CN103936800A - Preparation method of 1-(1-methoxy pyran glucosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene - Google Patents
Preparation method of 1-(1-methoxy pyran glucosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene Download PDFInfo
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- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 title claims abstract description 48
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 104
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims abstract description 42
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 33
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims abstract description 26
- 229930192474 thiophene Natural products 0.000 claims abstract description 21
- 238000003756 stirring Methods 0.000 claims abstract description 20
- 239000012044 organic layer Substances 0.000 claims abstract description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 17
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000010438 heat treatment Methods 0.000 claims abstract description 9
- 238000005406 washing Methods 0.000 claims abstract description 9
- 238000001816 cooling Methods 0.000 claims abstract description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000000243 solution Substances 0.000 claims description 35
- -1 bromo-2-methyl-benzyl Chemical group 0.000 claims description 24
- 239000002253 acid Substances 0.000 claims description 23
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 12
- 150000002596 lactones Chemical class 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 8
- 239000002994 raw material Substances 0.000 claims description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 8
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 5
- 235000019253 formic acid Nutrition 0.000 claims description 5
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 claims description 4
- 239000012670 alkaline solution Substances 0.000 claims description 4
- 239000007789 gas Substances 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 abstract description 7
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 238000000034 method Methods 0.000 abstract description 6
- 230000001738 genotoxic effect Effects 0.000 abstract description 4
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- 235000002639 sodium chloride Nutrition 0.000 description 6
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- 229910001220 stainless steel Inorganic materials 0.000 description 6
- 239000010935 stainless steel Substances 0.000 description 6
- 238000010792 warming Methods 0.000 description 6
- 235000009508 confectionery Nutrition 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- 231100000025 genetic toxicology Toxicity 0.000 description 3
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
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- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- DWNZWHKHMKQWFS-UHFFFAOYSA-N 7-methoxy-9h-pyrido[3,4-b]indole-1-carboxylic acid Chemical compound N1=CC=C2C3=CC=C(OC)C=C3NC2=C1C(O)=O DWNZWHKHMKQWFS-UHFFFAOYSA-N 0.000 description 1
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- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of 1-(1-methoxy pyran glucosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene. The method comprises the steps of adding tetrahydrofuran, toluene and 2-(5-bromine-2-methyl benzyl)-5-(4-fluorophenyl) thiophene in a reaction kettle, protecting by using N2 gas, cooling, and dropping a n-butyllithium solution; then dropping a toluene solution of 2,3,4,6-tetra-O-trimethylsilyl-D-glucolactone; finally, dropping an acidic methanol solution; adjusting the pH value to be 7-8, adding toluene, stirring, standing, collecting an organic layer, firstly washing the organic layer by using saturated salt water, and then concentrating and drying to obtain remainders; adding toluene into the remainders, heating and dissolving, cooling, then slowly adding n-hexane, stirring, filtering, and drying to obtain a product. The process disclosed by the invention is simple; genotoxic impurities can not be generated in a production process, so that side effects to a human body can be avoided.
Description
Technical field
The present invention relates to the preparation method of the clean key intermediate of Ka Gelie, relate to particularly a kind of 1-(1-methoxyl group glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] preparation method of benzene.
Background technology
Ka Gelie is the first SGLT2 inhibitor of FDA approval only, is used for the treatment of the type ii diabetes of adult patients.As Synthesis Card lattice, be listed as 1-(1-methoxyl group glucopyranosyl)-4-methyl-3-[5-(4-the fluorophenyl)-2-thienyl methyl of clean key intermediate] benzene, (notification number is CN101573368B to patent document, the day for announcing is on 06 20th, 2012) a kind of crystal type 1-(Β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl disclosed] benzene semihydrate and preparation method thereof, the methylsulfonic acid of using in this preparation method's reaction process can produce by product methylsulfonic acid alkyl ester, and methylsulfonic acid alkyl methyl esters is a kind of single function alkylating agent, can cause DNA damage, also be a kind of known carcinogenic substance.Methylsulfonic acid alkyl methyl esters mainly makes O, the N on DNA purine bases methylate, and causes DNA double splitting of chain, point mutation, can be at N
7the sweet acid of one deoxidation bird and N
3on the one sweet sour position of deoxidation gland, make DNA methylation.Although N
7the sweet acid adduct of one deoxidation bird may be non-toxicity and non-mutagenicity, but N
3the sweet acid of one deoxidation gland is but to suppress the synthetic fatal damage of DNA and need active reparation.The MMS genotoxicity impurity producing in building-up process, as the clean key intermediate of Ka Gelie, methylsulfonic acid alkyl methyl esters has increased the risk of drug administration to harm, and methylsulfonic acid has strong impulse to mucous membrane, the upper respiratory tract, eye and skin, after suction, can be because of larynx and bronchial spasm, inflammation, oedema, chemical pneumonitis or pulmonary edema and lethal, after contact, there is burning sensation, cough, pant, laryngitis, breathe hard, headache, nausea and vomiting, can cause and burn, the difficulty that has increased production operation process, has reduced safety coefficient.
Summary of the invention
The object of the present invention is to provide that a kind of preparation technology is safe and simple, can not produce 1-(1-methoxyl group glucopyranosyl)-4-methyl-3-[5-(4-the fluorophenyl)-2-thienyl methyl of the clean key intermediate of Ka Gelie of genotoxicity impurity in building-up process] preparation method of benzene.
Object of the present invention is achieved through the following technical solutions, a kind of 1-(1-methoxyl group glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] preparation method of benzene, comprise the following steps:
Step (1) adds tetrahydrofuran (THF), toluene and 2-(the bromo-2-methyl-benzyl of 5-)-5-(4-fluorophenyl) thiophene, N in reactor
2gas protection, is cooled to-60～-70 ℃, drips n-butyllithium solution, dropwises reaction 0.5～1.5 hour;
Step (2) is controlled the interior temperature of reactor under the condition of-60～-70 ℃, drip 2,3,4,6-, tetra--O-trimethyl silicon based-toluene solution of D-Glucose acid lactone, dropwise reaction 1～3 hour;
Step (3) finally drips sour methanol solution, after dropwising, reacts complete to raw material reaction, stopped reaction;
It is 7～8 that step (4) is adjusted pH with alkaline solution, adds toluene to stir, standing, layering, and collected organic layer, organic layer is first used saturated common salt water washing, then through concentrated, dry, obtain residuum;
Step (5) adds toluene heating for dissolving in described residuum, cooling, then slowly adds normal hexane, normal hexane to dropwise rear stirring 20～60 minutes, filters, and 20～40 ℃ dry, obtains target product.
Preferably, the mol ratio of described 2-(the bromo-2-methyl-benzyl of 5-)-5-(4-fluorophenyl) thiophene and described n-Butyl Lithium is 1:(1 ~ 3); Preferred, the mol ratio of 2-(the bromo-2-methyl-benzyl of 5-)-5-(4-fluorophenyl) thiophene and described n-Butyl Lithium is 1:(1 ~ 2).
Preferably, described 2-(the bromo-2-methyl-benzyl of 5-)-5-(4-fluorophenyl) thiophene and described 2,3,4,6-tetra--O-is trimethyl silicon based-mol ratio of D-Glucose acid lactone is 1:(1 ~ 2); Preferred, described 2-(the bromo-2-methyl-benzyl of 5-)-5-(4-fluorophenyl) thiophene and described 2,3,4,6-tetra--O-is trimethyl silicon based-mol ratio of D-Glucose acid lactone is 1:(1 ~ 1.5).
Preferably, in step (3), the acid in the methanol solution of described acid is selected from least one in hydrochloric acid, formic acid, acetic acid.
Preferably, the mol ratio of described 2-(the bromo-2-methyl-benzyl of 5-)-5-(4-fluorophenyl) thiophene and described acid is 1:(1 ~ 5); Preferred, the mol ratio of described 2-(the bromo-2-methyl-benzyl of 5-)-5-(4-fluorophenyl) thiophene and described acid is 1:(1 ~ 4).
Preferably, in step (4), described alkaline solution is sodium hydrogen carbonate solution.
Preferably, in step (1), dropwise reaction 1 hour; In step (2), dropwise reaction 2 hours; In step (5), the time of described stirring is 30 minutes, and described dry temperature is 30 ℃.
Compared with prior art, beneficial effect of the present invention is as follows: preparation method provided by the invention adopts hydrochloric acid, formic acid, at least one in acetic acid replaces methylsulfonic acid of the prior art, make production process easy, reduced the risk of production operation process, improved production safety coefficient, for 1-(1-methoxyl group glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] large-scale industrialization of benzene produces and lays a good foundation, in what is more important production process, can not produce genotoxicity impurity, for taking the type ii diabetes patient of the clean medicine of Ka Gelie, evaded relevant drug risk.
Embodiment
Below in conjunction with specific embodiment, the present invention is described in detail.Following examples will contribute to those skilled in the art further to understand the present invention, but not limit in any form the present invention.It should be pointed out that to those skilled in the art, without departing from the inventive concept of the premise, can also make some distortion and improvement.These all belong to protection scope of the present invention.
Embodiment 1
The present embodiment relates to a kind of 1-(1-methoxyl group glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene, comprise the following steps:
In stainless steel cauldron, add tetrahydrofuran (THF) 35mL, toluene 30mL and 2-(the bromo-2-methyl-benzyl of 5-)-5-(4-fluorophenyl) thiophene 5.8g, N
2protection, is cooled to-60 ℃, drips n-Butyl Lithium 6.5mL, dropwises, and reacts 1 hour; In controlling, temperature is at-70 ℃, drip 2,3,4,6-, tetra--O-trimethyl silicon based-the toluene 5mL solution of D-Glucose acid lactone solution 7.5g, dropwise, react 2 hours; The methyl alcohol 4.5mL solution that drips hydrochloric acid 0.6g, dropwises, and is naturally warming up to 15 ± 5 ℃ of reactions and stops after middle control detection raw material reaction is complete; With sodium hydrogen carbonate solution, adjusting pH is 7, adds toluene 30mL stirring, standing, layering organic layer, and saturated aqueous common salt 30mL washing for organic layer, dry, concentrated, obtain residuum; In residuum, add toluene 15mL heating for dissolving, slowly splash in the normal hexane 70mL of-5～5 ℃, dropwise, stir 30 minutes, filter, 40 ℃ dry, obtains target product.
Embodiment 2
The present embodiment relates to a kind of 1-(1-methoxyl group glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene, comprise the following steps:
In stainless steel cauldron, add tetrahydrofuran (THF) 45mL, toluene 40mL and 2-(the bromo-2-methyl-benzyl of 5-)-5-(4-fluorophenyl) thiophene 5.8g, N
2protection, is cooled to-65 ℃, drips n-Butyl Lithium 9.65mL, dropwises, and reacts 1.5 hours; In controlling, temperature is at-60 ℃, drip 2,3,4,6-, tetra--O-trimethyl silicon based-the toluene 5mL solution of D-Glucose acid lactone solution 10.5g, dropwise, react 3 hours; The methyl alcohol 9mL solution that drips hydrochloric acid 1.46g, dropwises, and is naturally warming up to 15 ± 5 ℃ of reactions and stops after middle control detection raw material reaction is complete; With sodium hydrogen carbonate solution, adjusting pH is 7.5, adds toluene 50mL stirring, standing, layering organic layer, and saturated aqueous common salt 35mL washing for organic layer, dry, concentrated, obtain residuum; In residuum, add toluene 15mL heating for dissolving, slowly splash in the normal hexane 90mL of-5～5 ℃, dropwise, stir 60 minutes, filter, 20 ℃ dry, obtains target product.
Embodiment 3
The present embodiment relates to a kind of 1-(1-methoxyl group glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene, comprise the following steps:
In stainless steel cauldron, add tetrahydrofuran (THF) 50mL, toluene 40mL and 2-(the bromo-2-methyl-benzyl of 5-)-5-(4-fluorophenyl) thiophene 5.8g, N
2protection, is cooled to-65 ℃, drips n-Butyl Lithium 13mL, dropwises, and reacts 0.5 hour; In controlling, temperature is at-65 ℃, drip 2,3,4,6-, tetra--O-trimethyl silicon based-the toluene 5mL solution of D-Glucose acid lactone solution 11.2g, dropwise, react 1 hour; The methyl alcohol 10mL solution that drips formic acid 1.5g, dropwises, and is naturally warming up to 15 ± 5 ℃ of reactions and stops after middle control detection raw material reaction is complete; With sodium hydrogen carbonate solution, adjusting pH is 8, adds toluene 50mL stirring, standing, layering organic layer, and saturated aqueous common salt 35mL washing for organic layer, dry, concentrated, obtain residuum; In residuum, add toluene 15mL heating for dissolving, slowly splash in the normal hexane 90mL of-5～5 ℃, dropwise, stir 20 minutes, filter, 30 ℃ dry, obtains target product.
Embodiment 4
The present embodiment relates to a kind of 1-(1-methoxyl group glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene, comprise the following steps:
In stainless steel cauldron, add tetrahydrofuran (THF) 40mL, toluene 40mL and 2-(the bromo-2-methyl-benzyl of 5-)-5-(4-fluorophenyl) thiophene 5.8g, N2 protection, is cooled to-70 ℃ and drips n-Butyl Lithium 9mL, dropwises, and reacts 1 hour; In controlling, temperature is at-70 ℃, drip 2,3,4,6-, tetra--O-trimethyl silicon based-the toluene 5mL solution of D-Glucose acid lactone solution 11.2g, dropwise, react 2 hours; The methyl alcohol 20mL solution that drips formic acid 3.0g, dropwises, and is naturally warming up to 15 ± 5 ℃ of reactions and stops after middle control detection raw material reaction is complete; With sodium hydrogen carbonate solution, adjusting pH is 7, adds toluene 50mL stirring, standing, layering organic layer, and saturated aqueous common salt 35mL washing for organic layer, dry, concentrated, obtain residuum; In residuum, add toluene 15mL heating for dissolving, slowly splash in the normal hexane 90mL of-5～5 ℃, dropwise, stir 30 minutes, filter, 40 ℃ dry, obtains target product.
Embodiment 5
The present embodiment relates to a kind of 1-(1-methoxyl group glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene, comprise the following steps:
In stainless steel cauldron, add tetrahydrofuran (THF) 40mL, toluene 40mL and 2-(the bromo-2-methyl-benzyl of 5-)-5-(4-fluorophenyl) thiophene 5.8g, N
2protection, is cooled to-60 ℃, drips n-Butyl Lithium 9mL, dropwises, and reacts 1.5 hours; In controlling, temperature is at-60 ℃, drip 2,3,4,6-, tetra--O-trimethyl silicon based-the toluene 5mL solution of D-Glucose acid lactone solution 11.2g, dropwise, react 3 hours; The methyl alcohol 8mL solution that drips acetic acid 1.0g, dropwises, and is naturally warming up to 15 ± 5 ℃ of reactions and stops after middle control detection raw material reaction is complete; With sodium hydrogen carbonate solution, adjusting pH is 7.5, adds toluene 50mL stirring, standing, layering organic layer, and saturated aqueous common salt 35mL washing for organic layer, dry, concentrated, obtain residuum; In residuum, add toluene 15mL heating for dissolving, slowly splash in the normal hexane 90mL of-5～5 ℃, dropwise, stir 60 minutes, filter, 20 ℃ dry, obtains target product.
Embodiment 6
The present embodiment relates to a kind of 1-(1-methoxyl group glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene, comprise the following steps:
In stainless steel cauldron, add tetrahydrofuran (THF) 45mL, toluene 40mL and 2-(the bromo-2-methyl-benzyl of 5-)-5-(4-fluorophenyl) thiophene 5.8g, N
2protection, cooling, to-65 ℃, n-Butyl Lithium 9.65mL, dropwises, and reacts 0.5 hour; In controlling, temperature is at-65 ℃, drip 2,3,4,6-, tetra--O-trimethyl silicon based-the toluene 5mL solution of D-Glucose acid lactone solution 10.5g, dropwise, react the methyl alcohol 9mL solution of dropping acetic acid 3.8g 1 hour; Dropwise, be naturally warming up to 15 ± 5 ℃ of reactions and stop after middle control detection raw material reaction is complete; With sodium hydrogen carbonate solution, adjusting pH is 8, adds toluene 50mL stirring, standing, layering organic layer, and saturated aqueous common salt 35mL washing for organic layer, dry, concentrated, obtain residuum; In residuum, add toluene 15mL heating for dissolving, slowly splash in the normal hexane 90mL of-5～5 ℃, dropwise, stir 20 minutes, filter, 30 ℃ dry, obtains target product.
Above specific embodiments of the invention are described.It will be appreciated that, the present invention is not limited to above-mentioned specific implementations, and those skilled in the art can make various distortion or modification within the scope of the claims, and this does not affect flesh and blood of the present invention.
Claims (10)
1. 1-(1-methoxyl group glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] preparation method of benzene, it is characterized in that, comprise the following steps:
Step (1) adds tetrahydrofuran (THF), toluene and 2-(the bromo-2-methyl-benzyl of 5-)-5-(4-fluorophenyl) thiophene, N in reactor
2gas protection, is cooled to-60～-70 ℃, drips n-butyllithium solution, dropwises reaction 0.5～1.5 hour;
Step (2) is controlled the interior temperature of reactor under the condition of-60～-70 ℃, drip 2,3,4,6-, tetra--O-trimethyl silicon based-toluene solution of D-Glucose acid lactone, dropwise reaction 1～3 hour;
Step (3) finally drips sour methanol solution, after dropwising, reacts complete to raw material reaction, stopped reaction;
It is 7～8 that step (4) is adjusted pH with alkaline solution, adds toluene to stir, standing, layering, and collected organic layer, organic layer is first used saturated common salt water washing, then through concentrated, dry, obtain residuum;
Step (5) adds toluene heating for dissolving in described residuum, cooling, then slowly adds normal hexane, normal hexane to dropwise rear stirring 20～60 minutes, filters, and 20～40 ℃ dry, obtains target product.
2. preparation method according to claim 1, is characterized in that, the mol ratio of described 2-(the bromo-2-methyl-benzyl of 5-)-5-(4-fluorophenyl) thiophene and described n-Butyl Lithium is 1:(1 ~ 3).
3. preparation method according to claim 2, is characterized in that, the mol ratio of described 2-(the bromo-2-methyl-benzyl of 5-)-5-(4-fluorophenyl) thiophene and described n-Butyl Lithium is 1:(1 ~ 2).
4. preparation method according to claim 1, is characterized in that, described 2-(the bromo-2-methyl-benzyl of 5-)-5-(4-fluorophenyl) thiophene and described 2,3,4, and 6-tetra--O-is trimethyl silicon based-mol ratio of D-Glucose acid lactone is 1:(1 ~ 2).
5. preparation method according to claim 4, is characterized in that, described 2-(the bromo-2-methyl-benzyl of 5-)-5-(4-fluorophenyl) thiophene and described 2,3,4, and 6-tetra--O-is trimethyl silicon based-mol ratio of D-Glucose acid lactone is 1:(1 ~ 1.5).
6. preparation method according to claim 1, is characterized in that, in step (3), the acid in the methanol solution of described acid is selected from least one in hydrochloric acid, formic acid, acetic acid.
7. preparation method according to claim 1, is characterized in that, the mol ratio of described 2-(the bromo-2-methyl-benzyl of 5-)-5-(4-fluorophenyl) thiophene and described acid is 1:(1 ~ 5).
8. preparation method according to claim 7, is characterized in that, the mol ratio of described 2-(the bromo-2-methyl-benzyl of 5-)-5-(4-fluorophenyl) thiophene and described acid is 1:(1 ~ 4).
9. preparation method according to claim 1, is characterized in that, in step (4), described alkaline solution is sodium hydrogen carbonate solution.
10. preparation method according to claim 1, is characterized in that, in step (1), dropwises reaction 1 hour; In step (2), dropwise reaction 2 hours; In step (5), the time of described stirring is 30 minutes, and described dry temperature is 30 ℃.
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|---|---|---|---|
| CN201410192271.1A CN103936800A (en) | 2014-05-08 | 2014-05-08 | Preparation method of 1-(1-methoxy pyran glucosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene |
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|---|---|---|---|
| CN201410192271.1A CN103936800A (en) | 2014-05-08 | 2014-05-08 | Preparation method of 1-(1-methoxy pyran glucosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2017071813A1 (en) * | 2015-10-30 | 2017-05-04 | Zaklady Farmaceutyczne Polpharma Sa | Process for the preparation of a pharmaceutical agent |
| CN107540706A (en) * | 2016-06-28 | 2018-01-05 | 山东诚创医药技术开发有限公司 | The preparation method of ipragliflozin intermediate |
| CN110141566A (en) * | 2018-02-11 | 2019-08-20 | 清华大学深圳研究生院 | Application of the SGLT2 inhibitor in regulation inflammation |
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| CN1829729A (en) * | 2003-08-01 | 2006-09-06 | 田边制药株式会社 | Novel compounds |
| CN101573368A (en) * | 2006-12-04 | 2009-11-04 | 田边三菱制药株式会社 | Crystalline form of 1- (beta-D-glucopyranosyl) -4-methyl-3- [ 5- (4-fluorophenyl) -2-thienylmethyl ] benzene hemihydrate |
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| CN1829729A (en) * | 2003-08-01 | 2006-09-06 | 田边制药株式会社 | Novel compounds |
| CN101573368A (en) * | 2006-12-04 | 2009-11-04 | 田边三菱制药株式会社 | Crystalline form of 1- (beta-D-glucopyranosyl) -4-methyl-3- [ 5- (4-fluorophenyl) -2-thienylmethyl ] benzene hemihydrate |
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| SUMIHIRO NOMURA，ET AL.: ""Discovery of Canagliflozin, a Novel C-Glucoside with Thiophene Ring, as Sodium-Dependent Glucose Cotransporter 2 Inhibitor for the Treatment of Type 2 Diabetes Mellitus"", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
| SUMIHIRO NOMURA，ET AL.: ""Discovery of Canagliflozin, a Novel C-Glucoside with Thiophene Ring, as Sodium-Dependent Glucose Cotransporter 2 Inhibitor for the Treatment of Type 2 Diabetes Mellitus"", 《JOURNAL OF MEDICINAL CHEMISTRY》, vol. 53, no. 17, 6 August 2010 (2010-08-06), pages 6355 - 6360, XP007915324, DOI: doi:10.1021/jm100332n * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017071813A1 (en) * | 2015-10-30 | 2017-05-04 | Zaklady Farmaceutyczne Polpharma Sa | Process for the preparation of a pharmaceutical agent |
| CN107540706A (en) * | 2016-06-28 | 2018-01-05 | 山东诚创医药技术开发有限公司 | The preparation method of ipragliflozin intermediate |
| CN110141566A (en) * | 2018-02-11 | 2019-08-20 | 清华大学深圳研究生院 | Application of the SGLT2 inhibitor in regulation inflammation |
| CN110141566B (en) * | 2018-02-11 | 2022-04-19 | 清华大学深圳研究生院 | Application of SGLT2inhibitor in regulation and control of inflammation |
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