CN109553609A - A kind of preparation method of canagliflozin - Google Patents
A kind of preparation method of canagliflozin Download PDFInfo
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- CN109553609A CN109553609A CN201710884648.3A CN201710884648A CN109553609A CN 109553609 A CN109553609 A CN 109553609A CN 201710884648 A CN201710884648 A CN 201710884648A CN 109553609 A CN109553609 A CN 109553609A
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
Abstract
The present invention relates to a kind of preparation methods of canagliflozin; it is characterized in that; the preparation method comprises the following steps: 1) thiophene is under cryogenic by 2- (4- fluorophenyl) -5- [(the iodo- 2- aminomethyl phenyl of 5-) methyl]; with alkaline reagent and 2; after 3,4,6- tetra--O- (trimethyl silicon substrate)-D-Glucose acid lactone is reacted; methylation and deprotection reaction are carried out with the methanol solution of methanesulfonic acid again, generates intermediate 1；2) it after under cryogenic, intermediate 1 is reacted with triethylsilane and boron trifluoride ether, post-processes to get intermediate 2；3) under cryogenic, intermediate 2 is reacted with organic base, DMAP and aceticanhydride, is purified to get intermediate 3；4) intermediate 3 and alkaline aqueous solution after being reacted, purify up to canagliflozin.Mild condition of the present invention, safe operation, post-processing are simple；Product purity is high, and alpha-isomer is not detected, and product is safer.
Description
Technical field
The invention belongs to pharmaceutical chemistry to synthesize field, and in particular to a kind of industrialized preparation method of canagliflozin.
Background technique
Canagliflozin (Canagliflozin) is be approved in the co- transport protein 2 of sodium-glucose (SGLT2) inhibitor
One drug, for there is the blood glucose of diabetes B adult patients.It, which is acted on, helps the re-absorbed of glucose in kidney
SGLT2 albumen excludes more sugar by the urine of patient, declines blood glucose level.The medicine is by day Honda side Mitsubishi
It is researched and developed jointly with Johnson Co., in March, 2013, FDA ratified its listing.The chemical name of canagliflozin: (1S) -1,5- is de-
Hydrogen -1- [3- [[5- (4- fluorophenyl) -2- thienyl] methyl] -4- aminomethyl phenyl]-D-Glucose semihydrate, molecular formula are
C24H25FO5S.1/2H2O, molecular weight 453.5, structural formula is as follows:
Currently, preparation method disclosed in canagliflozin includes: Chinese patent CN102264714A, patent WO2016128995
And CN10544002A, patent CN10180137A and CN201510981375A etc., disclosed preparation method is summarized as follows:
In the route, with the D- grape of 2- (4- fluorophenyl) -5- [(5- halogen -2- aminomethyl phenyl) methyl] thiophene and protection
Saccharic acid lactone is starting material, and through coupling reaction, reduction reaction and deprotection reaction obtain canagliflozin.During the preparation process,
Second step majority carries out reduction reaction using triethylsilane and boron trifluoride ether, and generating glycosidic bond has α-and β-two kinds of structures
Type, wherein beta configuration is Preferred conformations, and α-is configured as isomer impurities.
In disclosed documents and materials, the shortcomings that above-mentioned route, is as follows: 1. as in patent CN105440025, first step reaction
Middle needs cool to -78 DEG C, the high requirements on the equipment, and temperature control is stringent；2. it is different to generate α-configuration in second step reduction reaction
Structure body impurity thoroughly removes α-configuration isomer impurities without effective purification process in disclosed data, may influence
Drug safety；3. post-processing operation is complicated, it is unfavorable for industrialized production；4. in patent CN10180137 and CN105541815
Intermediate 1, stability is poor, is unfavorable for long-term preservation.
(2) patent CN1829729A, CN102264714A, WO2016016852, US20160228375,
Preparation method disclosed in WO2016142950 and US20130237487, CN103694230A, CN103936727A is summarized such as
Under:
In above-mentioned route, with 2- (4- fluorophenyl) -5- [(5- halogen -2- aminomethyl phenyl) methyl] thiophene of lithium metal activation
Pheno, and 2,3,4,6- tetra--O- (trimethyl silicon substrate)-D-Glucose acid lactone occurs coupling, methylation and hydrolysis and obtains intermediate
1；It is restored through triethylsilane and boron trifluoride ether, obtains canagliflozin crude product；Through acetylation, intermediate 3 is obtained, it will be intermediate
Body 3 purifies, then is deprotected, and obtains the higher canagliflozin of purity or canagliflozin crude product and L-PROLINE forms eutectic object
Purifying, then decompose, obtain the higher canagliflozin of purity.In above-mentioned preparation route, second step reduction reaction, generating glycosidic bond has
α-and β-two kinds of configurations, beta configuration is Preferred conformations, and α-is configured as isomer impurities.
In presently disclosed document, above-mentioned route there are the shortcomings that it is as follows: 1. as patent CN200480022007,
In WO2016016852 and WO2016142950, use n-BuLi as activating reagent, needs to cool to -70 DEG C hereinafter, right
Equipment requirement is high, and temperature control is stringent, and operational safety requires high；2. generating α-configuration isomers in second step reduction reaction
Impurity obtains intermediate 3-1 by acetylation, has not been able to thoroughly remove α-configuration isomer impurities to intermediate 3-1 purifying；
3. being easy impurity residual, in patent US20130237487, CN103694230, CN103936727, refers to and use canagliflozin
The purifying of eutectic object is formed with amino acid, then decomposes and tends to have amino acid impurity residual in the canagliflozin being obtained by extraction；
(3) synthetic route that US20140128595 is referred to is as follows:
Above-mentioned route is primarily present starting material raw material 1, and 6- inner ether -2,4-OTBDPS- β-D- glucopyranose is not easy to obtain,
Formatting reaction and n-BuLi are used in reaction, to operational safety requirement height, the disadvantages such as synthesis yield is low are not suitable for industry
Metaplasia produces.
Equally, there is also starting material L-GuA-gamma lactones to be not easy to obtain in patent CN105481915, and price is high
Expensive problem, thus it is difficult industrialized production.
(4) patent CN103596944A, CN103980263A and US20110087017 refers to direct Chiral Synthesis such as
Under:
In the route, 2,3,4,6-O- tetra- pivaloyl group-α-D- bromo glucopyranoses are expensive, production cost
Height, the reaction time is long, chromatographs to obtain the single isomers of intermediate 1 by column, thus is unsuitable for industrialized production.
(5) synthetic route referred in WO2015181692 is as follows:
It is that starting is former with (the iodo- 2- aminomethyl phenyl of 5-)-(5- (4- fluorophenyl) -2- thienyl) ketone in the synthetic route
Material reacts through 3 steps, obtains canagliflozin crude product, then through ethyl acetate, methyl tertiary butyl ether(MTBE), water crystallization, obtain canagliflozin.
There are the reactions of 2 steps to need temperature at -70 DEG C for the synthetic route, the high requirements on the equipment；And second step uses n-BuLi, operation
Security requirement is high；Canagliflozin crude crystalline purification step, the disadvantages such as yield is low.
Summary of the invention
Technology based on the above background, the object of the present invention is to provide a kind of industrialization systems of the canagliflozin of high-purity
Preparation Method；It is related specifically to the industry for obtaining the canagliflozin of high-purity by preparing high-purity canagliflozin intermediate 3
Change preparation method.Described method includes following steps:
1) 2- (4- fluorophenyl) -5- [(the iodo- 2- aminomethyl phenyl of 5-) methyl] thiophene under cryogenic, with alkaline reagent and
After 2,3,4,6- tetra--O- (trimethyl silicon substrate)-D-Glucose acid lactone is reacted, then with the methanol solution containing methanesulfonic acid into
Row methylation and deprotection reaction, generate intermediate 1；
2) intermediate 1 is reacted with triethylsilane and boron trifluoride ether, generates intermediate 2；
3) intermediate 2 is reacted with organic base, DMAP and aceticanhydride, generates intermediate 3；
4) intermediate 3 is reacted with alkaline aqueous solution generates canagliflozin
Base refers to alkaline reagent in step 1)；Acid/MeoH refers to methanesulfonic acid methanol solution；Et in step 2)3SiH is
Refer to triethylsilane；BF3.Et2O refers to boron trifluoride ether；Ac in step 3)2O refers to aceticanhydride.
Wherein, prepared by intermediate 1 specifically: 2- (4- fluorophenyl) -5- [(the iodo- 2- aminomethyl phenyl of 5-) methyl] thiophene is low
Under the conditions of temperature, and alkaline reagent and 2, after 3,4,6- tetra--O- (trimethyl silicon substrate)-D-Glucose acid lactone is reacted, then with
Methanol solution containing methanesulfonic acid carry out methylation and deprotection reaction to get.
Present invention further propose that, it the described method comprises the following steps:
1) in inert environments, 2- (4- fluorophenyl) -5- [(the iodo- 2- aminomethyl phenyl of 5-) methyl] thiophene is at -30 DEG C~-15 DEG C
At a temperature of, and alkaline reagent and 2 after 3,4,6- tetra--O- (trimethyl silicon substrate)-maltonic acid lactone reaction, are warming up to room
Temperature, then reacted with the methanol solution containing methanesulfonic acid, it purifies to get intermediate 1；
2) -30 DEG C~-15 DEG C at a temperature of, intermediate 1 made from step 1) is dissolved in organic solvent, with triethyl group
After silane and boron trifluoride ether are reacted, post-process to get intermediate 2；
3) intermediate 2 made from step 2) -5~5 DEG C at a temperature of, be added after organic base and DMAP mix, add
Aceticanhydride is reacted, and is purified to get intermediate 3；
4) intermediate 3 made from step 3) is dissolved in organic solvent, alkaline aqueous solution is added dropwise, after being reacted, purification
Up to canagliflozin.
Present invention further propose that, alkaline reagent described in step 1) is selected from isopropylmagnesium chloride lithium chloride, Zhong Ding
It is one or more in base magnesium chloride lithium chloride, isopropylmagnesium chloride, tert-butyl magnesium chloride or cyclohexyl magnesium chloride；It is preferably different
Propyl magnesium chloride lithium chloride, sec-butyl magnesium chloride lithium chloride.
In step 1), 2- (4- fluorophenyl) -5- [(the iodo- 2- aminomethyl phenyl of the 5-) methyl] thiophene and the alkaline reagent
Molar ratio be 1:1~2, preferably 1:1.3~1.5；
2- (4- fluorophenyl) -5- [(the iodo- 2- aminomethyl phenyl of the 5-) methyl] thiophene and the tetra--O- (three of 2,3,4,6-
Methylsilyl) molar ratio of-D-Glucose acid lactone is 1:1~2, preferably 1:1.3~1.6.
Present invention further propose that, step 1) specifically: using tetrahydrofuran as solvent, in -25 DEG C~-20 DEG C of temperature
Under, after 2- (4- fluorophenyl) -5- [(the iodo- 2- aminomethyl phenyl of 5-) methyl] thiophene is reacted with alkaline reagent, then addition 2,3 is added dropwise,
Tetra--O- of 4,6- (trimethyl silicon substrate)-D-Glucose acid lactone is reacted；.
Reaction is optimal in -25 DEG C~-20 DEG C of at a temperature of effect in step 1), but temperature is lower than -35 DEG C or higher than -15 DEG C
When, react very slow, or even do not react substantially.
Step 1) adds methanesulfonic acid and methanol after carrying out reaction early period, and wherein methanesulfonic acid not only acts as catalysis methyl
The effect for changing reaction, goes back the TMS protecting group of hydrolyzable hydroxyl.
2- described in step 1) (4- fluorophenyl) -5- [(the iodo- 2- aminomethyl phenyl of 5-) methyl] thiophene and the methanesulfonic acid
Molar ratio 1:2~2.7, preferably 1:2.1~2.3；
The additive amount of the methanol is every mole of 2- (4- fluorophenyl) -5- [(the iodo- 2- aminomethyl phenyl of 5-) methyl] thiophene
Pheno adds 2~5L methanol.
In step 1), 2- (4- fluorophenyl) -5- [(the iodo- 2- aminomethyl phenyl of 5-) methyl] thiophene reacts 0.8 with alkaline reagent
After~1.2 hours, 2,3,4,6- tetra--O- (trimethyl silicon substrate)-D-Glucose acid lactone is added, carries out reaction 1~3 hour；
The methanol solution containing methanesulfonic acid is added, heats up naturally, stirring, reaction carries out 12~18 hours.
Present invention further propose that, it is purified for the first time described in step 1) specifically: by reaction solution at -5 DEG C~5 DEG C
At a temperature of, the pH value of reaction solution is adjusted to 7~8；30~40 DEG C are warming up to, decompression rotation removes solvent, and organic solvent extraction is dry,
Further decompression rotation removes solvent after filtering, then is recrystallized to get intermediate 1；
The first time purification is further are as follows: reaction solution is cooled to -5~5 DEG C, sodium bicarbonate aqueous solution is instilled and is reacted
Quenching reaction in liquid adjusts the pH value of reaction solution to 7~8；At a temperature of 30~40 DEG C, decompression rotation removes organic solvent, then uses
Organic solvent extraction, anhydrous sodium sulfate further depressurize rotation except organic solvent, obtain crude product after drying, filtering；Crude product carries out weight again
Crystallization obtains 1 methyl 1-C- of centre (3- ((5- (4- fluorophenyl) -2- thienyl) methyl) -4- benzyl)-D glucopyranoside.
Present invention further propose that, in step 2), the molar ratio of the intermediate 1 and the triethylsilane is 1:
2~6, preferably 1:3；The molar ratio of the intermediate 1 and the boron trifluoride ether is 1:2~6, preferably 1:3.
Intermediate 1 described in step 2) is dissolved in organic solvent dichloromethane, and the usage amount of the methylene chloride is 6~
The intermediate 1 of 10ml/g, the intermediate 1 of preferably 7~8ml/g.
In step 2), in the organic solvent containing intermediate 1, triethylsilane is first added, then be added dropwise be added it is borontrifluoride
Borate ether.It is reacted at a temperature of -25~-5 DEG C；
Preferably, it is reacted at a temperature of -25~-10 DEG C.
In step 2), dichloromethane solution is added in intermediate 1, is stirred after completely dissolution, in triethylsilane and trifluoro
Change borate ether, reacts 2~4 hours.
The present invention into one propose, described in step 2) post-process specifically: not higher than -10 DEG C at a temperature of, instill
Saturated sodium bicarbonate solution, quenching reaction stand split-phase, take organic phase, dry, filter to get 2 organic solution of intermediate；
It is described dry using anhydrous sodium sulfate.
Present invention further propose that, in step 3), the organic base is selected from N-methylmorpholine, triethylamine, diisopropyl
It is one or more in ethamine；
Preferably, the molar ratio of the intermediate 2 and the organic base is 1:4~8；The intermediate 2 rubs with aceticanhydride
You are than being 1:4~8；The molar ratio of the intermediate 2 and DMAP is 1:0.08~0.12；
It is highly preferred that the molar ratio of the intermediate 2 and the organic base is 1:5~6；The intermediate 2 and aceticanhydride
Molar ratio be 1:5~6；The molar ratio of the intermediate 2 and DMAP is 1:0.1.
In step 3), after organic base and DMAP is added in the intermediate 2, then aceticanhydride is slowly added dropwise, after being added dropwise, rises
To room temperature, react 4~6 hours.
Organic base is used to neutralize the acid of generation, provides reaction system alkaline environment；DMAP is efficient acylation catalyst.
What the present invention was proposed into one, it is purified for second described in step 3) specifically: water, decompression rotation are added in reaction solution
Except solvent, filtering obtains off-white powder, is added in alcohol and is sufficiently stirred, is heated to flowing back, be cooled to room temperature, and filters, and decompression is dry
After dry, white solid is obtained.
Second of purification further comprises that white solid is added in organic solvent C, is heated to being completely dissolved,
Organic solvent D is instilled, is down to and is stirred overnight at room temperature naturally.Filtering is washed using organic solvent D, obtains white solid intermediate
3。
The alcohol is one or more in methanol, ethyl alcohol, isopropanol, preferred alcohol, methanol；
The organic solvent C is selected from methyl tertiary butyl ether(MTBE), methyl n-butyl ether, methyl sec-butyl ether, methyl tert-amyl
One of ether, ethyl acetate are a variety of, preferably methyl tertiary butyl ether(MTBE), methyl n-butyl ether, ethyl acetate；
The organic solvent D is selected from one of petroleum ether, n-hexane, normal heptane or a variety of, preferably n-hexane, positive heptan
Alkane.
Present invention further propose that, in step 4), alkali in the alkaline aqueous solution be selected from sodium methoxide, lithium hydroxide,
One of sodium hydroxide, potassium hydroxide are a variety of；
Preferably, the molar ratio of the intermediate 3 and the alkali is 1:2~5, more preferably 1:3~4.
In step 4), intermediate 3, as organic solvent, is added to tetrahydro using tetrahydrofuran by intermediate 3 by intermediate 3
It is mixed after in furans with methanol, after stirring, instills the aqueous solution of sodium methoxide, stirring at normal temperature 2~4 hours；
Present invention further propose that, it is purified for the third time described in step 4) specifically: after completion of the reaction, in reaction solution
Water is added, decompression rotation removes organic solvent, and filtering, pure water is dry, obtains white solid；White solid is completely dissolved in alcohol
In, water is added, white suspension is stirred to get, is filtered, washing is dry to get canagliflozin.
The third time purification is further are as follows: pure water is added in end of reaction, and decompression rotation removes organic solvent, filtering, and pure water is washed
It washs, it is dry, obtain white solid；White solid is added in alcohol, active carbon is added, is heated to reflux 30 minutes, is filtered, the
It is secondary to add pure water, it is stirred at room temperature 12 hours or more, obtains white suspension, filter, pure water obtains high-purity card lattice
Column are net.
The alcohol is selected from one of methanol, ethyl alcohol or isopropanol or a variety of, preferably ethyl alcohol, methanol；
The usage amount of the alcohol is the white solid of 5~6ml/g, preferably 5.5ml/g white solid；Described adding is pure
The usage amount of water is 5~4ml/g white solid, the preferably white solid of 4.5ml/g；
The pure and mild total dosage for adding pure water for the second time is the white solid of 10ml/g.
As a preferred solution of the present invention, a kind of preparation method of canagliflozin is provided, the preparation method includes following
Step:
1) in inert environments, using tetrahydrofuran as solvent, -25 DEG C~-20 DEG C at a temperature of, 2- (4- fluorophenyl) -5-
[(the iodo- 2- aminomethyl phenyl of 5-) methyl] thiophene and alkaline reagent are added with molar ratio for the ratio of 1:1.3~1.5, are reacted
Afterwards, it then is added dropwise by every mole of 2- (4- fluorophenyl) -5- [(the iodo- 2- aminomethyl phenyl of 5-) methyl] thiophene and is added 1.3~1.6mol's
Tetra--O- of 2,3,4,6- (trimethyl silicon substrate)-D-Glucose acid lactone is reacted；
The temperature is maintained, by 2- (4- fluorophenyl) -5- [(the iodo- 2- aminomethyl phenyl of 5-) methyl] thiophene and methanesulfonic acid mole
Than the ratio for 1:2.1~2.3, the methanol solution containing methanesulfonic acid is added, the reaction was continued；Reaction solution is cooled to -5 DEG C~5
DEG C, it is quenched, adjusts pH value to 7~8；It is warming up to 30~40 DEG C again, purifies to get intermediate 1；
Wherein methanol solution be every mole of 2- (4- fluorophenyl) -5- [(the bromo- 2- aminomethyl phenyl of 5-) methyl] thiophene addition 2~
5L；
2) -25 DEG C~-10 DEG C at a temperature of, intermediate 1 made from step 1) is dissolved in organic solvent, with triethyl group
Silane and boron trifluoride ether are the ratio addition of 1:3:3 in molar ratio, are reacted；Not higher than -10 DEG C at a temperature of, quench
It goes out to get intermediate 2；
3) intermediate 2 made from step 2) -5~5 DEG C at a temperature of, N-methylmorpholine or triethylamine is added, and
DMAP after mixing, then instills acetic anhydride, is warming up to room temperature, reacted, and purifies to get intermediate 3；
Wherein, the molar ratio of the intermediate 2 and the organic base is 1:5~6；The intermediate 2 rubs with aceticanhydride
You are than being 1:5~6；The molar ratio of the intermediate 2 and DMAP is 1:0.1；
4) intermediate 3 made from step 3) is dissolved in organic solvent, sodium methoxide or lithium hydroxide aqueous solution is added dropwise, it is described
The molar ratio of intermediate 3 and the sodium methoxide or lithium hydroxide is 1:3~4, is reacted, and is purified to get canagliflozin.
The present invention include at least it is following the utility model has the advantages that
1, used starting material is easy to get, cheap, advantageously reduces production cost；
2, high with alkali metal reagent relative safety in step 1), and couple temperature is at -25~-20 DEG C, device temperature
Demand is low, operation is safer, equipment volume demand is small；
3, in step 2), after sodium bicarbonate aqueous solution quenching reaction, get organic phase, it is anti-to be directly used in lower step through drying
It answers.The operation such as distillation, extraction is avoided, simplifies operation, while reducing solvent usage amount；
4, in step 3), obtained 3 crude product of intermediate is obtained by being purified twice with alcohol, organic solvent C and organic solvent D
To the high-purity canagliflozin intermediate 3 of individual isomer, purity reaches 99.8% or more, by obtaining the height of individual isomer
Purity canagliflozin intermediate 3 so react obtains individual isomer high-purity canagliflozin, purity reach 99.95% with
On.
Reaction condition of the present invention is mild, and operation is safer, and post-processing is simple, and obtained canagliflozin product purity is high,
Residual impurity type is few, content is low, and alpha-isomer is not detected, and product is safer.
Specific embodiment
The following examples are used to illustrate the present invention, but are not intended to limit the scope of the present invention..
Method therefor is conventional method unless otherwise instructed in following embodiments.
Embodiment 1
The present embodiment is a kind of preparation method of canagliflozin, and the preparation method comprises the following steps:
1, the preparation of intermediate 1:
3L there-necked flask is taken, mechanical stirring, thermometer and the low liquid funnel of constant pressure are loaded onto；300ml anhydrous tetrahydro furan is added, adds
Enter 100g (0.245mol) 2- (4- fluorophenyl) -5- [(the iodo- 2- aminomethyl phenyl of 5-) methyl] thiophene, stirring to dissolution；In nitrogen
Under protection, -25~-20 DEG C are cooled to, instills 263.8mL (0.343mol) sec-butyl magnesium chloride lithium chloride/THF solution, is added dropwise
It finishes, the reaction was continued 1 hour；
The temperature is maintained, -25~-20 DEG C of 2,3,4,6- tetra--O- (front three of 171.6g (0.368mol) will be cooled in advance
Base silicon substrate)-D-Glucose acid lactone is added dropwise and is added in reaction solution, wherein described 2,3,4,6- tetra--O- (trimethyl silicon substrate) Portugal-D-
Grape saccharic acid lactone is dissolved in the anhydrous tetrahydrofuran solution of 200mL.After being added dropwise, the reaction was continued 2 hours；
51.8g (0.539mol) methanesulfonic acid is instilled again, wherein the methanesulfonic acid is dissolved in 1L absolute methanol solution；Naturally it rises
Temperature reaction 18 hours.
Reaction solution is cooled to -5~5 DEG C, sodium bicarbonate aqueous solution is slowly dropped into reaction solution, is added dropwise, is monitored
PH is 7~8；Decompression rotation removes solvent, obtains aqueous solution methyl n-butyl ether (600ml*300ml) and extracts 2 times, merges organic
Phase, with anhydrous sodium sulfate dry a few hours, filtering, decompression rotation removes solvent, obtains clear yellow viscous solid；Under room temperature, 300ml is added
Methyl n-butyl ether stirring and dissolving instills in 600ml normal heptane, stirring, removes solvent, and vacuum drying obtains faint yellow solid
1 108.9g of intermediate, yield 93.7%, HPLC 85.2%.
2, the preparation of intermediate 2:
2L reaction flask is taken, mechanical stirring, thermometer and the low liquid funnel of constant pressure are loaded onto；700ml methylene chloride is added, is added
100g (0.211mol) intermediate 1, stirring and dissolving；- 25~-10 DEG C are cooled to, 73.5g (0.632mol) triethyl group silicon is added
Alkane；Temperature is maintained, 89.7g (0.632mol) boron trifluoride ether is slowly added dropwise；It is added dropwise, the reaction was continued 2 hours.
Temperature is adjusted to be below at -10 DEG C, sodium bicarbonate aqueous solution 800ml is instilled, is added dropwise, stops stirring, it is quiet
Split-phase is set, separates organic phase, anhydrous sodium sulfate dry a few hours, filtering obtains the dichloromethane solution about 850ml of intermediate 2.
HPLC detection, β-isomers 81.36%, alpha-isomer 3.22%.Yield is calculated with 100%.
3, the preparation of intermediate 3:
2L reaction flask is taken, mechanical stirring, thermometer and the low liquid funnel of constant pressure are loaded onto；By the dichloromethane solution of intermediate 2
About 850ml is added in reaction flask, is cooled to -5~5 DEG C, and 162g (1.27mol) N-methylmorpholine is added under stirring condition, is added
2.58g(0.0211mol)DMAP；Temperature is maintained, 129.3g (1.27mol) aceticanhydride is slowly added dropwise；It is added dropwise, the reaction was continued 4
Hour.
End of reaction instills 425ml pure water, stirs 30 minutes.Decompression rotation removes organic solvent, and filtering obtains white solid.
White solid is added in 1.3L ethyl alcohol, is heated to flowing back, stirs 30 minutes, is cooled to room temperature, is filtered, it is dry, it obtains white
Color solid 94.0g.White solid is added in 752ml methyl tertiary butyl ether(MTBE), is heated to flowing back, obtains clear solution, slowly
564ml normal heptane is added, continues to be heated to flowing back, obtains clear solution, be slowly dropped to room temperature, be stirred overnight；Solution is filtered,
Filter cake is washed with 50ml*2 normal heptane, obtains white solid 89.9g, yield 69.5%.HPLC detection, 3 purity of intermediate
99.81%, tetra-acetylated alpha-isomer is not detected.
4, the preparation of canagliflozin:
2L reaction flask is taken, mechanical stirring, thermometer and the low liquid funnel of constant pressure are loaded onto；89g (0.145mol) intermediate 3 is added
Enter the in the mixed solvent to 445ml methanol and 445ml tetrahydrofuran, stirs, obtain slurry solution.At room temperature, it is slowly added dropwise
The pure water solution (100ml) of 31.3g (0.58mol) sodium methoxide.It is added dropwise, the reaction was continued 4 hours.End of reaction is added
425ml pure water, decompression rotation remove organic solvent, are filtered under diminished pressure, dry with 50ml*2 pure water, obtain white solid 64g.It will
Obtained solid is added in 352ml methanol, stirring and dissolving, is added active carbon (3.2g, 5%), and reflux 30 minutes, mistake are heated to
Deactivation charcoal is filtered out, is added pure water (288ml), is heated to flowing back, obtains clear solution, room temperature is slowly dropped to, is stirred 12 hours
More than, it filters, it is dry, white solid 59.8g, yield 93.5% are obtained, alpha-isomer is not detected in HPLC purity 99.93%
Impurity.
Embodiment 2
The present embodiment is the preparation method of another canagliflozin, and the preparation method comprises the following steps:
1, the preparation of intermediate 1:
2L there-necked flask is taken, mechanical stirring, thermometer and the low liquid funnel of constant pressure are loaded onto；150ml anhydrous tetrahydro furan is added, adds
Enter 50g (0.122mol) 2- (4- fluorophenyl) -5- [(the iodo- 2- aminomethyl phenyl of 5-) methyl] thiophene, stirring to dissolution；Nitrogen is protected
Shield, and -25~-20 DEG C are cooled to, 122.5mL (0.159mol) isopropylmagnesium chloride lithium chloride/THF solution is instilled, is dripped
Bi Hou, the reaction was continued 1 hour；
The temperature is maintained, -25~-20 DEG C of 2,3,4,6- tetra--O- (front three of 74.3g (0.159mol) will be cooled in advance
Base silicon substrate)-D-Glucose acid lactone is added dropwise and is added in reaction solution, wherein described 2,3,4,6- tetra--O- (trimethyl silicon substrate) Portugal-D-
Grape saccharic acid lactone is dissolved in the anhydrous tetrahydrofuran solution of 100mL.After being added dropwise, the reaction was continued 2 hours；
25.8g (0.268mol) methanesulfonic acid is instilled again, wherein the methanesulfonic acid is dissolved in 350ml absolute methanol solution；From
Right temperature reaction 18 hours.
Reaction solution is cooled to -5~5 DEG C, sodium bicarbonate aqueous solution is slowly dropped into reaction solution, is added dropwise, is monitored
PH is 7~8；Decompression rotation removes solvent, obtains aqueous solution ethyl acetate (300ml*150ml) and extracts 2 times, merge organic phase, uses
Anhydrous sodium sulfate dries a few hours, filtering, and decompression rotation removes solvent, obtains clear yellow viscous solid；Under room temperature, 150ml acetic acid is added
Ethyl ester stirring and dissolving instills in 300ml n-hexane, stirring, removes solvent, and vacuum drying obtains faint yellow solid intermediate 1
50.9g, yield 87.7%, HPLC 86.7%.
2, the preparation of intermediate 2:
1L reaction flask is taken, mechanical stirring, thermometer and the low liquid funnel of constant pressure are loaded onto；400ml methylene chloride is added, is added
50g (0.105mol) intermediate 1, stirring and dissolving；- 25~-10 DEG C are cooled to, 36.8g (0.316mol) triethylsilane is added；
Temperature is maintained, 44.8g (0.316mol) boron trifluoride ether is slowly added dropwise；It is added dropwise, the reaction was continued 2 hours.
Temperature is adjusted to be below at -20 DEG C, sodium bicarbonate aqueous solution 800ml is instilled, temperature control is no more than -10 DEG C, is added dropwise
It finishes, stops stirring, stand split-phase, separate organic phase, anhydrous sodium sulfate dry a few hours, filtering obtains the dichloro of intermediate 2
Dichloromethane about 480ml.HPLC detection, β-isomers 80.51%, alpha-isomer 4.72%.Yield is calculated with 100%.
3, the preparation of intermediate 3:
1L reaction flask is taken, mechanical stirring, thermometer and the low liquid funnel of constant pressure are loaded onto；By the dichloromethane solution of intermediate 2
About 480ml is added in reaction flask, is cooled to -5~5 DEG C, and 53.6g (0.53mol) triethylamine is added under stirring condition, is added
1.28g(0.011mol)DMAP；Temperature is maintained, 54.1g (0.53mol) aceticanhydride is slowly added dropwise；It is added dropwise, it is 4 small that the reaction was continued
When.
End of reaction instills 215ml pure water, stirs 30 minutes.It maintains at 30~40 DEG C of temperature, decompression rotation is except organic molten
Agent, filtering, obtains white solid.White solid is added in 650ml methanol, is heated to flowing back, stirs 30 minutes, is cooled to
Room temperature filters, dry, obtains white solid 45.5g.White solid is added in 423ml ethyl acetate, is heated to flowing back,
Clear solution is obtained, 280ml n-hexane is slowly added to, is slowly dropped to room temperature, be stirred overnight；Solution is filtered, filter cake 25ml*
The washing of 2 n-hexanes, obtains white solid 41.1g, yield 63.9%.HPLC detection, 3 purity 99.79% of intermediate are not detected
Tetra-acetylated alpha-isomer.
4, the preparation of canagliflozin:
1L reaction flask is taken, mechanical stirring, thermometer and the low liquid funnel of constant pressure are loaded onto；40g (0.065mol) intermediate 3 is added
Enter the in the mixed solvent to 200ml methanol and 200ml tetrahydrofuran, stirs, obtain slurry solution.At room temperature, it is slowly added dropwise
The pure water solution (90ml) of 8.1g (0.196mol) lithium hydroxide.It being added dropwise, reacts about 1 hour, reaction solution becomes clarification, after
Continuous reaction 4 hours.End of reaction, is added 200ml pure water, and decompression rotation removes organic solvent, solid is precipitated, is filtered under diminished pressure, uses 30ml*
2 pure waters, it is dry, obtain white solid 27.6g.Obtained solid is added in 152ml methanol, stirring and dissolving, is added
Active carbon (1.4g, 5%) is heated to reflux 30 minutes, is filtered to remove active carbon, is added pure water (125ml), is heated to flowing back,
Clear solution is obtained, room temperature is slowly dropped to, stirring 12 hours or more, filters, it is dry, obtain white solid 25.9g, yield
89.8%.Alpha-isomer impurity is not detected in HPLC purity 99.95%, single miscellaneous less than 0.02%.
Although above having used general explanation, specific embodiment and test, the present invention is made to retouch in detail
It states, but on the basis of the present invention, it can be made some modifications or improvements, this is apparent to those skilled in the art
's.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, belong to claimed
Range.
Claims (10)
1. a kind of preparation method of canagliflozin, which comprises the following steps:
1) 2- (4- fluorophenyl) -5- [(the iodo- 2- aminomethyl phenyl of 5-) methyl] thiophene under cryogenic, and alkaline reagent and 2,3,
After 4,6- tetra--O- (trimethyl silicon substrate)-D-Glucose acid lactone is reacted, then with containing methanesulfonic acid methanol solution carry out first
Base and deprotection reaction generate intermediate 1；
2) intermediate 1 is reacted with triethylsilane and boron trifluoride ether, generates intermediate 2；
3) intermediate 2 is reacted with organic base, DMAP and aceticanhydride, generates intermediate 3；
4) intermediate 3 is reacted with alkaline aqueous solution generates canagliflozin
2. preparation method according to claim 1, which is characterized in that the preparation method comprises the following steps:
1) in inert environments, 2- (4- fluorophenyl) -5- [(the iodo- 2- aminomethyl phenyl of the 5-) methyl] temperature of thiophene at -30 DEG C~-15 DEG C
Under degree, and alkaline reagent and 2 after 3,4,6- tetra--O- (trimethyl silicon substrate)-maltonic acid lactone reaction, are warming up to room temperature, then
It is reacted, is purified to get intermediate 1 with the methanol solution containing methanesulfonic acid；
2) -30 DEG C~-15 DEG C at a temperature of, intermediate 1 made from step 1) is dissolved in organic solvent, with triethylsilane
And after boron trifluoride ether is reacted, post-process to get intermediate 2；
3) intermediate 2 made from step 2) -5~5 DEG C at a temperature of, be added after organic base and DMAP mix, add aceticanhydride
It is reacted, is purified to get intermediate 3；
4) intermediate 3 made from step 3) is dissolved in organic solvent, alkaline aqueous solution is added dropwise, after being reacted, purifies to obtain the final product
Canagliflozin.
3. preparation method according to claim 2, which is characterized in that alkaline reagent described in step 1) is selected from isopropyl chloride
Change one in magnesium lithium chloride, sec-butyl magnesium chloride lithium chloride, isopropylmagnesium chloride, tert-butyl magnesium chloride or cyclohexyl magnesium chloride
Kind is a variety of；
Preferably, mole of 2- (4- fluorophenyl) -5- [(the iodo- 2- aminomethyl phenyl of 5-) methyl] thiophene and the alkaline reagent
Than for 1:1~2；2- (4- fluorophenyl) -5- [(the iodo- 2- aminomethyl phenyl of the 5-) methyl] thiophene and the tetra--O- of 2,3,4,6-
The molar ratio of (trimethyl silicon substrate)-D-Glucose acid lactone is 1:1~2；
It is highly preferred that 2- (4- fluorophenyl) -5- [(the iodo- 2- aminomethyl phenyl of the 5-) methyl] thiophene rubs with the alkaline reagent
You are than being 1:1.3~1.5；2- (4- fluorophenyl) -5- [(the iodo- 2- aminomethyl phenyl of the 5-) methyl] thiophene and the 2,3,4,6-
Four-O- (trimethyl silicon substrate)-D-Glucose acid lactone molar ratio is 1:1.3~1.6.
4. described in any item preparation methods according to claim 1~3, which is characterized in that (the 4- fluorobenzene of 2- described in step 1)
Base) -5- [(the iodo- 2- aminomethyl phenyl of 5-) methyl] thiophene and the methanesulfonic acid molar ratio 1:2~2.7, preferably 1:2.1~
2.3；
The additive amount of the methanol is that every mole of 2- (4- fluorophenyl) -5- [(the iodo- 2- aminomethyl phenyl of 5-) methyl] thiophene adds
Add 2~5L methanol.
5. preparation method according to any one of claims 1 to 4, which is characterized in that step 1) specifically: with tetrahydrofuran
For solvent, -25 DEG C~-20 DEG C at a temperature of, 2- (4- fluorophenyl) -5- [(the iodo- 2- aminomethyl phenyl of 5-) methyl] thiophene and alkali
Property reagent reaction after, then addition 2 is added dropwise, 3,4,6- tetra--O- (trimethyl silicon substrate)-D-Glucose acid lactone tetrahydrofuran solution
It is reacted.
6. described in any item preparation methods according to claim 1~5, which is characterized in that step 2) specifically: containing centre
In the organic solvent of body 1, triethylsilane is first added, then addition boron trifluoride ether is added dropwise, is carried out at a temperature of -25~-5 DEG C
Reaction；
Preferably, it is reacted at a temperature of -25~-10 DEG C.
7. described in any item preparation methods according to claim 1~6, which is characterized in that in step 2), the intermediate 1 with
The molar ratio of the triethylsilane is 1:2~6, preferably 1:3；The molar ratio of the intermediate 1 and the boron trifluoride ether
For 1:2~6, preferably 1:3.
8. described in any item preparation methods according to claim 1~7, which is characterized in that in step 3), the organic base is selected from
It is N-methylmorpholine, triethylamine, one or more in diisopropylethylamine；
Preferably, the molar ratio of the intermediate 2 and the organic base is 1:4~8；The molar ratio of the intermediate 2 and aceticanhydride
For 1:4~8；The molar ratio of the intermediate 2 and DMAP is 1:0.08~0.12；
It is highly preferred that the molar ratio of the intermediate 2 and the organic base is 1:5~6；The intermediate 2 rubs with aceticanhydride
You are than being 1:5~6；The molar ratio of the intermediate 2 and DMAP is 1:0.1.
9. described in any item preparation methods according to claim 1~8, which is characterized in that in step 4), the alkaline aqueous solution
In alkali be selected from one of sodium methoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide or a variety of；
Preferably, the molar ratio of the intermediate 3 and the alkali is 1:2~5, more preferably 1:3~4.
10. preparation method according to claim 1 or 2, which is characterized in that the preparation method comprises the following steps:
1) in inert environments, using tetrahydrofuran as solvent, -25 DEG C~-20 DEG C at a temperature of, 2- (4- fluorophenyl) -5- [(5-
Iodo- 2- aminomethyl phenyl) methyl] thiophene and alkaline reagent add with the ratio that molar ratio is 1:1.3~1.5, after being reacted, then
It is added dropwise by every mole of 2- (4- fluorophenyl) -5- [(the iodo- 2- aminomethyl phenyl of 5-) methyl] thiophene and is added the 2,3,4 of 1.3~1.6mol,
Tetra--O- of 6- (trimethyl silicon substrate)-D-Glucose acid lactone is reacted；
The temperature is maintained, is with methanesulfonic acid molar ratio by 2- (4- fluorophenyl) -5- [(the iodo- 2- aminomethyl phenyl of 5-) methyl] thiophene
The ratio of 1:2.1~2.3 adds the methanol solution containing methanesulfonic acid, and the reaction was continued；Reaction solution is cooled to -5 DEG C~5 DEG C, is quenched
It goes out, adjusts pH value to 7~8；It is warming up to 30~40 DEG C again, purifies to get intermediate 1；
Wherein methanol solution is that every mole of 2- (4- fluorophenyl) -5- [(the bromo- 2- aminomethyl phenyl of 5-) methyl] thiophene adds 2~5L；
2) -25 DEG C~-10 DEG C at a temperature of, intermediate 1 made from step 1) is dissolved in organic solvent, with triethylsilane
And boron trifluoride ether is the ratio addition of 1:3:3 in molar ratio, is reacted；Not higher than -10 DEG C at a temperature of, be quenched,
Up to intermediate 2；
3) intermediate 2 made from step 2) -5~5 DEG C at a temperature of, N-methylmorpholine or triethylamine and DMAP is added, mixes
After even, then acetic anhydride is instilled, be warming up to room temperature, reacted, purified to get intermediate 3；
Wherein, the molar ratio of the intermediate 2 and the organic base is 1:5~6；The molar ratio of the intermediate 2 and aceticanhydride
For 1:5~6；The molar ratio of the intermediate 2 and DMAP is 1:0.1；
4) intermediate 3 made from step 3) is dissolved in organic solvent, sodium methoxide or lithium hydroxide aqueous solution, the centre is added dropwise
The molar ratio of body 3 and the sodium methoxide or lithium hydroxide is 1:3~4, is reacted, and is purified to get canagliflozin.
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