl]-D-glucopyranose compound and preparation method thereof - Google Patents

(1S)-1,6-dideoxygenated-1-[4-hydroxy-3-(trans-4-substituted cyclohexyl)methyl phenyl]-D-glucopyranose compound and preparation method thereof Download PDF

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CN103524469A
CN103524469A CN201310478372.0A CN201310478372A CN103524469A CN 103524469 A CN103524469 A CN 103524469A CN 201310478372 A CN201310478372 A CN 201310478372A CN 103524469 A CN103524469 A CN 103524469A
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赵桂龙
汤立达
邵华
魏群超
王玉丽
徐为人
邹美香
吴疆
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Tianjin Institute of Pharmaceutical Research Co Ltd
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    • 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
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms

Abstract

The invention belongs to the technical field of medicines, and specifically relates to a (1S)-1,6-dideoxygenated-1-[4-hydroxy-3-(trans-4-substituted cyclohexyl)methyl phenyl]-D-glucopyranose compound and a preparation method thereof, wherein R is equal to H, Me, Et and n-Pr.

Description

A kind of (1S)-1,6-dideoxy-1-[4-hydroxyl-3-(trans-4-substituted cyclohexyl) aminomethyl phenyl]-D-Glucopyranose compound and preparation method thereof
Technical field
The invention belongs to medical technical field, be specifically related to the preparation method containing the C-glucoside of saturated cyclohexane structure.
Background technology
Whole world diabetic subject is nearly 1.7 hundred million left and right at present, and wherein approximately most is II type (being non-insulin-depending type) diabetic subject.Antidiabetic medicine in clinical use mainly contains N1,N1-Dimethylbiguanide class, sulfonylurea, insulin type, thiazolidinediones, alpha-glucosidase inhibitor class and dipeptidyl peptidase-iv inhibitor class medicine at present, these medicines have good therapeutic action, but there is safety issue in long-term treatment, as: liver toxicity, some drugs still has the problems such as body weight increase.
2 type sodium glucose (SGLT2) that cotransports is the novel targets of the treatment diabetes of discovered in recent years.SGLT2 is mainly distributed in kidney proximal tubule, and its effect is the glucose absorbing in urine, and returns it in blood, and that therefore suppresses SGLT2 just can reduce the concentration of glucose in blood, and this method has reduced glucose level from the past different approach.When SGLT2 function is obstructed, in urine, will secrete more glucose, this will contribute to diabetic subject to keep correct glucose level.Because SGLT2 inhibitor stays out of glucose metabolism, it can be used as the means of supplementing out economy of glycemic control main stream approach.
Patent CN201010533301.2 and PCT/CN2011/000147 disclose the C-glucosides class SGLT2 inhibitor that contains saturated six-ring as next class,
Wherein, R 1, R 2independently be selected from H, F, Cl, Br, I, OR 3, SR 4, OCF 3, CF 3, CHF 2, CH 2f, C 1-C 3alkyl, containing the cycloalkyl of 3-5 carbon atom, R wherein 3and R 4independently be selected from C 1-C 3alkyl, abovementioned alkyl or cycloalkyl all can be replaced by one or more F, Cl atom; The definition of X and Y is selected from following several situation: (1) X=Y=carbon atom; (2) X=Y=nitrogen-atoms; (3) X=nitrogen-atoms, Y=Sauerstoffatom; (4) X=nitrogen-atoms, Y=carbon atom.
And above-mentioned patent also discloses as the preparation method of next compounds I (embodiment 4 and 11-13),
Wherein, R=H, Me, Et and n-Pr.
Summary of the invention
Still there are many shortcomings in the route of above-mentioned preparation SGLT2 inhibitor I: the productive rate that is converted into P4 by P3 is lower, and the general line productive rate that causes finally preparing I is lower, and the circulation ratio of this route is bad, productive rate batch between fluctuation larger.
Therefore, the higher and good method of circulation ratio of productive rate is expected in the preparation of SGLT2 inhibitor I.Object of the present invention is just to provide the preparation method of this compounds.
For solving the problems of the technologies described above, through further investigation, the present inventor has proposed the preparation method of the SGLT2 inhibitor that formula is I, wherein, and R=H, Me, Et and n-Pr.The present invention has adopted the OH on benzyl protection phenyl ring and has omitted after coupling acid catalysis methylglycoside and adopted the gentle innovative approachs such as acetylation reagent; overcome the shortcoming that synthetic method overall yield is lower and circulation ratio is bad that patent CN201010533301.2 and PCT/CN2011/000147 are used, obtained the good technique that a preparation has the SGLT2 inhibitor of general formula I structure.
Figure BDA0000395406190000031
The preparation process that the present invention comprises is as follows:
[1] compound of following general formula I (wherein R=H, Me, Et and n-Pr),
Figure BDA0000395406190000032
Can under alkaline condition, be hydrolyzed deacetylation by the compound of following general formula I I and prepare, wherein R=H, Me, Et and n-Pr.Alkaline condition used includes, but are not limited to the MeOH solution of MeONa, the EtOH aqueous solution and the K of the EtOH aqueous solution of NaOH, KOH 2cO 3methyl alcohol or ethanolic soln, temperature is that room temperature arrives backflow.
Figure BDA0000395406190000033
[2] above-mentioned general formula I I compound can be by following general formula I II compound methylate preparation, wherein R=H, Me, Et and n-Pr.Methylating reagent includes but not limited to MeI, Me 2sO 4and Me 3pO 4, solvent includes but not limited to DMF, DMSO, MeOH etc., temperature is that room temperature arrives backflow.
[3] compound of above-mentioned general formula III can also be prepared by the compound debenzylation of following general formula I V, wherein R=H, Me, Et and n-Pr.The condition of debenzylation includes, but are not limited to use Pd/C, Pd (OH) 2the catalytic hydrogenation of/C etc. and DDQ (2,3-Dichloro-5,6-dicyano-1,4-benzoquinone) oxidation.
Figure BDA0000395406190000041
[4] can also methylate by the compound selective of following general formula V preparation, wherein R=H, Me, Et and n-Pr of the compound of above-mentioned general formula I.Methylating reagent includes but not limited to MeI, Me 2sO 4and Me 3pO 4, solvent includes but not limited to DMF, DMSO, MeOH etc., temperature is that room temperature arrives backflow.
Figure BDA0000395406190000042
[5] compound of above-mentioned general formula V can be prepared by the compound debenzylation of following general formula VI, wherein R=H, Me, Et and n-Pr.The condition of debenzylation includes, but are not limited to use Pd/C, Pd (OH) 2the catalytic hydrogenation of/C etc. and DDQ (2,3-Dichloro-5,6-dicyano-1,4-benzoquinone) oxidation.
Figure BDA0000395406190000043
[6] compound of above-mentioned general formula VI can be prepared by compound deacetylation under the existence of alkali of following general formula I V, wherein R=H, Me, Et and n-Pr.Alkaline condition used includes, but are not limited to the MeOH solution of MeONa, the EtOH aqueous solution and the K of the EtOH aqueous solution of NaOH, KOH 2cO 3methyl alcohol or ethanolic soln, temperature is that room temperature arrives backflow.
Figure BDA0000395406190000044
[7] compound of above-mentioned general formula V can be prepared by compound deacetylation under alkali exists of following general formula I II, wherein R=H, Me, Et and n-Pr.Alkaline condition used includes, but are not limited to the MeOH solution of MeONa, the EtOH aqueous solution and the K of the EtOH aqueous solution of NaOH, KOH 2cO 3methyl alcohol or ethanolic soln, temperature is that room temperature arrives backflow.
Figure BDA0000395406190000051
[8] compound of above-mentioned general formula I V can make by compound recrystallization purifying or the column chromatography purification of following general formula VII.Wherein R=H, Me, Et and n-Pr.
[9] compound of above-mentioned general formula VII can make by the compound acetylize of following general formula VIII.Wherein R=H, Me, Et and n-Pr.Acetylizad reagent includes but not limited to diacetyl oxide and Acetyl Chloride 98Min.; the alkali using includes but not limited to pyridine, triethylamine, 2; 6-lutidine, diisopropyl ethyl amine, solvent includes but not limited to the aprotic solvent such as above-mentioned alkali itself and methylene dichloride and THF, temperature is-50 ℃ and arrives backflow.
Figure BDA0000395406190000053
[10] compound of above-mentioned general formula VIII can obtain by the compound reduction of following general formula I X, wherein R=H, Me, Et and n-Pr.The reagent of reduction includes but not limited to Et 3siH/BF 3et 2o, solvent includes but not limited to methylene dichloride, acetonitrile, ether and THF etc., temperature is-50 ℃ and arrives backflow.
Figure BDA0000395406190000054
[11] compound of above-mentioned general formula I X obtains X after can processing with lithium alkylide by the compound of following general formula X II, and after X reacts with the compound of general formula X I again, acidifying makes.Wherein R=H, Me, Et and n-Pr.Described lithium alkylide includes but not limited to n-BuLi, s-BuLi and t-BuLi etc., and described acid includes but not limited to various mineral acids and organic acid.
Figure BDA0000395406190000061
[12] compound of above-mentioned general formula X II can make by the compound reduction of following general formula X III, wherein R=H, Me, Et and n-Pr.The reagent of reduction includes but not limited to Et 3siH/BF 3et 2o and NaBH 3/ AlCl 3, solvent includes but not limited to methylene dichloride, acetonitrile, ether and THF etc., temperature is-50 ℃ and arrives backflow.
Figure BDA0000395406190000062
[13] compound of above-mentioned general formula X III can make by the compound benzyl of following general formula X IV, wherein R=H, Me, Et and n-Pr.Benzyl reagent includes but not limited to BnCl, BnBr and BnOC (=NH) CCl 3, solvent includes but not limited to DMF, DMSO, MeOH, EtOH and CH 2cl 2deng, temperature is-50 ℃ and arrives backflow.
Figure BDA0000395406190000063
Above-mentioned route gathers as follows:
Figure BDA0000395406190000071
Embodiment
Below in conjunction with embodiment, the present invention is further illustrated.It should be noted that, following embodiment is only for explanation, and not for limiting the present invention.The various variations that those skilled in the art's training centre according to the present invention is made all should be within the desired protection domain of the application's claim.
embodiment 1
Figure BDA0000395406190000081
In the round-bottomed flask of dry 500mL, add 32.52g (0.1mol) compounds X IV-1,20.52g (0.12mol) cylite, 27.64g (0.2mol) solid K 2cO 3, 5.00g solid K I and the dry DMF of 200mL, gained mixture at room temperature stirs and spends the night, TLC shows and has reacted.
Reaction mixture 500mL CH 2cl 2dilution, stirs 1 minute, and suction filtration is removed solid.Filtrate is used saturated common salt water washing, anhydrous Na 2sO 4dry, suction filtration boils off solvent at Rotary Evaporators after removing siccative, obtains a colorless oil, and column chromatography purification obtains the sterling of XIII-1,37.80g, productive rate 91%.Clear crystal, fusing point 63-65 ℃, 1h NMR (DMSO-d 6, 400MHz), δ 7.67 (dd, 1H, J=2.4Hzand8.8Hz), 7.53 (d, 1H, J=2.8Hz), 7.35-7.49 (m, 5H), 7.25 (d, 1H, J=8.8Hz), 5.19 (s, 2H), 3.01-3.08 (m, 1H), 1.71-1.74 (m, 2H), 1.59-1.63 (m, 2H), 1.02-1.27 (m, 7H), 0.83 (t, 3H, J=7.4Hz), 0.58-0.68 (m, 2H).
Figure BDA0000395406190000082
In the dry round-bottomed flask of 500mL, add 37.38g (0.09mol) compounds X III-1,34.88g (0.3mol) Et 3the dry CH of SiH and 200mL 2cl 2, gained mixture is in the cooling lower stirring of ice-water bath, toward wherein slowly dripping 21.29g (0.15mol) BF 3et 2o.After dropwising, reaction mixture at room temperature stirs and spends the night.
Reaction mixture, in the cooling lower stirring of ice-water bath, slowly adds the saturated Na of 200mL 2cO 3solution, stirring was poured in 500mL frozen water after half an hour.With concentrated hydrochloric acid, carefully regulate pH=3-4, with 100mL * 3CH 2cl 2extraction.Merge extraction phase, use saturated common salt water washing, anhydrous Na 2sO 4dry, suction filtration boils off solvent at Rotary Evaporators after removing siccative, obtains a colorless oil, and column chromatography purification obtains the sterling of XII-1,32.51g, productive rate 90%.Colorless oil, 1h NMR (DMSO-d 6, 400MHz), δ 7.29-7.44 (m, 6H), 7.25 (d, 1H, J=2.4Hz), 6.99 (d, 1H, J=8.4Hz), 5.11 (s, 2H), 2.46 (d, 2H, J=6.8Hz), 1.65-1.68 (m, 2H), 1.56-1.60 (m, 2H), 1.46-1.51 (m, 1H), 1.21-1.40 (m, 2H), 1.07-1.18 (m, 3H), 0.89-0.98 (m, 2H), 0.83 (t, 3H, J=7.2Hz), 0.72-0.78 (m, 2H).
Figure BDA0000395406190000091
In the round-bottomed flask of dry 500mL, add the compounds X II-1 of 32.11g (0.08mol), one piece of dry magneton and the dry THF of 200mL, after nitrogen purging with the sealing of rubber cork.It is cooling that flask is placed in and fills the vacuum jacketed flask of liquid nitrogen-ethanol of-78 ℃, start stirring, with syringe toward the hexane solution of n-BuLi that slowly drips the 1.6M of 56.3mL (0.09mol) in flask, after dropwising, reaction mixture continues to stir 1 hour at-78 ℃, then with syringe, slowly drips 46.69g (0.1mol) 2,3 again, 4,6-, tetra--O-TMS-D-Glucose acid lactone is dissolved into the solution of making in the toluene that 50mL is dry.After dropwising, withdraw cryostat, reaction mixture is automatic heating slowly at room temperature, continues to stir 3 hours.
Reaction mixture is under agitation carefully poured in the cooling saturated aqueous common salt of 1000mL, with concentrated hydrochloric acid, carefully regulates pH=3-4, continues to stir half an hour, with 150mL * 3CH 2cl 2extraction, merges extraction phase, uses saturated common salt water washing, anhydrous Na 2sO 4dry, suction filtration boils off solvent at Rotary Evaporators after removing siccative, obtains a light yellow solid, is the crude product of IX-1, and this crude product need not be further purified and can carry out next step reaction.ESI-MS,m/z=501([M+H] +)。
The IX-1 crude product that step [3] is made is placed in the round-bottomed flask of dry 500mL, with the dry CH of 200mL 2cl 2dissolve, add 13.95g (0.12mol) Et 3siH, is cooled to-30 ℃, under stirring, from constant pressure funnel, dropwise adds 8.52g (0.06mol) BF 3et 2o.After dropwising, reaction mixture at room temperature continues to stir 3 hours.
Reaction mixture, in the cooling lower stirring of ice-water bath, slowly adds the saturated NaHCO of 100mL 3solution, stirring was poured in 500mL frozen water after half an hour.With concentrated hydrochloric acid, carefully regulate pH=3-4, with 100mL * 3CH 2cl 2extraction.Merge extraction phase, use saturated common salt water washing, anhydrous Na 2sO 4dry, suction filtration boils off solvent at Rotary Evaporators after removing siccative, obtains a light yellow solid, is the crude product of VIII-1, and this crude product need not be further purified and can carry out next step reaction.ESI-MS,m/z=485([M+H] +)。
The VIII-1 and the dry pyridine of 200mL that in the round-bottomed flask of 500mL, add step [4] to prepare, the cooling lower stirring of ice-water bath, slowly drips 80mL acetic anhydride, adds 2g4-Dimethylamino pyridine after dropwising again, and then under room temperature, stirs and spends the night.
Reaction mixture is slowly poured in 1000mL frozen water under stirring, and adds 300mL CH 2cl 2, stir, with concentrated hydrochloric acid, regulate the pH=4-5 of water, separate organic phase.Water 100mL CH 2cl 2return extraction once.Merge organic phase, use saturated common salt water washing, anhydrous Na 2sO 4dry, suction filtration boils off solvent at Rotary Evaporators after removing siccative, obtains a yellow solid, is the crude product of VII-1, and this crude product is isolated IV-1 through column chromatography purification.White solid, 45.43g, productive rate 87% (calculating from XII-1), 1h NMR (DMSO-d 6, 400MHz), δ 7.37-7.44 (m, 4H), 7.30-7.33 (m, 1H), 7.14 (dd, 1H, J=1.8Hz and8.6Hz), 7.02 (d, 1H, J=2.0Hz), 7.00 (dd, 1H, J=8.8Hz), 5.33 (t, 1H, J=9.6Hz), 5.10 (s, 2H), 4.98-5.08 (m, 2H), 4.58 (d, 1H, J=10.0Hz), 4.03-4.14 (m, 3H), 2.44-2.47 (m, 2H), 2.02 (s, 3H), 2.00 (s, 3H), 1.93 (s, 3H), 1.72 (s, 3H), 1.64-1.67 (m, 2H), 1.54-1.58 (m, 2H), 1.46-1.48 (m, 1H), 1.23-1.29 (m, 2H), 1.07-1.12 (m, 3H), 0.87-0.96 (m, 2H), 0.83 (t, 3H, J=7.4Hz), 0.77-0.78 (m, 2H).
Figure BDA0000395406190000111
Compound IV-1, the 1.0g Pd (OH) that in the round-bottomed flask of 500mL, add 39.17g (0.06mol) 2(moisture 50%) and 200mL THF, with using again nitrogen in hydrogen exchange flask after the air in nitrogen replacement flask three times three times, reaction mixture hydrogenation 24 hours under 2 normal atmosphere of room temperature then.TLC demonstration has been reacted.
After the hydrogen in nitrogen replacement flask, reaction mixture suction filtration, filtrate is evaporate to dryness on Rotary Evaporators, obtain an off-white color solid, crude product for compound III-1, this crude product is with stirring 1 hour under 100mL sherwood oil and 3mL ethyl acetate room temperature, and suction filtration is collected solid, and under room temperature, vacuum-drying obtain the sterling of product III-1.White solid, 32.74g, productive rate 97%.ESI-MS,m/z=563([M+H] +)。
Figure BDA0000395406190000112
In the round-bottomed flask of dry 500mL, add 28.13g (0.05mol) compound III-1,8.52g (0.06mol) methyl iodide, 13.8g (0.1mol) solid K 2cO 3with the dry DMF of 120mL, gained mixture at room temperature stirs and spends the night, and TLC demonstration has been reacted.
Reaction mixture 400mL CH 2cl 2dilution, stirs 1 minute, and suction filtration is removed solid.Filtrate is used saturated common salt water washing, anhydrous Na 2sO 4dry, suction filtration boils off solvent at Rotary Evaporators after removing siccative, obtains a colorless oil, and column chromatography purification obtains the sterling of II-1,27.10g, productive rate 94%.White solid.ESI-MS,m/z=577([M+H] +)。
Figure BDA0000395406190000121
In the dry round-bottomed flask of 500mL, add methyl alcohol and 0.46g (0.02mol) sodium Metal 99.5 that 150mL is dry, under room temperature, stir, until sodium Metal 99.5 disappears.Add 23.07g (0.04mol) Compound I I-1 again, stir 3 hours under room temperature, now TLC shows that II-1 disappears.
In flask, add the 732 type storng-acid cation exchange resin (H that 20g is dry +form) and 150mL methyl alcohol, under room temperature, stir and spend the night, now reaction mixture pH=7.Suction filtration, filtrate is evaporate to dryness on Rotary Evaporators, and the resistates obtaining is dry under room temperature on vacuum pump, obtains product I-1.White foam shape solid, 16.18g, productive rate 99%.ESI-MS,m/z=409([M+H] +)。
In the dry round-bottomed flask of 500mL, add methyl alcohol and 0.46g (0.02mol) sodium Metal 99.5 that 150mL is dry, under room temperature, stir, until sodium Metal 99.5 disappears.Add 26.11g (0.04mol) compound IV-1 again, stir 3 hours under room temperature, now TLC shows that IV-1 disappears.
In flask, add the 732 type storng-acid cation exchange resin (H that 20g is dry +form) and 150mL methyl alcohol, under room temperature, stir and spend the night, now reaction mixture pH=7.Suction filtration, filtrate is evaporate to dryness on Rotary Evaporators, and the resistates obtaining is dry under room temperature on vacuum pump, obtains product IV-1.White foam shape solid, 19.38g, productive rate 100%.ESI-MS,m/z=485([M+H] +)。
Figure BDA0000395406190000131
Compound VI-1, the 1.0g Pd (OH) that in the round-bottomed flask of 500mL, add 19.38g (0.04mol) 2(moisture 50%) and 150mL THF, with using again nitrogen in hydrogen exchange flask after the air in nitrogen replacement flask three times three times, reaction mixture hydrogenation 24 hours under 2 normal atmosphere at room temperature then.TLC demonstration has been reacted.
After the hydrogen in nitrogen replacement flask, reaction mixture is at suction filtration, and filtrate is evaporate to dryness on Rotary Evaporators, obtains an off-white color solid, is compound V-1, and under room temperature, vacuum-drying obtain the sterling of product V-1.White solid, 15.15g, productive rate 96%.ESI-MS,m/z=395([M+H] +)。
Figure BDA0000395406190000132
In the round-bottomed flask of dry 500mL, add 15.78g (0.04mol) compound V-1,8.52g (0.06mol) methyl iodide, 13.8g (0.1mol) solid K 2cO 3with the dry DMF of 120mL, gained mixture at room temperature stirs and spends the night, and TLC demonstration has been reacted.
Reaction mixture 400mL CH 2cl 2dilution, stirs 1 minute, and suction filtration is removed solid.Filtrate is used saturated common salt water washing, anhydrous Na 2sO 4dry, suction filtration boils off solvent at Rotary Evaporators after removing siccative, obtains a colorless oil, and column chromatography purification obtains the sterling of I-1,15.20g, productive rate 93%.White solid.ESI-MS,m/z=409([M+H] +)。
Figure BDA0000395406190000141
In the round-bottomed flask of dry 500mL, add 28.13g (0.05mol) compound III-1 and 300mL ethanol, under room temperature, stir, carefully add the NaOH solution of 30mL40%, gained mixture refluxes half an hour in nitrogen atmosphere, and TLC demonstration has been reacted.
After reaction mixture is cooling, be poured in 500mL water, with concentrated hydrochloric acid, regulate pH=2-3, with 100mL * 3CH 2cl 2extraction.Merge extraction phase, use saturated common salt water washing, anhydrous Na 2sO 4dry, suction filtration boils off solvent at Rotary Evaporators after removing siccative, and the resistates column chromatography purification obtaining obtains the sterling of V-1,18.54g, productive rate 94%.White solid.ESI-MS,m/z=395([M+H] +)。

Claims (4)

1. suc as formula the compound described in V,
Figure FDA0000395406180000011
Wherein R=H, Me, Et, n-Pr.
2. a method of preparing compound V as claimed in claim 1, is characterized in that, the following step, consists of:
(1) general formula I V compound deacetylation under the existence of alkali makes VI;
(2) general formula VI compound debenzylation makes V;
Wherein the definition of R as claimed in claim 1.
3. preparation method as claimed in claim 2, the described deacetylation alkali used of step (1) is MeONa.
4. preparation method as claimed in claim 2, the method for the debenzylation that step (2) is described is catalytic hydrogenolysis, catalyzer is Pd/C.
CN201310478372.0A 2011-12-12 2011-12-12 (1S)-1,6-dideoxygenated-1-[4-hydroxy-3-(trans-4-substituted cyclohexyl)methyl phenyl]-D-glucopyranose compound and preparation method thereof Pending CN103524469A (en)

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Application publication date: 20140122