CN105440025A - Preparation methods for canagliflozin and intermediate thereof and intermediate - Google Patents
Preparation methods for canagliflozin and intermediate thereof and intermediate Download PDFInfo
- Publication number
- CN105440025A CN105440025A CN201410499537.7A CN201410499537A CN105440025A CN 105440025 A CN105440025 A CN 105440025A CN 201410499537 A CN201410499537 A CN 201410499537A CN 105440025 A CN105440025 A CN 105440025A
- Authority
- CN
- China
- Prior art keywords
- formula
- structural compounds
- benzyl
- methyl
- gelie
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 0 Cc1ccc(C([C@@]([C@]2OCc3ccccc3)OCc3ccccc3)(O)O[C@](C*)[C@@]2OCc2ccccc2)cc1Cc1ccc(-c(cc2)ccc2F)[s]1 Chemical compound Cc1ccc(C([C@@]([C@]2OCc3ccccc3)OCc3ccccc3)(O)O[C@](C*)[C@@]2OCc2ccccc2)cc1Cc1ccc(-c(cc2)ccc2F)[s]1 0.000 description 2
Abstract
The invention belongs to the field of medicine, and particularly relates to preparation methods for canagliflozin and an intermediate thereof and the intermediate. The preparation method for canagliflozin comprises the following steps: a compound having the structure represented by the formula (I) is subjected to a debenzylation reaction to obtain canagliflozin. The preparation methods provided by the invention have simple reaction route, the intermediate has no need for purification, and the products have high purity and high yield. Experimental results indicate that when the method provided by the invention is used for preparing canagliflozin, the product yield is greater than 88%, and the purity is greater than 99.5%.
Description
Technical field
The invention belongs to pharmaceutical field, particularly relate to and a kind ofly prepare the method for the clean and intermediate of Ka Gelie and described intermediate.
Background technology
Diabetes are a kind of because of a series of clinical syndromes that Regular Insulin in body is absolute or relative deficiency causes.The main clinical manifestation of diabetes is many drinks, diuresis, many foods, weight loss, blood sugar are high and contain glucose etc. in urine.Diabetes are mainly divided into type i diabetes and type ii diabetes, and wherein, type i diabetes is generally that the β cell owing to can produce Regular Insulin suffers that autoimmune system destruction causes; Type ii diabetes due to histiocytic insulin resistant, β cell function decline or other many reasons cause.At present, the treatment for type ii diabetes mainly passes through dietary control, simultaneously with the use of ofhypoglycemic medicine.
Ka Gelie is a kind of oral pharmaceutical being used for the treatment of adult patients type ii diabetes only, and Ka Gelie can suppress SGLT (glucose transporter) only, the glucose in uriniferous tubules heavily can not be absorbed and enter in blood, thus reduces blood sugar concentration.Patent WO2010043682 discloses the clean preparation method of a kind of Ka Gelie, and concrete reaction scheme is as follows:
The method adopts bromo grape derivative to be raw material, through nucleophilic substitution, upper protection with go to protect several reaction process to obtain target product.Because the price of acetylbromoglycose derivative is more expensive, reactive behavior is poor, and the cost therefore causing employing the method to produce Ka Gelie clean is higher.
Patent WO2009035969 discloses the clean preparation method of a kind of Ka Gelie, and concrete reaction scheme is as follows:
The Gluconolactone that the method adopts TMS (tetramethylsilane) to protect is that raw material reacts; successively through nucleophilic substitution, go TMS, reduction; obtain the clean thick product of Ka Gelie, then the clean thick product of Ka Gelie obtains the finished product after ethanoyl protection and deacetylate protection.Compared to acetylbromoglycose derivative; the price of Gluconolactone is comparatively cheap, and reactive behavior is higher, and therefore the method can reduce production cost to a certain extent; but the method needs to carry out ethanoyl protection and deacetylate protection to the clean thick product of Ka Gelie, and reaction scheme is comparatively complicated.
Summary of the invention
In view of this, the object of the present invention is to provide and a kind ofly prepare the method for the clean and intermediate of Ka Gelie and described intermediate.The clean preparation method's reaction scheme of Ka Gelie provided by the invention is simple, and the obtained clean purity of Ka Gelie is high.
The invention provides the preparation method that a kind of Ka Gelie is clean, comprise the following steps:
Shown in formula (I), structural compounds carries out debenzylation, obtains Ka Gelie clean;
Preferably, structural compounds shown in described formula (I) is at H
2debenzylation is carried out under existing with organic solvent.
Preferably, structural compounds shown in described formula (I) carries out debenzylation in the acetum of hydrogen bromide.
Preferably, in the acetum of described hydrogen bromide, the concentration of hydrogen bromide is 10 ~ 30wt%.
Preferably, structural compounds shown in described formula (I) prepares according to following steps:
Shown in formula (II), structural compounds carries out reduction reaction in the presence of a reducing agent, obtains structural compounds shown in formula (I);
In formula (II), R is selected from hydrogen or methyl.
Preferably, described reductive agent is triethyl silicane and boron trifluoride diethyl etherate.
Preferably, described R is hydrogen, and shown in formula (II), structural compounds prepares according to following steps:
2-(2-methyl-5-halogen benzyl)-5-(4-fluorobenzene) thiophene and the mixing of 2,3,4,6-tetra--O-benzyl-D Gluconolactone, react, obtain structural compounds shown in formula (II).
Preferably, described R is methyl, and shown in formula (II), structural compounds prepares according to following steps:
2-(2-methyl-5-halogen benzyl)-5-(4-fluorobenzene) thiophene, 2,3,4,6-tetra--O-benzyl-D Gluconolactones and methylsulfonic acid mix, and react, and obtain structural compounds shown in formula (II).
The invention provides the clean intermediate of Ka Gelie with formula (I) structure;
The invention provides the preparation method of the clean intermediate of a kind of Ka Gelie, comprising:
Shown in formula (II), structural compounds reacts in the presence of a reducing agent, obtains the clean intermediate of Ka Gelie of structure shown in formula (I);
In formula (II), R is selected from hydrogen or methyl.
Compared with prior art, the invention provides and a kind ofly prepare the method for the clean and intermediate of Ka Gelie and described intermediate.The preparation method that Ka Gelie provided by the invention is clean, comprises the following steps: shown in formula (I), structural compounds carries out debenzylation, obtains Ka Gelie clean.Preparation method's reaction scheme provided by the invention is simple, intermediate without the need to purifying, goods purity and yield high.Experimental result shows, adopt method provided by the invention prepare Ka Gelie clean time, product yield is greater than 88%, and purity is greater than 99.5%.
Embodiment
Be clearly and completely described the technical scheme in the embodiment of the present invention below, obviously, described embodiment is only the present invention's part embodiment, instead of whole embodiments.Based on the embodiment in the present invention, those of ordinary skill in the art, not making the every other embodiment obtained under creative work prerequisite, belong to the scope of protection of the invention.
The invention provides the preparation method that a kind of Ka Gelie is clean, comprise the following steps:
Shown in formula (I), structural compounds carries out debenzylation, obtains Ka Gelie clean;
In the present invention, shown in formula (I), structural compounds carries out debenzylation, obtains Ka Gelie clean.Shown in described formula (I), structural compounds preferably prepares according to following steps:
Shown in formula (II), structural compounds carries out reduction reaction in the presence of a reducing agent, obtains structural compounds shown in formula (I);
In formula (II), R is selected from hydrogen or methyl.
Shown in described formula (II), structural compounds has formula (II-I) or formula (II-II) structure;
In the present invention, shown in formula (II), structural compounds carries out reduction reaction in the presence of a reducing agent, obtains structural compounds shown in formula (I).When shown in described formula (II), the R of structural compounds is hydrogen, shown in formula (II), structural compounds is formula (II-I) structure; When R is methyl, shown in formula (II), structural compounds is formula (II-II) structure.
In the present invention, when shown in formula (II), the R of structural compounds is hydrogen, i.e. structural compounds shown in formula (II-I), preferably prepares according to following steps:
2-(2-methyl-5-halogen benzyl)-5-(4-fluorobenzene) thiophene and the mixing of 2,3,4,6-tetra--O-benzyl-D Gluconolactone, react, obtain structural compounds shown in formula (II-I).Wherein, the structure of described 2-(2-methyl-5-halogen benzyl)-5-(4-fluorobenzene) thiophene is such as formula shown in (III):
In formula (III), X is halogen, is preferably bromine or iodine.
The structure of described 2,3,4,6-tetra--O-benzyl-D Gluconolactones is such as formula shown in (IV):
The mol ratio of described 2-(2-methyl-5-halogen benzyl)-5-(4-fluorobenzene) thiophene and 2,3,4,6-tetra--O-benzyl-D Gluconolactone is preferably 1:1 ~ 2, is more preferably 1:1 ~ 1.5.In the present invention, described 2-(2-methyl-5-halogen benzyl)-5-(4-fluorobenzene) thiophene and 2,3,4,6-tetra--O-benzyl-D Gluconolactone preferably react under n-Butyl Lithium, organic solvent and shielding gas exist.Described organic solvent is preferably tetrahydrofuran (THF) and/or toluene.Described shielding gas is preferably argon gas.The process that described 2-(2-methyl-5-halogen benzyl)-5-(4-fluorobenzene) thiophene and 2,3,4,6-tetra--O-benzyl-D Gluconolactone carry out reacting under n-Butyl Lithium, organic solvent and shielding gas exist is specially:
In shielding gas atmosphere, 2-(2-methyl-5-halogen benzyl)-5-(4-fluorobenzene) thiophene, n-Butyl Lithium and organic solvent mix, and obtain 2-(2-methyl-5-halogen benzyl)-5-(4-fluorobenzene) thiophene mixed solution.The amount ratio of described 2-(2-methyl-5-halogen benzyl)-5-(4-fluorobenzene) thiophene, n-Butyl Lithium and organic solvent is preferably 200 ~ 300 (mol): 200 ~ 400 (mol): 250 ~ 500 (L), are more preferably 250 ~ 280 (mol): 250 ~ 370 (mol): 300 ~ 450 (L).The mode of described mixing is preferably: first by 2-(2-methyl-5-halogen benzyl)-5-(4-fluorobenzene) thiophene and organic solvent mixing, obtain the organic solvent solution of 2-(2-methyl-5-halogen benzyl)-5-(4-fluorobenzene) thiophene.In described 2-(2-methyl-5-halogen benzyl)-5-(4-fluorobenzene) thiophene and organic solvent mixing process, mixed system temperature is preferably-50 ~-90 DEG C, is more preferably-70 ~-80 DEG C.Then the organic solvent solution of n-Butyl Lithium with 2-(2-methyl-5-halogen benzyl)-5-(4-fluorobenzene) thiophene is mixed, obtain 2-(2-methyl-5-halogen benzyl)-5-(4-fluorobenzene) thiophene mixed solution.The mode that described n-Butyl Lithium mixes with the organic solvent solution of 2-(2-methyl-5-halogen benzyl)-5-(4-fluorobenzene) thiophene is preferably: added by n-Butyl Lithium in the organic solvent solution of 2-(2-methyl-5-halogen benzyl)-5-(4-fluorobenzene) thiophene.The mode that described n-Butyl Lithium adds is preferably and drips.In the process that n-Butyl Lithium mixes with the organic solvent solution of 2-(2-methyl-5-halogen benzyl)-5-(4-fluorobenzene) thiophene, the temperature of mixed system is preferably lower than-40 DEG C, is more preferably-80 ~-40 DEG C.After mixing, mixed system preferably leaves standstill.The described standing time is preferably 0.5 ~ 5h, is more preferably 0.5 ~ 2h.Described standing temperature is preferably-50 ~-90 DEG C, is more preferably-70 ~-80 DEG C.
2,3,4,6-tetra--O-benzyl-D Gluconolactone and organic solvent mixing, obtain the organic solvent solution of 2,3,4,6-tetra--O-benzyl-D Gluconolactone.The amount ratio of described 2,3,4,6-tetra--O-benzyl-D Gluconolactones and organic solvent is preferably 250 ~ 370 (mol): 200 ~ 400 (L), is more preferably 250 ~ 370 (mol): 250 ~ 300 (L).
In shielding gas atmosphere, the organic solvent solution mixing of 2-(2-methyl-5-halogen benzyl)-5-(4-fluorobenzene) the thiophene mixed solution after above-mentioned leaving standstill and 2,3,4,6-tetra--O-benzyl-D Gluconolactone is reacted.The mode of described mixing is preferably: added by the organic solvent solution of 2,3,4,6-tetra--O-benzyl-D Gluconolactone in 2-(2-methyl-5-halogen benzyl)-5-(4-fluorobenzene) thiophene mixed solution.The mode that the organic solvent solution of described 2,3,4,6-tetra--O-benzyl-D Gluconolactones adds is preferably dropping.Preferably in dropping process, mixed system is stirred.In mixing process, the temperature of mixed system is preferably-50 ~-90 DEG C, is more preferably-70 ~-80 DEG C.After mixing, by the temperature return of mixed system to room temperature, then keep room temperature conditioned response 1 ~ 5h, be preferably 2 ~ 4h.
After reaction terminates, cancellation, obtains reaction product solution.The solution of described cancellation is preferably saturated NaHCO
3, the temperature of described cancellation is preferably-5 ~ 5 DEG C, is more preferably 0 DEG C.Described reaction product solution, through aftertreatment, obtains structural compounds shown in formula (II-I).The process of described aftertreatment is preferably: reaction product solution passes through extraction, drying successively and concentrates, and obtains structural compounds shown in formula (II-I).The extraction agent of described extraction is preferably ethyl acetate; The siccative of described drying is preferably anhydrous magnesium sulfate; Described concentrated mode is preferably concentrating under reduced pressure.
In the present invention, when shown in formula (II), the R of structural compounds is methyl, i.e. structural compounds shown in formula (II-II), preferably prepares according to following steps:
2-(2-methyl-5-halogen benzyl)-5-(4-fluorobenzene) thiophene, 2,3,4,6-tetra--O-benzyl-D Gluconolactones and methylsulfonic acid mix, and react, and obtain structural compounds shown in formula (II-II).Described 2-(2-methyl-5-halogen benzyl)-5-(4-fluorobenzene) thiophene, 2,3,4, the amount ratio of 6-tetra--O-benzyl-D Gluconolactone and methylsulfonic acid is preferably 140 (mol): 140 ~ 170 (mol): 20 ~ 50 (L), is more preferably 140 (mol): 150 ~ 160 (mol): 25 ~ 30 (L).In the present invention, described 2-(2-methyl-5-halogen benzyl)-5-(4-fluorobenzene) thiophene, 2,3,4,6-tetra--O-benzyl-D Gluconolactones and methylsulfonic acid preferably react under n-Butyl Lithium, organic solvent and shielding gas exist.Described organic solvent is preferably tetrahydrofuran (THF) and/or toluene.Described shielding gas is preferably argon gas.The process that described 2-(2-methyl-5-halogen benzyl)-5-(4-fluorobenzene) thiophene, 2,3,4,6-tetra--O-benzyl-D Gluconolactones and methylsulfonic acid carry out reacting under n-Butyl Lithium, organic solvent and shielding gas exist is specially:
In shielding gas atmosphere, 2-(2-methyl-5-halogen benzyl)-5-(4-fluorobenzene) thiophene, n-Butyl Lithium and organic solvent mix, and obtain 2-(2-methyl-5-halogen benzyl)-5-(4-fluorobenzene) thiophene mixed solution.The amount ratio of described 2-(2-methyl-5-halogen benzyl)-5-(4-fluorobenzene) thiophene, n-Butyl Lithium and organic solvent is preferably 200 ~ 300 (mol): 200 ~ 400 (mol): 250 ~ 500 (L), are more preferably 250 ~ 280 (mol): 250 ~ 370 (mol): 300 ~ 450 (L).The mode of described mixing is preferably: first by 2-(2-methyl-5-halogen benzyl)-5-(4-fluorobenzene) thiophene and organic solvent mixing, obtain the organic solvent solution of 2-(2-methyl-5-halogen benzyl)-5-(4-fluorobenzene) thiophene.In described 2-(2-methyl-5-halogen benzyl)-5-(4-fluorobenzene) thiophene and organic solvent mixing process, mixed system temperature is preferably-50 ~-90 DEG C, is more preferably-70 ~-80 DEG C.Then the organic solvent solution of n-Butyl Lithium with 2-(2-methyl-5-halogen benzyl)-5-(4-fluorobenzene) thiophene is mixed, obtain 2-(2-methyl-5-halogen benzyl)-5-(4-fluorobenzene) thiophene mixed solution.The mode that described n-Butyl Lithium mixes with the organic solvent solution of 2-(2-methyl-5-halogen benzyl)-5-(4-fluorobenzene) thiophene is preferably: joined by n-Butyl Lithium in the organic solvent solution of 2-(2-methyl-5-halogen benzyl)-5-(4-fluorobenzene) thiophene.The mode that described n-Butyl Lithium adds is preferably and drips.In the process that n-Butyl Lithium mixes with the organic solvent solution of 2-(2-methyl-5-halogen benzyl)-5-(4-fluorobenzene) thiophene, the temperature of mixed system is preferably lower than-40 DEG C, is more preferably-80 ~-40 DEG C.After mixing, mixed system preferably leaves standstill.The described standing time is preferably 0.5 ~ 5h, is more preferably 0.5 ~ 2h.Described standing temperature is preferably-50 ~-90 DEG C, is more preferably-70 ~-80 DEG C.
2,3,4,6-tetra--O-benzyl-D Gluconolactone and organic solvent mixing, obtain the organic solvent solution of 2,3,4,6-tetra--O-benzyl-D Gluconolactone.Described organic solvent is preferably tetrahydrofuran (THF) and/or toluene.The amount ratio of described 2,3,4,6-tetra--O-benzyl-D Gluconolactones and organic solvent is preferably, and is more preferably 250 ~ 370 (mol): 250 ~ 300 (L).
In shielding gas atmosphere, the organic solvent solution mixing of 2-(2-methyl-5-halogen benzyl)-5-(4-fluorobenzene) the thiophene mixed solution after above-mentioned leaving standstill and 2,3,4,6-tetra--O-benzyl-D Gluconolactone is reacted.The mode of described mixing is preferably: added by the organic solvent solution of 2,3,4,6-tetra--O-benzyl-D Gluconolactone in 2-(2-methyl-5-halogen benzyl)-5-(4-fluorobenzene) thiophene mixed solution.The mode that the organic solvent solution of described 2,3,4,6-tetra--O-benzyl-D Gluconolactones adds is preferably dropping.Preferably in dropping process, mixed system is stirred.In mixing process, the temperature of mixed system is preferably-50 ~-90 DEG C, is more preferably-70 ~-80 DEG C.After mixing, by mixed system temperature return to room temperature, then keep room temperature conditioned response 1 ~ 5h, be preferably 2 ~ 4h.
After reaction terminates, obtain reaction solution.Described reaction solution mixes with methylsulfonic acid and reacts.The mode of described mixing is preferably: added in described reaction solution by methylsulfonic acid.The described mode added is preferably and drips.In mixing process, the temperature of mixed system is preferably-50 ~-90 DEG C, is more preferably-70 ~-80 DEG C.After mixing, by the temperature return of mixed system to room temperature, then keep room temperature conditioned response 4 ~ 24h, be preferably 6 ~ 12h.
After reaction terminates, cancellation, obtains reaction product solution.The solution of described cancellation is preferably saturated NaHCO
3, the temperature of described cancellation is preferably-5 ~ 5 DEG C, is more preferably 0 DEG C.Described reaction product solution, through aftertreatment, obtains structural compounds shown in formula (II-II).The process of described aftertreatment is preferably: reaction product solution passes through extraction, drying successively and concentrates, and obtains structural compounds shown in formula (II-II).The extraction agent of described extraction is preferably ethyl acetate; The siccative of described drying is preferably anhydrous magnesium sulfate; Described concentrated mode is preferably concentrating under reduced pressure.
In the present invention, shown in described formula (II), structural compounds carries out reduction reaction in the presence of a reducing agent, obtains structural compounds shown in formula (I).Wherein, described reductive agent is preferably triethyl silicane and boron trifluoride diethyl etherate.The mol ratio of described triethyl silicane and boron trifluoride diethyl etherate is preferably 1:0.5 ~ 2, is more preferably 1:1.Structural compounds shown in described formula (II) and reductive agent mol ratio be preferably 0.28:1 ~ 4, be more preferably 0.28:1.5 ~ 2.8.In the present invention, structural compounds shown in described formula (II) preferably carries out reduction reaction under shielding gas and organic solvent exist.Described shielding gas is preferably argon gas.Described have solvent to be preferably methylene dichloride or trichloromethane.Shown in described organic solvent and formula (II), the amount ratio of structural compounds is preferably 100 ~ 220 (g): 500 ~ 1000 (mL), are more preferably 100 ~ 220 (g): 600 ~ 700 (mL).The process that structural compounds shown in described formula (II) carries out reduction reaction under shielding gas and organic solvent exist is specially:
In shielding gas atmosphere, first structural compounds formula (II) Suo Shi is mixed with organic solvent, obtain the organic solvent solution of structural compounds shown in formula (II).In mixing process, the temperature of mixed system is preferably-60 ~-30 DEG C, is more preferably-40 DEG C.Then mixed with reductive agent by the organic solvent solution of structural compounds described formula (II) Suo Shi and react, the mode of described mixing is preferably: added by reductive agent in the organic solvent solution of structural compounds shown in formula (II).The mode that described reductive agent adds is preferably and drips.The organic solvent solution of structural compounds shown in formula (II) is with reductive agent mixing process, and the temperature of mixed system preferably less than-10 DEG C, is more preferably-40 ~-10 DEG C.After mixing, by the temperature return of mixed system to room temperature, then keep room temperature conditioned response 1 ~ 5h, be preferably 2 ~ 4h.
After reaction terminates, obtain reaction product solution.Described reaction product solution, through aftertreatment, obtains structural compounds shown in formula (I).The process of described aftertreatment is preferably: first reaction product solution mix with frozen water, then successively through extraction, washing, dry and concentrated, obtains the shown structural compounds of formula (I).The volume ratio of described frozen water and reductive agent is preferably 80 ~ 120:15 ~ 40; The extraction agent of described extraction is preferably ethyl acetate; The washing composition of described washing is preferably saturated sodium bicarbonate solution and saturated nacl aqueous solution; The siccative of described drying is preferably anhydrous magnesium sulfate; Described concentrated mode is concentrating under reduced pressure.
In the present invention, shown in described formula (I), structural compounds carries out debenzylation, obtains Ka Gelie clean.
In certain embodiments of the present invention, structural compounds shown in described formula (I) is preferably at H
2debenzylation is carried out under existing with organic solvent.Described H
2add-on be preferably 1 ~ 5 hydrogen pressure, be more preferably 1 hydrogen pressure.Described organic solvent is preferably methylene dichloride.Shown in described formula (I), the amount ratio of compound and organic solution is preferably 100 ~ 200 (mol): 700 ~ 800 (L), is more preferably 150 ~ 180 (mol): 700 ~ 800 (L).Shown in described formula (I), structural compounds is at H
2the journey of carrying out debenzylation under existing with organic solvent is specially:
First structural compounds formula (I) Suo Shi is mixed with organic solvent, obtain the organic solvent solution of structural compounds shown in formula (I), then in this solution, pass into H
2, react.Before reaction, preferably in reaction system, add catalyzer, described catalyzer is preferably Pd/C, and shown in described catalyzer and formula (I), the mass ratio of structural compounds is preferably 50:100 ~ 200, is more preferably 50:140 ~ 150.The present invention preferably uses thin-layer chromatography (TLC) to follow the tracks of reaction process, judges whether reaction terminates.
After reaction terminates, obtain reaction product solution.Described reaction product solution, through aftertreatment, obtains Ka Gelie clean.The process of described aftertreatment is preferably: reaction product solution through filtration, concentrated, recrystallization, solid-liquid separation, obtains Ka Gelie clean successively.Described concentrated mode is preferably concentrating under reduced pressure; Described recrystallization carries out in organic solvent, described organic solvent is preferably ethyl acetate and normal heptane, the volume ratio of described ethyl acetate and normal heptane is preferably 1 ~ 3:1, be more preferably 2:1, shown in described organic solvent and described formula (I), the amount ratio of structural compounds is preferably 350 ~ 500 (mL): 100 ~ 200 (g), is more preferably 400 ~ 450 (mL): 140 ~ 150 (g).
In certain embodiments of the present invention, structural compounds shown in described formula (I) preferably carries out debenzylation in the acetum of hydrogen bromide.In the acetum of described hydrogen bromide, the concentration of hydrogen bromide is preferably 10 ~ 30wt%, is more preferably 15 ~ 25wt%.Shown in described formula (I), the amount ratio of the acetum of structural compounds and hydrogen bromide is preferably 220 (mol): 500 ~ 1000 (L), is more preferably 220 (mol): 800 ~ 900 (L).The time of described reaction is preferably 1 ~ 10h, is more preferably 2 ~ 5h.The temperature of described reaction is preferably room temperature.After reaction terminates, obtain reaction product solution.Described reaction product solution, through aftertreatment, obtains Ka Gelie clean.The process of described aftertreatment is preferably: first reaction product solution mixes with frozen water, then centrifugation, obtains oily throw out.The acetum of described hydrogen bromide and the volume ratio of frozen water are preferably 0.5 ~ 2:10, are more preferably 0.5 ~ 1:10.Described oily throw out successively through dissolving, washing, after dry, concentrated, recrystallization and solid-liquid separation, obtain Ka Gelie clean.The solvent of described dissolving is preferably methylene dichloride; The washings of described washing is preferably saturated sodium bicarbonate and saturated nacl aqueous solution; The siccative of described drying is preferably anhydrous sodium sulphate; Described condensing mode is preferably concentrating under reduced pressure; Described recrystallization carries out in organic solvent, described organic solvent is preferably ethyl acetate and normal heptane, the volume ratio of described ethyl acetate and normal heptane is preferably 1 ~ 3:1, be more preferably 2:1, shown in described organic solvent and described formula (I), the amount ratio of compound is preferably 500 ~ 600 (mL): 100 ~ 300 (g), is more preferably 500 ~ 600 (mL): 150 ~ 200 (g).
Preparation method's reaction scheme provided by the invention is simple, intermediate without the need to purifying, goods purity and yield high.Experimental result shows, adopt method provided by the invention prepare Ka Gelie clean time, product yield is greater than 88%, and purity is greater than 99.5%.
In optimal technical scheme provided by the invention; the Gluconolactone adopting benzyl protection is raw material; through nucleophilic substitution reaction, reduction reaction with go benzyl to react three processes to obtain target compound; simple to operate in whole reaction process; namely intermediate, without the need to purifying, in the end obtains highly purified Ka Gelie by recrystallization in step clean.Adopt this method prepare Ka Gelie clean time, product synthesis total recovery reach 75%, purity is greater than 99.5%.Program reaction scheme is simple, is easy to amplify produce.
For the purpose of clearer, be described in detail below by following examples.
Embodiment 1
Under argon shield; tetrahydrofuran (THF) after being dewatered by 300mL and 90.4g (250mmol) 2-(2-methyl-5-bromobenzyl)-5-(4-fluorobenzene) thiophene add in 1000mL three-necked bottle; with acetone/the dry ice bath, the temperature of mixed system is controlled at-78 DEG C; 100mL (2.5mol/L is dripped in three-necked bottle; 250mmol; 1eq) n-Butyl Lithium drips; the temperature of reaction system is controlled at-78 DEG C in dropping process; after being added dropwise to complete, under-78 DEG C of conditions, leave standstill 1 hour.2,3,4 are dripped in reaction system, the tetrahydrofuran solution (2 of 6-tetra--O-benzyl-D Gluconolactone, 3,4,6-tetra--O-benzyl-D Gluconolactone 135.6g, tetrahydrofuran (THF) 150mL), dropping limit, limit is stirred, and dropwises recession except dry ice/acetone batch, slowly reacts after the temperature return of reaction system to room temperature 3 hours, after reaction stops, with saturated NaHCO under condition of ice bath
3solution cancellation is reacted, and the reaction product solution after cancellation, successively through extraction into ethyl acetate, organic phase merging, dried over mgso and concentrating under reduced pressure, obtains the yellow thick liquid of 210.1g.Detect this yellow thick liquid and yield calculating, result shows, this yellow thick liquid has formula (II-I) structure, and purity is 87.7%, and yield is 99%.
Under argon shield, above-mentioned obtained yellow thick liquid 220.5g (280mmol) is dissolved in the three-necked bottle of 2L with 660mL trichloromethane, by dry ice/acetone batch, the temperature of reaction system is controlled at-40 DEG C, in three-necked bottle, 120mL (750mmol) triethyl silicane and 95mL (750mmol) boron trifluoride ether solution is dripped in 1 hour, control temperature of reaction system in dropping process and be no more than-10 DEG C, dropwise recession except dry ice/acetone batch, reaction system is reacted 3 hours after slowly returning to room temperature, after reaction terminates, reaction system is poured in 1L frozen water, extraction into ethyl acetate, successively with saturated sodium bicarbonate solution and saturated nacl aqueous solution washing, anhydrous magnesium sulfate drying, concentrating under reduced pressure, obtain the yellow oily crude product of 172.5g benzyl protection.In yellow oily crude product, add 240mL methyl alcohol stir 2 hours, then filtration under diminished pressure, obtain 145.2g off-white color solid.Detect such white solid and yield calculating, result shows, such white solid has formula (I) structure, and purity is 98%, and yield is 71%.The analytical data of mass spectrum of such white solid is: [M+H]=805.3, the spectral analysis of the nuclear magnetic resonance data of such white solid are: 1H-NMR (DMSO-d6) 2.24 (s, 3H), 3.04-3.10 (m, 1H), 3.12-3.18 (m, 1H), 3.22-3.25 (m, 1H), 3.25-3.30 (m, 1H), 3.33-3.47 (m, 1H), 3.55-3.74 (m, 1H), 3.88-3.92 (m, 1H), 4.00-4.10 (m, 2H), 4.44 (t, J=5.98Hz, 1H), 4.62 (s, 8H), 4.73 (d, J=5.98Hz, 1H), 4.93 (d, J=4.96Hz, 2H), 6.80-6.88 (m, 1H), 7.04-7.10 (m, 3H), 7.11-7.16 (m, 3H), 7.16-7.21 (m, 6H), 7.28-7.33 (m, 5H), 7.33-7.40 (m, 9H), 7.52-7.62 (m, 2H).
Above-mentioned obtained off-white color solid 145.2g (177mmol) is placed in the round-bottomed flask of 2L, by 730mL methylene dichloride stirring and dissolving, add 51.3gPd/C (10%, wet56.99%), with nitrogen replacement air three times, hydrogen exchange nitrogen three times, carries out debenzylation under a hydrogen pressure, TLC follows the tracks of reaction, constantly adds hydrogen until TLC display raw material reaction is complete in reaction process.Mistake after raw material reaction, filters Pd/C, and concentrating under reduced pressure obtains flaxen foaming solid, and this foaming solid is recrystallization, then solid-liquid separation in 280mL ethyl acetate and 140mL normal heptane, obtains 70.2g off-white color solid.Detect such white solid and yield calculating, result shows, such white solid is that Ka Gelie is clean, and purity is 99.5%, and yield is 88%.The analytical data of mass spectrum of such white solid is: [M+Na]=467.3, the spectral analysis of the nuclear magnetic resonance data of such white solid are: 1H-NMR (DMSO-d6) 2.27 (s, 3H), 3.14-3.17 (m, 1H), 3.17-3.19 (m, 1H), 3.20-3.24 (m, 1H), 3.25-3.29 (m, 1H), 3.42-3.47 (m, 1H), 3.68-3.73 (m, 1H), 3.97 (d, J=9.44Hz, 1H), 4.07-4.17 (m, 2H), 4.44 (t, J=6.04Hz, 1H), 4.73 (d, J=5.67Hz, 1H), 4.93 (d, J=4.91Hz, 2H), 6.80 (d, J=3.78Hz, 1H), 7.12 (d, J=7.55Hz, 1H), 7.15 (dd, J=7.55, 1.51Hz, 1H), 7.20 (t, J=8.68Hz, 2H), 7.23 (d, J=1.13Hz, 1H), 7.28 (d, J=3.40Hz, 1H), 7.57-7.61 (m, 2H), 13C-NMR (DMSO-d6) 18.81,33.44,61.43,70.42,74.67,78.48,81.21,81.32,115.88 (d, J=21.96Hz, 2C), 123.39,126.25,126.36,126.95 (d, J=7.68Hz, 2C), 129.06,129.65,130.52 (d, J=3.29Hz, 1C), 134.93,137.36,138.24,140.22,143.63,161.37 (d, J=243.70Hz, 1C).
Embodiment 2
Under the condition of argon shield, tetrahydrofuran (THF) after 150mL is dewatered, 300mL toluene and 114.8g (280mmol) 2-(2-methyl-5-iodine benzyl)-5-(4-fluorobenzene) thiophene add in 1000mL three-necked bottle, with acetone/the dry ice bath, the temperature of mixed system is controlled at-78 DEG C, 146mL (2.5mol/L is dripped in three-necked bottle, 364mmol, 1.3eq) n-Butyl Lithium, the temperature controlling reaction system in dropping process is no more than-40 DEG C, after being added dropwise to complete, 1 hour is left standstill under-78 DEG C of conditions, 2 are dripped in reaction system, 3, 4, tetrahydrofuran (THF)/the toluene solution (2 of 6-tetra--O-benzyl-D Gluconolactone, 3, 4, 6-tetra--O-benzyl-D Gluconolactone 196.2g, tetrahydrofuran (THF) 100mL, toluene 200mL), dropping limit, limit is stirred, dry ice/acetone batch is withdrawn from after dropwising, slowly react after the temperature return of reaction system to room temperature 3 hours, reaction stop after under condition of ice bath with saturated NaHCO
3solution cancellation is reacted, and the reaction product solution after cancellation, successively through extraction into ethyl acetate, merging organic phase, dried over mgso and concentrating under reduced pressure, obtains the yellow thick liquid of 220.5g.Detect this yellow thick liquid and yield calculating, result shows, this yellow thick liquid has formula (II-I) structure, and purity is 78.2%, and yield is 95%.
Under the condition of argon shield, above-mentioned obtained yellow thick liquid 220.5g (280mmol) is dissolved in the three-necked bottle of 2L with 670mL methylene dichloride, by dry ice/acetone batch, the temperature of reaction system is controlled at-40 DEG C, in three-necked bottle, 224mL (1.4mol) triethyl silicane and 176mL (1.4mol) boron trifluoride ether solution is dripped in 1 hour, control temperature of reaction system in dropping process and be no more than-10 DEG C, dropwise recession except dry ice/acetone batch, reaction system is reacted 3 hours after slowly returning to room temperature, after reaction terminates, reaction system is poured in 1.2L frozen water, extraction into ethyl acetate, successively with saturated sodium bicarbonate solution and saturated nacl aqueous solution washing, anhydrous magnesium sulfate drying, concentrating under reduced pressure, obtain the yellow oily crude product of 188.6g benzyl protection.In yellow oily crude product, add 270mL methyl alcohol stir 2 hours, then filtration under diminished pressure, obtain 178.1g off-white color solid.Detect such white solid and yield calculating, result shows, such white solid has formula (I) structure, and purity is 98%, and yield is 79%.The analytical data of mass spectrum of such white solid is: [M+H]=805.3, the spectral analysis of the nuclear magnetic resonance data of such white solid are: 1H-NMR (DMSO-d6) 2.24 (s, 3H), 3.04-3.10 (m, 1H), 3.12-3.18 (m, 1H), 3.22-3.25 (m, 1H), 3.25-3.30 (m, 1H), 3.33-3.47 (m, 1H), 3.55-3.74 (m, 1H), 3.88-3.92 (m, 1H), 4.00-4.10 (m, 2H), 4.44 (t, J=5.98Hz, 1H), 4.62 (s, 8H), 4.73 (d, J=5.98Hz, 1H), 4.93 (d, J=4.96Hz, 2H), 6.80-6.88 (m, 1H), 7.04-7.10 (m, 3H), 7.11-7.16 (m, 3H), 7.16-7.21 (m, 6H), 7.28-7.33 (m, 5H), 7.33-7.40 (m, 9H), 7.52-7.62 (m, 2H).
Obtained off-white color solid 178.1g (221mmol) is placed in the round-bottomed flask of 2L, dissolve with the acetum of the hydrogen bromide of 890mL24wt%, stirred at ambient temperature 3 is little complete up to raw material reaction.After reaction terminates, reaction product solution is dropped in 10L frozen water, there is a large amount of oily matter Precipitations, centrifugal removing supernatant liquid, organic phase is used successively through methylene dichloride dissolving, saturated sodium bicarbonate and saturated nacl aqueous solution washing, anhydrous sodium sulfate drying and concentrating under reduced pressure, and obtain weak yellow foam shape solid, this foaming solid is recrystallization in 360mL ethyl acetate and 180mL normal heptane, then solid-liquid separation, obtains 88.3g off-white color solid.Detect such white solid and yield calculating, result shows, such white solid is that Ka Gelie is clean, and purity is 99.5%, and yield is 90%.The analytical data of mass spectrum of such white solid is: [M+Na]=467.3, the spectral analysis of the nuclear magnetic resonance data of such white solid are: 1H-NMR (DMSO-d6) 2.27 (s, 3H), 3.14-3.17 (m, 1H), 3.17-3.19 (m, 1H), 3.20-3.24 (m, 1H), 3.25-3.29 (m, 1H), 3.42-3.47 (m, 1H), 3.68-3.73 (m, 1H), 3.97 (d, J=9.44Hz, 1H), 4.07-4.17 (m, 2H), 4.44 (t, J=6.04Hz, 1H), 4.73 (d, J=5.67Hz, 1H), 4.93 (d, J=4.91Hz, 2H), 6.80 (d, J=3.78Hz, 1H), 7.12 (d, J=7.55Hz, 1H), 7.15 (dd, J=7.55, 1.51Hz, 1H), 7.20 (t, J=8.68Hz, 2H), 7.23 (d, J=1.13Hz, 1H), 7.28 (d, J=3.40Hz, 1H), 7.57-7.61 (m, 2H), 13C-NMR (DMSO-d6) 18.81,33.44,61.43,70.42,74.67,78.48,81.21,81.32,115.88 (d, J=21.96Hz, 2C), 123.39,126.25,126.36,126.95 (d, J=7.68Hz, 2C), 129.06,129.65,130.52 (d, J=3.29Hz, 1C), 134.93,137.36,138.24,140.22,143.63,161.37 (d, J=243.70Hz, 1C).
Embodiment 3
Under the condition of argon shield, tetrahydrofuran (THF) after 300mL is dewatered, 60g (141mmol) 2-(2-methyl-5-bromobenzyl)-5-(4-fluorobenzene) thiophene adds in 1000mL three-necked bottle, with acetone/the dry ice bath, the temperature of mixed system is controlled at-78 DEG C, 62mL (2.5mol/L is dripped in three-necked bottle, 155mmol, 1.1eq) n-Butyl Lithium, the temperature of reaction system is controlled at-78 DEG C in dropping process, after being added dropwise to complete, 1 hour is left standstill under-78 DEG C of conditions, 2 are dripped in reaction system, 3, 4, the tetrahydrofuran solution (2 of 6-tetra--O-benzyl-D Gluconolactone, 3, 4, 6-tetra--O-benzyl-D Gluconolactone 135.6g, tetrahydrofuran (THF) 150mL), dropping limit, limit is stirred, dry ice/acetone batch is withdrawn from after dropwising, slowly react after the temperature return of reaction system to room temperature 3 hours, react and again reaction solution is cooled to-78 DEG C after 3 hours, methanol solution (the methylsulfonic acid 27.3mL of methylsulfonic acid is added in reaction solution, methyl alcohol 270mL), after dropwising, reaction system slowly returns to room temperature reaction and spends the night.Reaction uses saturated NaHCO after stopping under condition of ice bath
3solution cancellation is reacted, and the reaction product solution after cancellation, successively through extraction into ethyl acetate, merging organic phase, dried over mgso and concentrating under reduced pressure, obtains the yellow thick liquid of 115.6g.Detect this yellow thick liquid and yield calculating, result shows, this yellow thick liquid has formula (II-II) structure, and purity is 89.6%, and yield is 98%.
Under the condition of argon shield, above-mentioned obtained yellow thick liquid 115.6g (141mmol) is dissolved in the three-necked bottle of 2L with 700mL methylene dichloride, by dry ice/acetone batch, the temperature of reaction system is controlled at-40 DEG C, in three-necked bottle, (81mL is dripped in 1 hour, 565mmol) triethyl silicane and 72mL (565mmol) boron trifluoride ether solution, control temperature of reaction system in dropping process and be no more than-10 DEG C, dropwise recession except dry ice/acetone batch, reaction system is reacted 3 hours after slowly returning to room temperature, after reaction terminates, reaction system is poured in 800mL frozen water, extraction into ethyl acetate, successively with saturated sodium bicarbonate solution and saturated nacl aqueous solution washing, anhydrous magnesium sulfate drying, concentrating under reduced pressure, obtain the yellow oily crude product of 101g benzyl protection.In yellow oily crude product, add 200mL methyl alcohol stir 2 hours, then filtration under diminished pressure, obtain 95.8g off-white color solid.Detect such white solid and yield calculating, result shows, such white solid has formula (I) structure, and purity is 98%, and yield is 84%.The analytical data of mass spectrum of such white solid is: [M+H]=805.3, the spectral analysis of the nuclear magnetic resonance data of such white solid are: 1H-NMR (DMSO-d6) 2.24 (s, 3H), 3.04-3.10 (m, 1H), 3.12-3.18 (m, 1H), 3.22-3.25 (m, 1H), 3.25-3.30 (m, 1H), 3.33-3.47 (m, 1H), 3.55-3.74 (m, 1H), 3.88-3.92 (m, 1H), 4.00-4.10 (m, 2H), 4.44 (t, J=5.98Hz, 1H), 4.62 (s, 8H), 4.73 (d, J=5.98Hz, 1H), 4.93 (d, J=4.96Hz, 2H), 6.80-6.88 (m, 1H), 7.04-7.10 (m, 3H), 7.11-7.16 (m, 3H), 7.16-7.21 (m, 6H), 7.28-7.33 (m, 5H), 7.33-7.40 (m, 9H), 7.52-7.62 (m, 2H).
Above-mentioned obtained off-white color solid 95.8g (119mmol) is placed in the round-bottomed flask of 2L, dissolve with the acetum of the hydrogen bromide of 960mL15wt%, stirring at room temperature is complete to raw material reaction.After reaction terminates, reaction product solution is dropped in 10L frozen water, there is a large amount of oily matter Precipitations, centrifugal removing supernatant liquid, organic phase is successively through methylene dichloride dissolving, saturated sodium bicarbonate and saturated nacl aqueous solution washing, anhydrous sodium sulfate drying and concentrating under reduced pressure, and obtain weak yellow foam shape solid, this foaming solid is at 190mL ethyl acetate and 95mL normal heptane recrystallization, then solid-liquid separation, obtains 47.8g off-white color solid.Detect such white solid and yield calculating, result shows, such white solid is that Ka Gelie is clean, and purity is 99.5%, and yield is 90%.The analytical data of mass spectrum of such white solid is: [M+Na]=467.3, the spectral analysis of the nuclear magnetic resonance data of such white solid are: 1H-NMR (DMSO-d6) 2.27 (s, 3H), 3.14-3.17 (m, 1H), 3.17-3.19 (m, 1H), 3.20-3.24 (m, 1H), 3.25-3.29 (m, 1H), 3.42-3.47 (m, 1H), 3.68-3.73 (m, 1H), 3.97 (d, J=9.44Hz, 1H), 4.07-4.17 (m, 2H), 4.44 (t, J=6.04Hz, 1H), 4.73 (d, J=5.67Hz, 1H), 4.93 (d, J=4.91Hz, 2H), 6.80 (d, J=3.78Hz, 1H), 7.12 (d, J=7.55Hz, 1H), 7.15 (dd, J=7.55, 1.51Hz, 1H), 7.20 (t, J=8.68Hz, 2H), 7.23 (d, J=1.13Hz, 1H), 7.28 (d, J=3.40Hz, 1H), 7.57-7.61 (m, 2H), 13C-NMR (DMSO-d6) 18.81,33.44,61.43,70.42,74.67,78.48,81.21,81.32,115.88 (d, J=21.96Hz, 2C), 123.39,126.25,126.36,126.95 (d, J=7.68Hz, 2C), 129.06,129.65,130.52 (d, J=3.29Hz, 1C), 134.93,137.36,138.24,140.22,143.63,161.37 (d, J=243.70Hz, 1C).
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (10)
1. the preparation method that Yi Zhong Ka Gelie is clean, comprises the following steps:
Shown in formula (I), structural compounds carries out debenzylation, obtains Ka Gelie clean;
2. preparation method according to claim 1, is characterized in that, shown in described formula (I), structural compounds is at H
2debenzylation is carried out under existing with organic solvent.
3. preparation method according to claim 1, is characterized in that, shown in described formula (I), structural compounds carries out debenzylation in the acetum of hydrogen bromide.
4. preparation method according to claim 3, is characterized in that, in the acetum of described hydrogen bromide, the concentration of hydrogen bromide is 10 ~ 30wt%.
5. preparation method according to claim 1, is characterized in that, shown in described formula (I), structural compounds prepares according to following steps:
Shown in formula (II), structural compounds carries out reduction reaction in the presence of a reducing agent, obtains structural compounds shown in formula (I);
In formula (II), R is selected from hydrogen or methyl.
6. preparation method according to claim 5, is characterized in that, described reductive agent is triethyl silicane and boron trifluoride diethyl etherate.
7. preparation method according to claim 5, is characterized in that, described R is hydrogen, and shown in formula (II), structural compounds prepares according to following steps:
2-(2-methyl-5-halogen benzyl)-5-(4-fluorobenzene) thiophene and the mixing of 2,3,4,6-tetra--O-benzyl-D Gluconolactone, react, obtain structural compounds shown in formula (II).
8. preparation method according to claim 5, is characterized in that, described R is methyl, and shown in formula (II), structural compounds prepares according to following steps:
2-(2-methyl-5-halogen benzyl)-5-(4-fluorobenzene) thiophene, 2,3,4,6-tetra--O-benzyl-D Gluconolactones and methylsulfonic acid mix, and react, and obtain structural compounds shown in formula (II).
9. there is the clean intermediate of Ka Gelie of formula (I) structure;
10. the preparation method of the clean intermediate of Yi Zhong Ka Gelie, comprising:
Shown in formula (II), structural compounds reacts in the presence of a reducing agent, obtains the clean intermediate of Ka Gelie of structure shown in formula (I);
In formula (II), R is selected from hydrogen or methyl.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410499537.7A CN105440025B (en) | 2014-09-25 | 2014-09-25 | A kind of method preparing canagliflozin and its intermediate and the intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410499537.7A CN105440025B (en) | 2014-09-25 | 2014-09-25 | A kind of method preparing canagliflozin and its intermediate and the intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105440025A true CN105440025A (en) | 2016-03-30 |
| CN105440025B CN105440025B (en) | 2019-02-12 |
Family
ID=55550718
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410499537.7A Expired - Fee Related CN105440025B (en) | 2014-09-25 | 2014-09-25 | A kind of method preparing canagliflozin and its intermediate and the intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105440025B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016128995A1 (en) * | 2015-02-09 | 2016-08-18 | Indoco Remedies Limited | Process for the preparation of sglt inhibitor compounds |
| CN110698468A (en) * | 2019-09-24 | 2020-01-17 | 杭州华东医药集团新药研究院有限公司 | Preparation method of canagliflozin |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101801371A (en) * | 2007-09-10 | 2010-08-11 | 詹森药业有限公司 | The preparation method of the chemical compound of useful as inhibitors of sglt |
| WO2012140120A1 (en) * | 2011-04-13 | 2012-10-18 | Janssen Pharmaceutica Nv | Process for the preparation of compounds useful as inhibitors of sglt2 |
| CN104151306A (en) * | 2013-05-13 | 2014-11-19 | 北京新天宇科技开发有限公司 | Canagliflozin new preparation method |
-
2014
- 2014-09-25 CN CN201410499537.7A patent/CN105440025B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101801371A (en) * | 2007-09-10 | 2010-08-11 | 詹森药业有限公司 | The preparation method of the chemical compound of useful as inhibitors of sglt |
| WO2012140120A1 (en) * | 2011-04-13 | 2012-10-18 | Janssen Pharmaceutica Nv | Process for the preparation of compounds useful as inhibitors of sglt2 |
| CN103596944A (en) * | 2011-04-13 | 2014-02-19 | 詹森药业有限公司 | Process for the preparation of compounds useful as inhibitors of SGLT2 |
| CN104151306A (en) * | 2013-05-13 | 2014-11-19 | 北京新天宇科技开发有限公司 | Canagliflozin new preparation method |
Non-Patent Citations (3)
| Title |
|---|
| JUNWON LEE，等: "Novel C-aryl glucoside SGLT2 inhibitors as potential antidiabetic agents: 1,3,4-Thiadiazolylmethylphenyl glucoside congeners", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
| 华东理工大学有机化学教研组: "《有机合成中的保护基》", 31 October 2004 * |
| 姚其正，等: "《药物合成反应》", 30 September 2012 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016128995A1 (en) * | 2015-02-09 | 2016-08-18 | Indoco Remedies Limited | Process for the preparation of sglt inhibitor compounds |
| US10508128B2 (en) | 2015-02-09 | 2019-12-17 | Indoco Remedies Limited | Process for the preparation of SGLT inhibitor compounds |
| CN110698468A (en) * | 2019-09-24 | 2020-01-17 | 杭州华东医药集团新药研究院有限公司 | Preparation method of canagliflozin |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105440025B (en) | 2019-02-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104496952A (en) | Synthesis method of dapagliflozin | |
| CN105061373A (en) | Synthesis method of dapagliflozin isomer impurity | |
| CN102060867A (en) | Method for preparing potassium trifluoroborate series compounds | |
| CN104119324B (en) | The preparation method that a kind of Ka Gelie is clean | |
| CN105440025A (en) | Preparation methods for canagliflozin and intermediate thereof and intermediate | |
| CN101962379A (en) | Method for refining sulfonyl isoquinoline derivative | |
| CN106279175A (en) | A kind of preparation method of Ertapenem Sodium | |
| CN102391259B (en) | Nifuratel compound and preparation method thereof | |
| CN102190647A (en) | Preparation method of nebivolol intermediate | |
| CN106674112A (en) | Synthetic methods of 7-azaspiro[3,5]-nonane-2-ol and hydrochloride compound thereof | |
| CN108264529A (en) | A kind of synthetic method of bis- piperidines -5-O- mycamino syl-tylono lides of 20,23- | |
| CN104961787B (en) | Synthetic method of cordycepin | |
| CN102863419B (en) | Flavane 3-alcohol acetylate and its preparation method and application | |
| CN103896938B (en) | A kind of preparation method of succsinic acid YM-905 | |
| CN103193800A (en) | Method for separating and purifying various components from cefaclor enzymatic reaction solution | |
| CN102942449B (en) | Synthetic method of 2,2-bis (trifluoroethyl) propanol | |
| CN102911085A (en) | Synthesis process of compound D-2- aminoxy-3-methylbutyric acid | |
| CN104045639B (en) | A kind of preparation method of figured silk fabrics acyclovir | |
| CN103848756B (en) | Preparation method of teriflunomide and intermediate thereof | |
| CN103265514B (en) | A kind of method preparing mycophenolate mofetile | |
| CN102603599B (en) | Method for preparing (S)-oxiracetam | |
| CN108047291A (en) | A kind of synthetic method of decanoy acetaldehyde heterozygosis flavone compound | |
| CN106496263A (en) | The preparation method of hexahydro furyl furan 01 derivatives, its intermediate and preparation method thereof | |
| CN113121578A (en) | Preparation method of benzoborazole compound | |
| CN104860961B (en) | One kind prepares 5 oxygen（P-nitrophenyl formyl）The method of nimoctin |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20190212 Termination date: 20200925 |