CN104045513A - 4-substituted-1-chloro-2-(4-fluorobenzyl)benzene, its preparation method and application as intermediate in preparation of anti-type II diabetes drugs - Google Patents
4-substituted-1-chloro-2-(4-fluorobenzyl)benzene, its preparation method and application as intermediate in preparation of anti-type II diabetes drugs Download PDFInfo
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Abstract
The invention discloses a compound 4-substituted-1-chloro-2-(4-fluorobenzyl)benzene shown as formula V, its preparation method and application as an intermediate in preparation of anti-type II diabetes drugs, and especially discloses the compound 4-substituted-1-chloro-2-(4-fluorobenzyl)benzene shown as formula V and its application as an intermediate in preparation of anti-type II diabetes drug Empagliflozin shown as formula I. The method provided by the invention has the advantages of relatively cheap raw material and reagent, low cost, simple and safe operation, good yield, small environmental pollution, and very good economic effect, thus being suitable for industrial production.
Description
Technical field
The present invention relates to a kind of suc as formula the chloro-2-of compound 4-replacement-1-(4-luorobenzyl) benzene shown in V and preparation method thereof with as intermediate application in anti-type ii diabetes medicine in preparation, particularly relate to a kind of suc as formula the chloro-2-of compound 4-replacement-1-(4-luorobenzyl) benzene shown in V and as intermediate for the preparation of the anti-type ii diabetes medicine Empagliflozin suc as formula described in I.
Technical background
Empagliflozin(is as shown in the formula shown in I, CAS:864070-44-0) Shi You Boehringer Ingelheim company develops, be called as sodium glucose co-transporter 2 white-2(SGLT-2) a kind of in the compound of new generation of inhibitor, the effect of the reduction blood high glucose level (hyperglycemia) that does not rely on Regular Insulin can be provided, thereby its mechanism of action be blocking-up glucose kidney heavily absorb body in too much glucose via urine, discharge, reach and fall the hypoglycemic while and further alleviate patient's body weight.
Boehringer Ingelheim company discloses respectively two kinds of new preparation technologies of above-mentioned formula I compound in patent WO2006120208A, WO2011039108A.Yet up to the present, the route of synthesis of this compound is also more limited.
Summary of the invention
It is a kind of suc as formula the chloro-2-of compound 4-replacement-1-(4-luorobenzyl) benzene shown in V and preparation method thereof that technical problem to be solved by this invention is to provide, and this compound as intermediate for the preparation of the anti-type ii diabetes medicine Empagliflozin suc as formula described in I.The inventive method desired raw material and reagent price are relatively cheap, with low cost, safety simple to operation, and yield is good, and environmental pollution is simultaneously little, has good economic benefits, suitable industrial production.
The described chloro-2-of formula V compound 4-replacement-1-(4-luorobenzyl) benzene, its structural formula is as follows:
Wherein, X is halogen, preferably bromine or iodine.
The preparation method of described formula V compound, comprises the following steps: take formula VI compound as starting raw material (this compou nd synthesis is referring to patent WO2006120208A), under reductive agent effect, carbonyl reduction makes formula V compound.Reaction formula is as follows:
Wherein, described reductive agent is selected from: 1) silane of C1-C3 is as triethyl silicane, trimethyl silane, three n-propyl silane, or tri isopropyl silane; 2) hydroborate is as sodium borohydride, POTASSIUM BOROHYDRIDE, or borine; Or 3) alanate is as lithium aluminum hydride; Above system is reduced under lewis acidic existence, and described Lewis acid is selected from: boron trifluoride diethyl etherate, three perfluorophenyl borines, trifluoroacetic acid, hydrogenchloride and solution, hydrogen bromide and solution thereof, aluminum chloride, or Indium-111 chloride; Described reaction is carried out in aprotic solvent, and aprotic solvent is selected from: methylene dichloride, 1,2-ethylene dichloride, benzene,toluene,xylene, acetonitrile, tetrahydrofuran (THF), normal hexane, sherwood oil, normal heptane, or any two or more mixed solvent wherein; Temperature of reaction is-20～130 ℃, preferably 20～100 ℃.
The above-mentioned formula V compound of take is key intermediate, is used for synthesizing suc as formula the anti-type ii diabetes medicine Empagliflozin described in I, specifically comprises the following steps:
1) formula V compound and formula VII compound carry out addition reaction by basic metal reagent, obtain formula IV compound subsequently in C1-C3 alcoholic solution through acid catalysis;
2) formula IV compound is reduced to obtain formula III compound under the effect of reductive agent and acid additives;
3) formula III compound reacts to obtain formula II compound with formula VIII compound under basic cpd effect;
4) formula II compound Deprotection under the effect of metal catalyst obtains formula I compound, or formula II compound Deprotection under acid effect obtains formula I compound.
Reaction formula is as follows:
X is bromine or iodine, R
1for C1-C6 silylation protecting group or benzyl class protecting group, R
2for C1-C3 alkyl.
Preferably, described C1-C6 silylation protecting group as: trimethyl silicon based, triethyl is silica-based, triisopropylsilyl, or t-Butyldimethylsilyl; Described benzyl class protecting group is as trityl Trity, benzyl Bn, 4-methoxy-benzyl PMB, 4-methyl-benzyl, 4-nitrobenzyl, 2,4-dimethoxy-benzyl DMB, carbobenzoxy-(Cbz) Cbz, 4-methoxyl group benzyloxy carbonyl, or 4-methyl carbobenzoxy-(Cbz); Described C1-C3 alkyl is as methyl, ethyl, n-propyl, or sec.-propyl.
Wherein, in step 1), described basic metal reagent is selected from: a) alkyl lithium reagents is as n-Butyl Lithium, s-butyl lithium, tert-butyl lithium, and b) Grignard reagent is as sec.-propyl Grignard reagent, or c) mixed system of normal-butyl Grignard reagent and lithium chloride; Described addition reaction is carried out in organic solvent, organic solvent is selected from: C2-C8 ether or its inertia aromatic solvents, wherein C2-C8 ether is as tetrahydrofuran (THF), dioxane, ether, methyl tertiary butyl ether, or methyl-phenoxide, and aromatic solvents is as benzene,toluene,xylene or their mixed solution; Temperature of reaction is-90～140 ℃, preferably-80～80 ℃; Described C1-C3 alcoholic solution is methyl alcohol, ethanol, n-propyl alcohol, or Virahol; Described acid catalyst is as: methylsulfonic acid, benzene methanesulfonic acid, to methylbenzene methylsulfonic acid, trifluoromethanesulfonic acid, or hydrogenchloride and solution thereof.
Step 2) in, described reductive agent is selected from: a) silane of C1-C3 is as triethyl silicane, trimethyl silane, three n-propyl silane, or tri isopropyl silane; B) hydroborate is as sodium borohydride, POTASSIUM BOROHYDRIDE, or borine; Or c) alanate is as lithium aluminum hydride; Described acid additives is as boron trifluoride diethyl etherate, three perfluorophenyl borines, trifluoroacetic acid, hydrogenchloride and solution, hydrogen bromide and solution thereof, aluminum chloride, or Indium-111 chloride; Described reaction is carried out in aprotic solvent, and aprotic solvent is selected from: methylene dichloride, 1,2-ethylene dichloride, benzene,toluene,xylene, acetonitrile, tetrahydrofuran (THF), normal hexane, sherwood oil, normal heptane, or any two or more mixed solvent wherein; Temperature of reaction is-20～130 ℃, preferably 20～100 ℃.
In step 3), described basic cpd is selected from: the alcohol alkali of C1-C8 or phenol alkali, carbonic acid alkali, alkali metal hydroxide, the tertiary amine of C1-C3, or other nitrogenous class organic basess, for example: potassium tert.-butoxide, sodium tert-butoxide, trimethyl carbinol lithium, sodium methylate, potassium methylate, sodium ethylate, potassium ethylate, salt of wormwood, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, triethylamine, diisopropyl ethyl amine, hexamethyldisilane base sodium amide, hexamethyldisilane base Lithamide, hexamethyldisilane base potassium amide, 1, 8-diazabicylo [5.4.0] 11 carbon-7-alkene (DBU), triethylene diamine (DABCO) or their mixture, preferred potassium tert.-butoxide, sodium tert-butoxide, trimethyl carbinol lithium, salt of wormwood, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide and composition thereof, the consumption of described basic cpd is 1-5 times of formula III compound mol ratio, and preferably 1-1.5 doubly.The consumption of formula VIII compound is 1-3 times of formula III compound mol ratio, and preferably 1-1.3 doubly; Reaction solvent is tetrahydrofuran (THF), 2-methyltetrahydrofuran, Isosorbide-5-Nitrae-dioxane, or dimethyl sulfoxide (DMSO); Temperature of reaction is-20～80 ℃, preferably-10～30 ℃.
In step 4), described metal catalyst is selected from Ni/C, Pd/C, or Pt/C class catalyzer, in wherein said Ni/C catalyzer, Ni content is 2-20%, preferably 5-10%, Ni/C consumption is the 5-50wt% of formula II compound, preferred 20-30%, temperature of reaction is 0～100 ℃, preferably 20-80 ℃, hydrogenation pressure is 0.1-25MPa, preferably 10-15MPa; Described Pd/C Palladium Content in Catalyst is 5-10%, and Pd/C usage quantity is the 10-50% of formula II compound, preferably 20-30%; Reaction solvent is selected from: C1-C4 alkyl alcohol is as methyl alcohol, ethanol, Virahol, butanols, or C1-C4 alkyl oxide is as ether, methyl tertiary butyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, methyl-phenoxide, and acetonitrile, benzene, toluene, dimethylbenzene.
Described Pd/C catalyzer can be used jointly with LiCl, and wherein LiCl consumption is the 5-50% of formula II compound molar weight, preferably 10-20%; Or described Pd/C catalyzer can use jointly with formiate, to avoid using hydrogen, wherein formate is potassium formiate or ammonium formiate, the consumption of formate be formula II compound mol ratio 4-10 doubly.
In step 4), described acid is organic acid or mineral acid, wherein organic carboxyl acid is as citric acid, oxalic acid, acetic acid, methylsulfonic acid, benzene methanesulfonic acid, trifluoromethanesulfonic acid, or tosic acid, mineral acid is as hydrogenchloride and solution, hydrogen bromide and solution thereof, sulfuric acid, or phosphoric acid, temperature of reaction is-10～60 ℃, preferably 20-30 ℃.
The present invention is usingd formula V and is synthesized suc as formula the anti-type ii diabetes medicine Empagliflozin shown in I as key intermediate, desired raw material and reagent price are relatively cheap, with low cost, operational path section, safety simple to operation, yield is good, and environmental pollution is simultaneously little, there are good economic benefits, suitable industrial production.
Embodiment
Below in conjunction with specific embodiment, technical scheme of the present invention is described in further detail, but described embodiment does not limit the scope of the invention.Should be noted that, following examples are only unrestricted in order to technical scheme of the present invention to be described, although the present invention is had been described in detail with reference to preferred embodiment, those of ordinary skill in the art is to be understood that, can modify or be equal to replacement the technical scheme of invention, and not departing from the spirit and scope of technical solution of the present invention, it all should be encompassed in claim scope of the present invention.
Synthesizing of the chloro-2-of the bromo-1-of example 14-(4-luorobenzyl) benzene (Va)
In 500mL there-necked flask, add (the bromo-2-chloro-phenyl-of 5-) (4-fluorophenyl) ketone (VIa, 31.3g, 100mmol) with methylene dichloride 190mL, under room temperature, after stirring and dissolving, be down to 0～5 ℃, slowly drip triethyl silicane (44.2g, 380mmol), control afterwards temperature and between 0～5 ℃, slowly drip boron trifluoride diethyl etherate (51.8g, 365mmol), rise again to 20～30 ℃ of reactions 4～6 hours, HPLC tracks to raw material residue <3%.In reaction flask, add 150mL saturated sodium bicarbonate aqueous solution, stir separatory 30 minutes.Organic phase is concentrated into without cut and flows out, and adds 230g deionized water, is stirred to solid and separates out, and filters.Solid dissolves with 110mL acetonitrile, drips 110mL2% aqueous sodium hydroxide solution, stirs, and system is filtered, and filter cake, with after little water washing, is dried, and obtains off-white color solid, i.e. the chloro-2-of the bromo-1-of compound 4-(4-luorobenzyl) benzene (Va) (25.1g, yield 84%).
MS(ESI)301.0(M+H
+，100%)
Synthesizing of the chloro-2-of example 21-(4-luorobenzyl)-4-iodobenzene (Vb)
In 500mL there-necked flask, add (the chloro-5-iodophenyl of 2-) (4-fluorophenyl) ketone (VIb, 36.1g, 100mmol) with acetonitrile 180mL, under room temperature, after stirring and dissolving, be down to 0～5 ℃, slowly drip triethyl silicane (44.2g, 380mmol), control afterwards and at 0～5 ℃ of temperature, slowly drip boron trifluoride diethyl etherate (51.8g, 365mmol), rise again to 20-30 ℃ of reaction 4-6 hour, HPLC tracks to raw material residue and is less than 3%.In reaction flask, add 150mL saturated sodium bicarbonate aqueous solution, stir separatory 30 minutes.Organic phase is concentrated into 95～110mL, adds 230g deionized water, is stirred to solid and separates out, and filters.The system drip washing (100mL) of acetonitrile/water for solid=1/3, dries, and obtains off-white color solid, i.e. the chloro-2-of compound 1-(4-luorobenzyl)-4-iodobenzene (Vb) (27.4g, yield 79%).
MS(ESI)347.0(M+H
+，100%)
Example 3 (2S, 3R, 4S, 5R, 6R)-3,4,5-tri-(benzyloxy)-6-(benzyloxymethyl)-2-(the chloro-3-of 4-(4-luorobenzyl) phenyl)-2-methoxyl group tetrahydrochysene-2H-pyrans (IVa) synthetic
Method 1): in there-necked flask, add the bromo-1-of 4-chloro-2-(4-luorobenzyl) benzene (Va, 3g, 10mmol) and 15mL THF; nitrogen protection borehole cooling, to-78 ℃, slowly drips the n-heptane solution (10mL, 10mmol) of n-Butyl Lithium; dropwise-78 ℃ of insulated and stirred 1 hour.At-78 ℃, drip (3R, 4S, 5R, 6R)-3,4, the THF solution of 5-tri-(benzyloxy)-6-(benzyloxymethyl) tetrahydrochysene-2H-pyran-2-one (10mmol, is dissolved in 6mL THF for VIIa, 5.4g), system is reacted 1 hour at-78 ℃.Add afterwards the methanol solution 20mL containing 1.5mL methylsulfonic acid, system is risen again to stirred overnight at room temperature.In system, add saturated sodium bicarbonate aqueous solution cancellation reaction, separatory, water extracts at twice by 50mL ethyl acetate, merge organic phase, use saturated common salt water washing, anhydrous sodium sulfate drying, concentrate to obtain yellow oil 5.4g, be compound (2S, 3R, 4S, 5R, 6R)-3,4,5-tri-(benzyloxy)-6-(benzyloxymethyl)-2-(the chloro-3-of 4-(4-luorobenzyl) phenyl)-2-methoxyl group tetrahydrochysene-2H-pyrans (IVa) (crude product yield 70%).
MS(ESI)773.3(M+H
+，100%)
Method 2): use the chloro-2-of 1-(4-luorobenzyl)-4-iodobenzene (Vb) as starting raw material, other operation stepss are with method 1), obtain dark oily matter 6g, be compound (2S, 3R, 4S, 5R, 6R)-3,4,5-tri-(benzyloxy)-6-(benzyloxymethyl)-2-(the chloro-3-of 4-(4-luorobenzyl) phenyl)-2-methoxyl group tetrahydrochysene-2H-pyrans (IVa) (crude product yield 77%).
MS(ESI)773.3(M+H
+，100%)
Synthesizing of example 4 ((2S, 3R, 4S, 5R, 6R)-2-(the chloro-3-of 4-(4-luorobenzyl) phenyl)-2-methoxyl group-6-((trimethylsiloxy group) methyl) tetrahydrochysene-2H-pyrans-3,4,5-, tri-bases) Trimethoxy silane (IVb)
Method 1): in the there-necked flask of nitrogen protection, add the chloro-2-of 1-(4-luorobenzyl)-4-iodobenzene (Vb; 6.9g; 20mmol) and 15mLTHF; control temperature between-20 to-10 ℃; the mixing solutions (10mL Grignard reagent dissolves in 0.85g Lithium chloride (anhydrous)) that drips sec.-propyl Grignard reagent and Lithium chloride (anhydrous), drips rear reaction system insulation reaction 1.5h at-20～-10 ℃.Slowly drip afterwards (3R, 4S, 5R, 6R)-3,4, the THF solution (VIIb of 5-tri-(trimethylsiloxy group)-6-((trimethylsiloxy group) methyl) tetrahydrochysene-2H-pyran-2-one, 9.3g, 20mmol, is dissolved in 15mLTHF), insulation reaction 0.5-1h at-10～-5 ℃.Aqueous citric acid solution 30mL to adding 10% in system, rises again to stirring at room 2h, separatory, and ethyl acetate 50mL extraction twice for water, merges organic phase, saturated common salt water washing, organic phase anhydrous sodium sulfate drying, concentrates and to obtain oily matter.In this oily matter, add 20mL dissolve with methanol, slowly add the HCl methanol solution 2mL of 1.25N under room temperature, system reaction is spent the night, and concentrated organic phase is also with three times with methylene dichloride 20mL * 3 are de-.Add afterwards 30mL methylene dichloride, system is cooled to 0～10 ℃, to system, add 12g(118mmol) triethylamine, and slowly drip TMSCl(12g, 111mmol), system, to room temperature reaction 2h, filters out white solid, filtrate is used saturated aqueous common salt washed twice, anhydrous sodium sulfate drying, concentrates to obtain dark oily matter 8.5g, i.e. compound ((2S, 3R, 4S, 5R, 6R)-2-(the chloro-3-of 4-(4-luorobenzyl) phenyl)-2-methoxyl group-6-((trimethylsiloxy group) methyl) tetrahydrochysene-2H-pyrans-3,4,5-, tri-bases) Trimethoxy silane (IVb) (crude product yield 61%).
MS(ESI)701.3(M+H
+，100%)
Method 2): use the bromo-1-of 4-chloro-2-(4-luorobenzyl) benzene (Va) as starting raw material, other operation stepss are with method 1), obtain dark oily matter 7.5g, be compound ((2S, 3R, 4S, 5R, 6R)-2-(the chloro-3-of 4-(4-luorobenzyl) phenyl)-2-methoxyl group-6-((trimethylsiloxy group) methyl) tetrahydrochysene-2H-pyrans-3,4,5-, tri-bases) Trimethoxy silane (IVb) (crude product yield 54%).
MS(ESI)701.3(M+H
+，100%)
Example 5 (2R, 3R, 4R, 5S, 6S)-3,4,5-tri-(benzyloxy)-2-(benzyloxymethyl)-6-(the chloro-3-of 4-(4-luorobenzyl) phenyl) tetrahydrochysene-2H-pyrans (IIIa) synthetic
In there-necked flask, add (2S, 3R, 4S, 5R, 6R)-3,4,5-tri-(benzyloxy)-6-(benzyloxymethyl)-2-(the chloro-3-of 4-(4-luorobenzyl) phenyl)-2-methoxyl group tetrahydrochysene-2H-pyrans crude product (IVa, 5g, 6.5mmol) and 20mL methylene dichloride, be cooled between-10～-5 ℃, to system, drip 4.5mL triethyl silicane, keep afterwards this temperature, drip 1.2mL boron trifluoride diethyl etherate.Reaction system is reacted 4h between-5～0 ℃.To system, add 5% sodium bicarbonate aqueous solution 30mL, stir separatory after 0.5h, water dichloromethane extraction, merge organic phase, use saturated common salt water washing, anhydrous sodium sulfate drying, filtering and concentrating obtains faint yellow oily matter 3.8g, be compound (2R, 3R, 4R, 5S, 6S)-3,4,5-tri-(benzyloxy)-2-(benzyloxymethyl)-6-(the chloro-3-of 4-(4-luorobenzyl) phenyl) tetrahydrochysene-2H-pyrans (IIIa) (yield 80%.）。
MS(ESI)743.3(M+H
+，100%)
Synthesizing of example 6 ((2S, 3S, 4R, 5R, 6R)-2-(the chloro-3-of 4-(4-luorobenzyl) phenyl)-6-((trimethylsiloxy group) methyl) tetrahydrochysene-2H-pyrans-3,4,5-, tri-bases) trimethicone (IIIb)
With ((2S, 3R, 4S, 5R, 6R)-2-(the chloro-3-of 4-(4-luorobenzyl) phenyl)-2-methoxyl group-6-((trimethylsiloxy group) methyl) tetrahydrochysene-2H-pyrans-3,4,5-, tri-bases) Trimethoxy silane (IVb) is starting raw material, the similar example 5 of synthetic operation, obtain yellow oil, i.e. compound ((2S, 3S, 4R, 5R, 6R)-2-(the chloro-3-of 4-(4-luorobenzyl) phenyl)-6-((trimethylsiloxy group) methyl) tetrahydrochysene-2H-pyrans-3,4,5-tri-bases) trimethicone (IIIb), yield 74%.
MS(ESI)671.3(M+H
+，100%)
Example 7 (2R, 3R, 4R, 5S, 6S)-3,4,5-tri-(benzyloxy)-2-(benzyloxymethyl)-6-(the chloro-3-of 4-(4-((S)-tetrahydrofuran (THF)-3-oxygen base) benzyl) phenyl) tetrahydrochysene-2H-pyrans (IIa) synthetic
In there-necked flask, add (2R, 3R, 4R, 5S, 6S)-3,4,5-tri-(benzyloxy)-2-(benzyloxymethyl)-6-(the chloro-3-of 4-(4-luorobenzyl) phenyl) tetrahydrochysene-2H-pyrans (IIIa, 7.4g, 10mmol) and 20mL THF, at 10～20 ℃, add (S)-3-hydroxyl tetrahydrofuran (VIII, 0.9g, 11mmol), at this temperature, continue to add solid potassium tert-butoxide (1.3g, 12mmol), system at room temperature stirs 1 hour.In system, add 20mL water, stir 15 minutes, separate organic phase, water is extracted with ethyl acetate three times, merges organic phase, concentrated rear column chromatography for separation (PE/EA=2/1), obtain off-white color solid 7.0g, be compound (2R, 3R, 4R, 5S, 6S)-3,4,5-tri-(benzyloxy)-2-(benzyloxymethyl)-6-(the chloro-3-of 4-(4-((S)-tetrahydrofuran (THF)-3-oxygen base) benzyl) phenyl) tetrahydrochysene-2H-pyrans (IIa) (yield 86%).
MS(ESI)811.3(M+H
+，100%)
Example 8 ((2S, 3S, 4R, 5R, 6R)-2-(the chloro-3-of 4-(4-((S)-tetrahydrofuran (THF)-3-oxygen base) benzyl) phenyl)-6-((trimethylsiloxy group) methyl) tetrahydrochysene-2H-pyrans-3,4,5-, tri-bases) trimethoxy siloxane (IIb) is synthetic
With ((2S, 3S, 4R, 5R, 6R)-2-(the chloro-3-of 4-(4-luorobenzyl) phenyl)-6-((trimethylsiloxy group) methyl) tetrahydrochysene-2H-pyrans-3,4,5-, tri-bases) trimethicone (IIIb) is starting raw material, the similar example 7 of synthetic operation, obtain white solid, i.e. compound ((2S, 3S, 4R, 5R, 6R)-2-(the chloro-3-of 4-(4-((S)-tetrahydrofuran (THF)-3-oxygen base) benzyl) phenyl)-6-((trimethylsiloxy group) methyl) tetrahydrochysene-2H-pyrans-3,4,5-tri-bases) trimethoxy siloxane (IIb), yield 80%.
MS(ESI)739.3(M+H
+，100%)
Example 9 (1S)-1, the chloro-3-[[4-[[(3S of 5-dehydration-1-C-[4-)-tetrahydrochysene-3-furyl] oxygen base] phenyl] methyl] phenyl]-D-Glucose alcohol (I) synthetic
Method 1): in autoclave, add (2R, 3R, 4R, 5S, 6S)-3,4, the methanol solution (methyl alcohol 20mL) of 5-tri-(benzyloxy)-2-(benzyloxymethyl)-6-(the chloro-3-of 4-(4-((S)-tetrahydrofuran (THF)-3-oxygen base) benzyl) phenyl) tetrahydrochysene-2H-pyrans (IIa, 5g, 6.2mmol), add 10%Pa/C(1.5g, 30%wt) and lithium chloride (0.5g, 10%wt), system is at 20～25 ℃, under 0.1-0.3MPa hydrogen pressure, react 24h, filtration system, concentrated rear column chromatography (DCM/EA=5/1), obtains white solid, be formula I compound (1.7g, yield 61%).
Method 2): in autoclave, add (2R, 3R, 4R, 5S, 6S)-3,4,5-tri-(benzyloxy)-2-(benzyloxymethyl)-6-(the chloro-3-of 4-(4-((S)-tetrahydrofuran (THF)-3-oxygen base) benzyl) phenyl) tetrahydrochysene-2H-pyrans (IIa, 5g, 6.2mmol) methanol solution (methyl alcohol 20mL), add 10%Ni/C(1.5g, 30%wt), system, at 40～50 ℃, is reacted 12h under 20～25MPa pressure, filters, column chromatography (DCM/EA=5/1) after concentrated, obtain white solid, i.e. formula I compound (2.5g, yield 89%).
Method 3): in there-necked flask, add (2R, 3R, 4R, 5S, 6S)-3,4, the tetrahydrofuran solution (tetrahydrofuran (THF) 20mL) of 5-tri-(benzyloxy)-2-(benzyloxymethyl)-6-(the chloro-3-of 4-(4-((S)-tetrahydrofuran (THF)-3-oxygen base) benzyl) phenyl) tetrahydrochysene-2H-pyrans (IIa, 5g, 6.2mmol), add 10%Pa/C(1.5g, 30%wt), add ammonium formiate (3.89g, 62mmol), system backflow 4h, cooled and filtered, column chromatography (DCM/EA=5/1) after filtrate is concentrated, obtains white solid, be formula I compound (2.0g, yield 71%).
MS(ESI)451.2(M+H
+，100%)
Example 10 (1S)-1, the chloro-3-[[4-[[(3S of 5-dehydration-1-C-[4-)-tetrahydrochysene-3-furyl] oxygen base] phenyl] methyl] phenyl]-D-Glucose alcohol (I) synthetic
In reaction flask, add ((2S, 3S, 4R, 5R, 6R)-2-(the chloro-3-of 4-(4-((S)-tetrahydrofuran (THF)-3-oxygen base) benzyl) phenyl)-6-((trimethylsiloxy group) methyl) tetrahydrochysene-2H-pyrans-3,4,5-tri-bases) trimethoxy siloxane (IIb, 7.4g, 10mmol) and 25mL ethanol, hierarchy of control temperature 10-20 ℃, to system, slowly drip 10% HCl ethanolic soln 5mL, system at room temperature stirs 2h, and phase system adds saturated sodium bicarbonate to adjust pH to 6.5～7.5, to system, add 20mL ethyl acetate, separatory.Water is extracted with ethyl acetate three times, merges organic phase, and concentrated rear column chromatography (DCM/EA=5/1), obtains white solid, i.e. formula I compound (3.6g, yield 85%).
MS(ESI)451.2(M+H
+，100%)
Claims (10)
1. as shown in the formula the chloro-2-of compound 4-replacement-1-(4-luorobenzyl) benzene shown in V,
Wherein, X is bromine or iodine.
2. the preparation method of formula V compound claimed in claim 1, is characterized in that, comprises the following steps: the formula VI compound of take is starting raw material, carbonyl reduction preparation formula V compound under reductive agent effect; Reaction formula is as follows:
Wherein, described reductive agent is selected from: 1) silane of C1-C3 is as triethyl silicane, trimethyl silane, three n-propyl silane, or tri isopropyl silane; 2) hydroborate is as sodium borohydride, POTASSIUM BOROHYDRIDE, or borine; Or 3) alanate is as lithium aluminum hydride; Above system is reduced under lewis acidic existence, and described Lewis acid is selected from: boron trifluoride diethyl etherate, three perfluorophenyl borines, trifluoroacetic acid, hydrogenchloride and solution, hydrogen bromide and solution thereof, aluminum chloride, or Indium-111 chloride; Described reaction is carried out in aprotic solvent, and aprotic solvent is selected from: methylene dichloride, 1,2-ethylene dichloride, benzene,toluene,xylene, acetonitrile, tetrahydrofuran (THF), normal hexane, sherwood oil, normal heptane, or any two or more mixed solvent wherein; Temperature of reaction is-20～130 ℃.
3. suc as formula a preparation method for the anti-type ii diabetes medicine described in I, it is characterized in that, the formula V compound of usining synthesizes as key intermediate, specifically comprises the following steps:
1) formula V compound and formula VII compound carry out addition reaction by basic metal reagent, obtain formula IV compound subsequently in C1-C3 alcoholic solution through acid catalysis;
2) formula IV compound is reduced to obtain formula III compound under the effect of reductive agent and acid additives;
3) formula III compound reacts to obtain formula II compound with formula VIII compound under basic cpd effect;
4) formula II compound Deprotection under the effect of metal catalyst obtains formula I compound, or formula II compound Deprotection under acid effect obtains formula I compound; Reaction formula is as follows:
Wherein X is bromine or iodine, and R1 is C1-C6 silylation protecting group or benzyl class protecting group, and R2 is C1-C3 alkyl.
4. method according to claim 3, is characterized in that, described C1-C6 silylation protecting group as: trimethyl silicon based, triethyl is silica-based, triisopropylsilyl, or t-Butyldimethylsilyl; Described benzyl class protecting group is as trityl Trity, benzyl Bn, 4-methoxy-benzyl PMB, 4-methyl-benzyl, 4-nitrobenzyl, 2,4-dimethoxy-benzyl DMB, carbobenzoxy-(Cbz) Cbz, 4-methoxyl group benzyloxy carbonyl, or 4-methyl carbobenzoxy-(Cbz); Described C1-C3 alkyl is as methyl, ethyl, n-propyl, or sec.-propyl.
5. method according to claim 3, it is characterized in that, in step 1), described basic metal reagent is selected from: a) alkyl lithium reagents is as n-Butyl Lithium, s-butyl lithium, tert-butyl lithium, b) Grignard reagent is as sec.-propyl Grignard reagent, or c) mixed system of normal-butyl Grignard reagent and lithium chloride; Described addition reaction is carried out in organic solvent, organic solvent is selected from: C2-C8 ether or its inertia aromatic solvents, wherein C2-C8 ether is as tetrahydrofuran (THF), dioxane, ether, methyl tertiary butyl ether, or methyl-phenoxide, and aromatic solvents is as benzene,toluene,xylene or their mixed solution; Temperature of reaction is-90～140 ℃; Described C1-C3 alcoholic solution is methyl alcohol, ethanol, n-propyl alcohol, or Virahol; Described acid catalyst is as: methylsulfonic acid, benzene methanesulfonic acid, to methylbenzene methylsulfonic acid, trifluoromethanesulfonic acid, or hydrogenchloride and solution thereof.
6. method according to claim 3, is characterized in that step 2) in, described reductive agent is selected from: a) silane of C1-C3 is as triethyl silicane, trimethyl silane, three n-propyl silane, or tri isopropyl silane; B) hydroborate is as sodium borohydride, POTASSIUM BOROHYDRIDE, or borine; Or c) alanate is as lithium aluminum hydride; Described acid additives is as boron trifluoride diethyl etherate, three perfluorophenyl borines, trifluoroacetic acid, hydrogenchloride and solution, hydrogen bromide and solution thereof, aluminum chloride, or Indium-111 chloride; Described reaction is carried out in aprotic solvent, and aprotic solvent is selected from: methylene dichloride, 1,2-ethylene dichloride, benzene,toluene,xylene, acetonitrile, tetrahydrofuran (THF), normal hexane, sherwood oil, normal heptane, or any two or more mixed solvent wherein; Temperature of reaction is-20～130 ℃.
7. method according to claim 3, it is characterized in that, in step 3), described basic cpd is selected from: potassium tert.-butoxide, sodium tert-butoxide, trimethyl carbinol lithium, sodium methylate, potassium methylate, sodium ethylate, potassium ethylate, salt of wormwood, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, triethylamine, diisopropyl ethyl amine, hexamethyldisilane base sodium amide, hexamethyldisilane base Lithamide, hexamethyldisilane base potassium amide, 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene (DBU), triethylene diamine (DABCO), or their mixture; The consumption of described basic cpd is 1-5 times of formula III compound mol ratio; The consumption of formula VIII compound is 1-3 times of formula III compound mol ratio; Reaction solvent is tetrahydrofuran (THF), 2-methyltetrahydrofuran, Isosorbide-5-Nitrae-dioxane, or dimethyl sulfoxide (DMSO); Temperature of reaction is-20～80 ℃.
8. method according to claim 3, is characterized in that, in step 4), described metal catalyst is selected from Ni/C, Pd/C, or Pt/C class catalyzer; In wherein said Ni/C catalyzer, Ni content is 2-20wt%, and Ni/C consumption is the 5-50wt% of formula II compound, and temperature of reaction is 0～100 ℃, and hydrogenation pressure is 0.1-25MPa; Described Pd/C Palladium Content in Catalyst is 5-10wt%, and Pd/C usage quantity is the 10-50wt% of formula II compound; Reaction solvent is selected from: methyl alcohol, ethanol, Virahol, butanols, ether, methyl tertiary butyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, methyl-phenoxide, acetonitrile, benzene, toluene, or dimethylbenzene.
9. method according to claim 3, is characterized in that, in step 4), described Pd/C catalyzer can be used jointly with LiCl, and wherein LiCl consumption is the 5-50% of formula II compound molar weight; Or described Pd/C catalyzer can use jointly with formiate, to avoid using hydrogen, wherein formate is potassium formiate or ammonium formiate, the consumption of formate be formula II compound mol ratio 4-10 doubly.
10. method according to claim 3, it is characterized in that, in step 4), described acid is organic acid or mineral acid, wherein organic carboxyl acid is as citric acid, oxalic acid, acetic acid, methylsulfonic acid, benzene methanesulfonic acid, trifluoromethanesulfonic acid, or tosic acid, and mineral acid is as hydrogenchloride and solution, hydrogen bromide and solution thereof, sulfuric acid, or phosphoric acid, temperature of reaction is-10～60 ℃.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104877136A (en) * | 2015-04-30 | 2015-09-02 | 大连理工大学 | Long-branched-chain polysulfone anionic membrane and preparation method thereof |
| CN106117192A (en) * | 2016-06-23 | 2016-11-16 | 甘肃成纪生物药业有限公司 | The synthetic method that a kind of En Gelie is clean |
| CN106336403A (en) * | 2015-07-14 | 2017-01-18 | 江苏豪森药业集团有限公司 | Industrial preparation method for empagliflozin |
| CN106674080A (en) * | 2015-11-10 | 2017-05-17 | 南京卡文迪许生物工程技术有限公司 | Synthesis method of panobinostat |
| CN108752170A (en) * | 2018-07-20 | 2018-11-06 | 中山大学 | A method of catalysis benzalcohol derivatives etherificate |
| CN111410639A (en) * | 2020-04-14 | 2020-07-14 | 天津法莫西医药科技有限公司 | Preparation method of empagliflozin intermediate impurity |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1930141A (en) * | 2004-03-16 | 2007-03-14 | 贝林格尔·英格海姆国际有限公司 | Glucopyranosyl-substituted benzol derivatives, drugs containing said compounds, the use thereof and method for the production thereof |
| CN101193903A (en) * | 2005-05-10 | 2008-06-04 | 贝林格尔.英格海姆国际有限公司 | Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives and intermediates therein |
| WO2010023594A1 (en) * | 2008-08-28 | 2010-03-04 | Pfizer Inc. | Dioxa-bicyclo[3.2.1.]octane-2,3,4-triol derivatives |
-
2013
- 2013-03-14 CN CN201310080816.5A patent/CN104045513A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1930141A (en) * | 2004-03-16 | 2007-03-14 | 贝林格尔·英格海姆国际有限公司 | Glucopyranosyl-substituted benzol derivatives, drugs containing said compounds, the use thereof and method for the production thereof |
| CN101193903A (en) * | 2005-05-10 | 2008-06-04 | 贝林格尔.英格海姆国际有限公司 | Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives and intermediates therein |
| WO2010023594A1 (en) * | 2008-08-28 | 2010-03-04 | Pfizer Inc. | Dioxa-bicyclo[3.2.1.]octane-2,3,4-triol derivatives |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104877136A (en) * | 2015-04-30 | 2015-09-02 | 大连理工大学 | Long-branched-chain polysulfone anionic membrane and preparation method thereof |
| CN104877136B (en) * | 2015-04-30 | 2017-08-01 | 大连理工大学 | A kind of long-chain branch polysulfones anionic membrane and preparation method thereof |
| CN106336403A (en) * | 2015-07-14 | 2017-01-18 | 江苏豪森药业集团有限公司 | Industrial preparation method for empagliflozin |
| CN106674080A (en) * | 2015-11-10 | 2017-05-17 | 南京卡文迪许生物工程技术有限公司 | Synthesis method of panobinostat |
| CN106117192A (en) * | 2016-06-23 | 2016-11-16 | 甘肃成纪生物药业有限公司 | The synthetic method that a kind of En Gelie is clean |
| CN106117192B (en) * | 2016-06-23 | 2018-11-23 | 甘肃成纪生物药业有限公司 | A kind of synthetic method that En Gelie is net |
| CN108752170A (en) * | 2018-07-20 | 2018-11-06 | 中山大学 | A method of catalysis benzalcohol derivatives etherificate |
| CN111410639A (en) * | 2020-04-14 | 2020-07-14 | 天津法莫西医药科技有限公司 | Preparation method of empagliflozin intermediate impurity |
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