CN104926803B - A kind of preparation method of new SGLT2 inhibitor medicine - Google Patents
A kind of preparation method of new SGLT2 inhibitor medicine Download PDFInfo
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Abstract
The invention discloses a kind of preparation method of new SGLT2 inhibitor medicine, it is as follows that it includes step：Using D glucolactones as initiation material, reacted with acylating reagent to obtain the glucolactone intermediate of hydroxyl protection under alkali effect；The methyl benzoic acid of 5 bromine 2 is prepared into chloride compounds again with 2 through acylating reagent（4 fluorophenyls）Thiophene under lewis acid effect with carrying out F-K reaction；2 (methyl benzoyl of 5 bromine 2) 5 (4 fluorophenyl) thiophene carries out electrophilic substitution reaction with glucolactone intermediate under super base effect, then etherified reaction obtains methyl ether compound；Carbonyl reduction is methylene under reducing agent effect by methyl ether compound, is sloughed methoxyl group and is formed S configuration fragrance glucolactone intermediates；The hydrolysis under alkali effect of fragrant glucolactone intermediate obtains canagliflozin product.Synthesis route of the invention is brief, middle weight is easily controllable, reaction yield is high, production cost is low, suitable for industrialized production.
Description
Technical field
The present invention relates to a kind of preparation method of new SGLT2 inhibitor medicine, specifically, it is related to a kind of canagliflozin
Preparation method.
Background technology
Diabetes (diabetes mellitus, DM) are a kind of because defect of insulin secretion and (or) insulin are made
Show the metabolic disease that hyperglycaemia is characterized with obstacle.According to IDF（IDF）Estimation, the whole world has within 2013
3.82 hundred million people suffer from diabetes, and the people for having 3.16 hundred million impaired glucose tolerances (IGT) is in the excessive risk for suffering from diabetes.Due to
Global obese people expands, and the incidence of disease of diabetes is in rising trend, and such as without intervening, by 2035, its patient numbers might
4.71 hundred million can be increased to.Since Canadian Banting in 1921 et al. has found insulin and is used successfully to clinic, diabetes
Good treatment and control have been obtained, and existing more than 40 kinds of antidiabetic is approved for treating diabetes, but at present
1st, 2 patients with type Ⅰ DM can not still be cured completely, and diabetic still cannot to the demand of safely and effectively Remedies for diabetes
Fully meet, this is greatly promoted the research and development of Novel antidiabetic, developmental function in novel targets, traditional anti-diabetic can be avoided
The 2 patients with type Ⅰ DM treatment new drug of drug side-effect turns into the focus researched and developed both at home and abroad.
Canagliflozin (Canagliflozin), trade name Invokana, entitled (1S) -1,5-Anhydro-1-C- of chemistry
[3- [[5- (4-fluorophenyl) -2-thienyl] methyl] -4-methylphenyl]-D-glucitol, (1S) -1,
5- dehydrogenations -1-C- [3- [[5- (4- fluorophenyls) -2- thienyls] methyl] -4- aminomethyl phenyls]-D-Glucose alcohol, such as formula 1, be by
Mitsubishi Tanabe Pharma companies original is ground, a kind of new antidiabetic medicine of Johson ＆ Johnson's exploitation, in 2013
On March 29, in is by FDA (Food and Drug Adminstration)（FDA）Approval listing.Canagliflozin is first and is approved to list by U.S. FDA
Sodium glucose co-transporter 2 white 2 for treating diabetes B（Sodium-glucose co-transporter-2,
SGLT2）Inhibitor.The medicine can suppress reabsorption of the kidney to glucose, increase the excretion of glucose, can so as to reduce blood glucose
Mitigate patient's weight, the risk of hypoglycemia is smaller.
Formula 1
Report the synthesis of canagliflozin first in original grinds patent WO2005012326, its synthesis technique is bromo- with 5-
2- tolyl aldehydes and 2- chlorothiophenes are initiation material, and the glucolactone after docking with trimethylsilyl protection reacts,
Glucolactone derivative is obtained, then the docking of etherified, hydroxyl protection, boric acid compound and support protection obtain canagliflozin.Should
There is the shortcomings such as synthesis technique is cumbersome, route is long, step is more, intermediate is not easy solidification purifying, reaction yield is low in process route, no
It is suitable for industrialized production on a large scale.
Reported in patent CN104109157 with the glucolactone and connection boric acid pinacol ester of pivaloyl group protection
Reaction forms borate intermediate, then with 2-（4- fluorophenyls）-5-[（The iodo- 2- aminomethyl phenyls of 5-）Methyl] thiophene carries out docking system
It is standby into canagliflozin.The route needs to use expensive Metal Palladium and intermediate containing iodine, and production cost is high, is not suitable for big
The industrialized production of scale.
The content of the invention
To solve present in existing preparation canagliflozin, synthesis route is long, preparation technology is cumbersome, intermediate is not easy
The problems such as solidifying purification process, synthetic route yield, the invention provides it is a kind of it is new, synthesis route is brief, intermediate
The canagliflozin that quality is easily controllable, reaction yield is high prepares scheme.
The technical solution adopted by the present invention is：
A kind of preparation method of new SGLT2 inhibitor medicine, it is as follows that it includes step：
A. the preparation of grape acid lactone intermediate：
Using D-Glucose acid lactone as initiation material, reacted with acylating reagent to obtain hydroxyl protection under alkali effect
Glucolactone intermediate；
B.2- the preparation of (the bromo- 2- methyl benzoyls of 5-) -5- (4- fluorophenyls) thiophene：
The bromo- 2- methyl benzoic acids of 5- through acylating reagent be prepared into chloride compounds again with 2-（4- fluorophenyls）Thiophene with road
Lewis acid effect is lower to carry out F-K reaction, obtains 2- (the bromo- 2- methyl benzoyls of 5-) -5- (4- fluorophenyls) thiophene；
C. the preparation of methyl ether compound：
2- (the bromo- 2- methyl benzoyls of 5-) -5- (4- fluorophenyls) thiophene is with glucolactone intermediate in super base
Effect is lower to carry out electrophilic substitution reaction, then etherified reaction obtains methyl ether compound；
D. the preparation of fragrant glucolactone intermediate：
Carbonyl reduction is methylene under reducing agent effect by methyl ether compound, is sloughed methoxyl group and is formed S configuration fragrance grapes
Saccharic acid lactone intermediate；
E. the preparation of canagliflozin：
The hydrolysis under alkali effect of fragrant glucolactone intermediate obtains canagliflozin product.
In a steps, acylating reagent used is chloroacetic chloride or methane sulfonyl chloride, and alkali used is piperidines, triethylamine, DMAP
Or DIPEA, solvent for use any mixture of two or more for toluene, dichloromethane, ether or isopropyl ether or wherein are used
The proportioning of acylating reagent and reaction substrate is 1.5:1—3.5:1.
In the b step, acylating reagent used is thionyl chloride, oxalyl chloride, and lewis acid used is alchlor or chlorine
Change zinc, solvent for use is that dichloromethane, toluene, DMF or ether or wherein any mixture of two or more, the 5- are bromo-
2- methyl benzoic acids and 2-（4- fluorophenyls）The proportioning of thiophene is 1:1.0-1:2.5.
In the step c, super base used is n-BuLi, tert-butyl lithium, hexamethyldisilane amine base potassium or hexamethyl
Disilane amido sodium, solvent for use are tetrahydrofuran, toluene, DMF, ether or methanol or wherein any mixing of two or more
The proportioning of thing, reaction substrate and super base is：1:1.05-1:3.05.
In the Step d, reducing agent used is sodium borohydride, lithium borohydride, potassium borohydride, BFEE or trifluoro
Change boron methyl ether, solvent for use is dichloromethane, toluene, tetrahydrofuran, ether, DMF, methanol or methyl tertiary butyl ether(MTBE) or wherein appointed
Anticipate the mixture of two or more, the proportioning of substrate and reducing agent is：1:2.5-1:5.5.
In the step e, alkali used is lithium hydroxide, potassium hydroxide or sodium hydroxide, and solvent for use is tetrahydrofuran, first
The proportioning of alcohol, isopropanol or water or wherein any mixture of two or more, substrate and alkali is：1:0.5-1:3.5.
It is an advantage of the invention that：Synthesis route is brief, middle weight is easily controllable, reaction yield is high, is produced into
This is low, suitable for industrialized production.
Brief description of the drawings
Fig. 1 is reaction equation of the present invention.
Embodiment
Embodiment 1
(1) preparation of grapes acid lactone intermediate
500mL toluene is added in reaction bulb, opens stirring, adds 50g D-Glucoses acid lactone and 5g piperidines, cooling
To -5 ~ 0 DEG C, 30mL 1-METHYLPYRROLIDONEs are added, temperature control -5 ~ 0 DEG C, 33.5g chloroacetic chlorides, temperature control -5 ~ 0 DEG C are then added dropwise；Drop
Finish, be warming up to 20-25 DEG C, be stirred overnight.After reaction terminates, -5 ~ 0 DEG C is cooled to, adds 200mL saturated sodium bicarbonate solutions,
Stirring, liquid separation is stood, water layer is extracted once with 300mL toluene, merges organic phase, with 500mL water washings, then with 300mL saturations
Sodium-chloride water solution washs, anhydrous sodium sulfate drying, filters, and the organic phase that is concentrated under reduced pressure produces oily product 80.2g.Yield
93.5%。
(2) preparation of .2- (the bromo- 2- methyl benzoyls of 5-) -5- (4- fluorophenyls) thiophene
The bromo- 2- methyl benzoic acids of 50g 5-, 10mL DMF and 500mL dichloromethane, stirring are added in reaction bulb.Room
Temperature is lower to be added dropwise 32.5g thionyl chlorides；Drop finishes, and is warming up to 20-25 DEG C of reaction, TLC monitoring reactions.Reaction finishes, into reaction bulb
36.6g anhydrous Aluminum chlorides are added portionwise, stir 30min, are cooled to 0-5 DEG C, are added dropwise the two of 42.5g 2- (4- fluorophenyls)-thiophene
Chloromethanes solution；Drop finishes, and is warming up to 25-30 DEG C and reacts 12 hours, TLC tracking reactions.After reaction terminates, reaction solution is poured into
It is quenched, stirs, stratification in 1000mL frozen water.Aqueous phase is extracted with 300mL dichloromethane, is merged organic phase, is concentrated to give palm fibre
Color solid.Above-mentioned solid is dissolved by heating with 1000mL ethyl acetate, 300mL n-hexanes, stirring and crystallizing, filtering, drying is added dropwise
Obtain 79.5g yellow solid products, yield 91.3%.
(3) preparation of methyl ethers compound
Under the conditions of anhydrous and oxygen-free, 70g 2- (the bromo- 2- methyl benzoyls of 5-) -5- (4- fluorobenzene is added in reaction bulb
Base) thiophene, nitrogen displacement, 800mL tetrahydrofurans and 100mL DMF are added, stirring, -50 ~ -40 DEG C is cooled to, is slowly added dropwise
85g n-BuLis are into reaction bulb；Drop finishes, and insulated and stirred 3 hours, 73.5g grape acid lactone intermediates is then slowly added dropwise
Tetrahydrofuran solution is into reaction bulb；Drop finishes, insulation reaction 8 hours, TLC monitoring reactions；After raw material conversion completely, 115g is added dropwise
The tetrahydrofuran solution of methanesulfonic acid is into reaction bulb；Drop finishes, and is warmed to room temperature reaction overnight, TLC monitoring reactions.Reaction terminates, and uses
Reaction is quenched in 1000mL saturated sodium bicarbonate solutions, adds 800mL water, stirring, stands liquid separation, aqueous phase 1500mL ethyl acetate
It is extracted twice, merges organic phase, anhydrous sodium sulfate drying.Organic phase is concentrated to dry, obtains foaming solid, with 600mL just oneself
The mixed solution room temperature of alkane and 300mL ethyl acetate is beaten, and is filtered, is dried to obtain 81.7g solids, yield 85.8%.
(4) preparation of fragrance glucolactone intermediate
80g methyl ethers compound, 700mL tetrahydrofurans and 200mL methanol are added in reaction bulb, stirring, is added into reaction bulb
Enter 85.3g anhydrous Aluminum chlorides, 25.7g sodium borohydrides are added portionwise at 25-30 DEG C in temperature control；Finish, be heated to 50-60 DEG C
Reaction, TLC monitoring reactions.Reaction terminates, and removes tetrahydrofuran and methanol under reduced pressure, adds the dissolving of 800mL dichloromethane, uses
0.1N hydrochloric acids are reacted, and stirring, stand liquid separation, and water layer is extracted twice with 300mL dichloromethane, are merged organic phase, stirring, are added
Enter 65g triethyl silicanes, be cooled to -30 DEG C, nitrogen protection.95.6g BFEEs are slowly added dropwise；Drop finishes, and is warmed to room temperature
Overnight, TLC monitoring is reacted for reaction.After reaction terminates, reaction is quenched with 1000mL saturated sodium bicarbonate solutions, stirs, stands and divides
Liquid, aqueous phase are extracted twice with 500mL ethyl acetate, are merged organic phase, anhydrous sodium sulfate drying, are filtered, be concentrated under reduced pressure into dry, obtain
To 63.5g solid products, yield 87.6%.
(5) preparation of canagliflozins
Sequentially add 60g fragrance glucolactone intermediates in reaction bulb, 5.5g lithium hydroxides, 500mL methanol and
250mL water, stirring, overnight, TLC monitoring is reacted for room temperature reaction.After reaction terminates, diluted with 800mL water, then with 600mL acetic acid
Ethyl ester is extracted twice, and merges organic phase, anhydrous sodium sulfate drying.Concentrate and dry obtain off-white powder 42g.Above-mentioned crude product is dissolved in
The in the mixed solvent of 450mL ethyl acetate and 500mL n-hexanes, 55-60 DEG C of dissolving is warming up to, stirs, be then cooled to 30-35
DEG C, a small amount of crystal seed crystallization is added, crystallization is overnight, filters, and dries, obtains 37.5g white solid products, yield 88%.
Embodiment 2
(1) preparation of grapes acid lactone intermediate
700mL dichloromethane is added in reaction bulb, opens stirring, adds 50g D-Glucoses acid lactone and the second of 10g tri-
Amine, -5 ~ 0 DEG C is cooled to, adds 20mL 1-METHYLPYRROLIDONEs, temperature control -5 ~ 0 DEG C, 38.9g methane sulfonyl chlorides, control is then added dropwise
- 5 ~ 0 DEG C of temperature；Drop finishes, and is warming up to 20-25 DEG C, is stirred overnight.After reaction terminates, -5 ~ 0 DEG C is cooled to, adds 300mL saturated carbons
Sour hydrogen sodium solution, stirring, liquid separation is stood, water layer is extracted once with 500mL dichloromethane, is merged organic phase, is washed with 500mL
Wash, then washed with 500mL saturated sodium-chloride water solutions, anhydrous sodium sulfate drying, filtered, the organic phase that is concentrated under reduced pressure produces oily production
Product 81.5g.Yield 95.2%.
(2) preparation of .2- (the bromo- 2- methyl benzoyls of 5-) -5- (4- fluorophenyls) thiophene
The bromo- 2- methyl benzoic acids of 50g 5-, 10mL DMF and 600mL toluene, stirring are added in reaction bulb.At room temperature
32.5g oxalyl chlorides are added dropwise；Drop finishes, and is warming up to 20-25 DEG C of reaction, TLC monitoring reactions.Reaction finishes, and adds in batches into reaction bulb
Enter 35.7g anhydrous Aluminum chlorides, stir 30min, be cooled to 0-5 DEG C, the toluene that 43.9g 2- (4- fluorophenyls)-thiophene is added dropwise is molten
Liquid；Drop finishes, and is warming up to 25-30 DEG C and reacts 12 hours, TLC tracking reactions.After reaction terminates, reaction solution is poured into 1000mL frozen water
In be quenched, stir, stratification.Aqueous phase is extracted with 500mL toluene, is merged organic phase, is concentrated to give brown solid.Will be above-mentioned solid
Body is dissolved by heating with 1000mL ethyl acetate, 300mL n-hexanes is added dropwise, stirring and crystallizing, filtering, drying obtain 80.4g yellow and consolidated
Body product, yield 92.4%.
(3) preparation of methyl ethers compound
Under the conditions of anhydrous and oxygen-free, 75g 2- (the bromo- 2- methyl benzoyls of 5-) -5- (4- fluorobenzene is added in reaction bulb
Base) thiophene, nitrogen displacement, 900mL tetrahydrofurans and 200mL toluene are added, stirring, -50 ~ -40 DEG C is cooled to, is slowly added dropwise
115.6g hexamethyldisilane amine base potassium is into reaction bulb；Drop finishes, insulated and stirred 3 hours, and 78.6g grapes acid is then slowly added dropwise
The tetrahydrofuran solution of lactone intermediate is into reaction bulb；Drop finishes, insulation reaction 8 hours, TLC monitoring reactions；Raw material has converted
Quan Hou, the tetrahydrofuran solution of 123.5g methanesulfonic acids is added dropwise into reaction bulb；Drop finishes, and is warmed to room temperature reaction overnight, and TLC monitoring is anti-
Should.Reaction terminates, and reaction is quenched with 1000mL saturated sodium bicarbonate solutions, adds 800mL water, and stirring stands liquid separation, and aqueous phase is used
1500mL ethyl acetate is extracted twice, and merges organic phase, anhydrous sodium sulfate drying.Organic phase is concentrated to doing, foam-like is obtained and consolidates
Body, it is beaten with the mixed solution room temperature of 600mL n-hexanes and 300mL ethyl acetate, filters, be dried to obtain 85.4g solids, yield
For 83.9%.
(4) preparation of fragrance glucolactone intermediate
82g methyl ethers compound, 800mL tetrahydrofurans and 250mL methanol are added in reaction bulb, stirring, is added into reaction bulb
Enter 87.3g anhydrous Aluminum chlorides, 22.4g lithium borohydrides are added portionwise at 25-30 DEG C in temperature control；Finish, be heated to 50-60 DEG C
Reaction, TLC monitoring reactions.Reaction terminates, and removes tetrahydrofuran and methanol under reduced pressure, adds the dissolving of 1000mL toluene, uses 0.1N
Hydrochloric acid is reacted, and stirring, stands liquid separation, and water layer is extracted twice with 500mL toluene, is merged organic phase, stirring, is added 75g tri-
Ethylsilane, -30 DEG C are cooled to, nitrogen protection.109.6g BFEEs are slowly added dropwise；Drop finishes, and is warmed to room temperature and reacted
Night, TLC monitoring reactions.After reaction terminates, reaction is quenched with 1500mL saturated sodium bicarbonate solutions, stirs, stands liquid separation, aqueous phase
It is extracted twice with 600mL toluene, merges organic phase, anhydrous sodium sulfate drying, filter, be concentrated under reduced pressure into dry, obtain 65.8g solids
Product, yield 88.3%.
(5) preparation of canagliflozins
65g fragrance glucolactone intermediates, 6.5g sodium hydroxides, 600mL tetrahydrochysene furans are sequentially added in reaction bulb
Mutter and 250mL water, stir, overnight, TLC monitoring is reacted for room temperature reaction.After reaction terminates, diluted with 500mL water, then use 800mL
Ether is extracted twice, and merges organic phase, anhydrous sodium sulfate drying.Concentrate and dry obtain off-white powder 42g.Above-mentioned crude product is dissolved in
The in the mixed solvent of 500mL ethyl acetate and 600mL n-hexanes, 55-60 DEG C of dissolving is warming up to, stirs, be then cooled to 30-35
DEG C, a small amount of crystal seed crystallization is added, crystallization is overnight, filters, and dries, obtains 42.3g white solid products, yield 87.6%.
Embodiment 3
(1) preparation of grapes acid lactone intermediate
500mL ether is added in reaction bulb, opens stirring, adds 40g D-Glucoses acid lactone and 6gDMAP, cooling
To -5 ~ 0 DEG C, 10mL 1-METHYLPYRROLIDONEs are added, temperature control -5 ~ 0 DEG C, 38.9g chloroacetic chlorides, temperature control -5 ~ 0 DEG C are then added dropwise；Drop
Finish, be warming up to 20-25 DEG C, be stirred overnight.After reaction terminates, -5 ~ 0 DEG C is cooled to, adds 200mL saturated sodium bicarbonate solutions,
Stirring, liquid separation is stood, water layer is extracted once with 300mL ether, merges organic phase, with 500mL water washings, then with 500mL saturations
Sodium-chloride water solution washs, anhydrous sodium sulfate drying, filters, and the organic phase that is concentrated under reduced pressure produces oily product 63.6g.Yield
95.2%。
(2) preparation of .2- (the bromo- 2- methyl benzoyls of 5-) -5- (4- fluorophenyls) thiophene
The bromo- 2- methyl benzoic acids of 30g 5-, 6mL DMF and 400mL dichloromethane, stirring are added in reaction bulb.Room temperature
Lower dropwise addition 24.6g thionyl chlorides；Drop finishes, and is warming up to 20-25 DEG C of reaction, TLC monitoring reactions.Reaction finishes, and divides into reaction bulb
Criticize and add 25.2g anhydrous Aluminum chlorides, stir 30min, be cooled to 0-5 DEG C, the dichloro of 26.5g 2- (4- fluorophenyls)-thiophene is added dropwise
Dichloromethane；Drop finishes, and is warming up to 25-30 DEG C and reacts 12 hours, TLC tracking reactions.After reaction terminates, reaction solution is poured into
It is quenched, stirs, stratification in 800mL frozen water.Aqueous phase is extracted with 300mL dichloromethane, is merged organic phase, is concentrated to give brown
Solid.Above-mentioned solid is dissolved by heating with 800mL ethyl acetate, 200mL n-hexanes are added dropwise, stirring and crystallizing, filtering, drying obtain
48.7g yellow solid products, yield 93.2%.
(3) preparation of methyl ethers compound
Under the conditions of anhydrous and oxygen-free, 45g 2- (the bromo- 2- methyl benzoyls of 5-) -5- (4- fluorobenzene is added in reaction bulb
Base) thiophene, nitrogen displacement, 400mL tetrahydrofurans and 100mL toluene are added, stirring, -50 ~ -40 DEG C is cooled to, is slowly added dropwise
74.3g butyl lithiums are into reaction bulb；Drop finishes, and insulated and stirred 3 hours, 46.4g grape acid lactone intermediates is then slowly added dropwise
Tetrahydrofuran solution is into reaction bulb；Drop finishes, insulation reaction 8 hours, TLC monitoring reactions；After raw material conversion completely, it is added dropwise
The tetrahydrofuran solution of 73.4g methanesulfonic acids is into reaction bulb；Drop finishes, and is warmed to room temperature reaction overnight, TLC monitoring reactions.Reaction knot
Beam, reaction is quenched with 800mL saturated sodium bicarbonate solutions, adds 500mL water, stirring, stand liquid separation, aqueous phase 900mL acetic acid
Ethyl ester is extracted twice, and merges organic phase, anhydrous sodium sulfate drying.Organic phase is concentrated to doing, foaming solid is obtained, uses 400mL
The mixed solution room temperature of n-hexane and 200mL ethyl acetate is beaten, and is filtered, is dried to obtain 51.6g solids, yield 83.9%.
(4) preparation of fragrance glucolactone intermediate
50g methyl ethers compound, 500mL tetrahydrofurans and 150mL methanol are added in reaction bulb, stirring, is added into reaction bulb
Enter 53.6g anhydrous Aluminum chlorides, 19.5g lithium borohydrides are added portionwise at 25-30 DEG C in temperature control；Finish, be heated to 50-60 DEG C
Reaction, TLC monitoring reactions.Reaction terminates, and removes tetrahydrofuran and methanol under reduced pressure, adds the dissolving of 800mL methyl tertiary butyl ether(MTBE)s,
Being reacted with 0.1N hydrochloric acids, stirring, stand liquid separation, water layer is extracted twice with 300mL methyl tertiary butyl ether(MTBE)s, merges organic phase,
Stirring, 44.6g triethyl silicanes are added, be cooled to -30 DEG C, nitrogen protection.65.8g BFEEs are slowly added dropwise；Drop finishes,
It is warmed to room temperature reaction overnight, TLC monitoring reactions.After reaction terminates, reaction is quenched with 800mL saturated sodium bicarbonate solutions, stirs,
Liquid separation is stood, aqueous phase is extracted twice with 400mL methyl tertiary butyl ether(MTBE)s, is merged organic phase, anhydrous sodium sulfate drying, is filtered, decompression
It is concentrated to dryness, obtains 39.1g solid products, yield 87.2%.
(5) preparation of canagliflozins
35g fragrance glucolactone intermediates, 3.5g potassium hydroxide, 300mL isopropanols are sequentially added in reaction bulb
With 250mL water, stirring, overnight, TLC monitoring is reacted for room temperature reaction.After reaction terminates, diluted with 300mL water, then with 400mL first
Base tertbutyl ether is extracted twice, and merges organic phase, anhydrous sodium sulfate drying.Concentrate and dry obtain off-white powder 26g.Will be above-mentioned thick
Product are dissolved in the in the mixed solvent of 300mL ethyl acetate and 300mL n-hexanes, are warming up to 55-60 DEG C of dissolving, stirring, then cool
To 30-35 DEG C, a small amount of crystal seed crystallization is added, crystallization is overnight, filters, and dries, obtains 22.3g white solid products, yield 86.9%.
Claims (10)
- A kind of 1. preparation method of new SGLT2 inhibitor medicine canagliflozin, it is characterised in that：It is as follows including step：A. the preparation of grape acid lactone intermediate：Using D-Glucose acid lactone as initiation material, reacted with acylating reagent to obtain the grape of hydroxyl protection under alkali effect Saccharic acid lactone intermediate；B.2- the preparation of (the bromo- 2- methyl benzoyls of 5-) -5- (4- fluorophenyls) thiophene：The bromo- 2- methyl benzoic acids of 5- through acylating reagent be prepared into chloride compounds again with 2-（4- fluorophenyls）Thiophene with Louis Acid effect is lower to carry out F-K reaction, obtains 2- (the bromo- 2- methyl benzoyls of 5-) -5- (4- fluorophenyls) thiophene；C. the preparation of methyl ether compound：2- (the bromo- 2- methyl benzoyls of 5-) -5- (4- fluorophenyls) thiophene acts on glucolactone intermediate in super base Lower carry out electrophilic substitution reaction, then etherified reaction obtain methyl ether compound；D. the preparation of fragrant glucolactone intermediate：Carbonyl reduction is methylene under reducing agent effect by methyl ether compound, is sloughed methoxyl group and is formed S configuration fragrance gluconic acids Lactone intermediate；E. the preparation of canagliflozin：The hydrolysis under alkali effect of fragrant glucolactone intermediate obtains canagliflozin product.
- 2. a kind of preparation method of new SGLT2 inhibitor medicine canagliflozin according to claim 1, its feature exist In：In a steps, acylating reagent used is chloroacetic chloride or methane sulfonyl chloride, alkali used be piperidines, triethylamine, DMAP or DIPEA, solvent for use are toluene, dichloromethane, ether or isopropyl ether or wherein any mixture of two or more.
- 3. a kind of preparation method of new SGLT2 inhibitor medicine canagliflozin according to claim 1 or 2, its feature It is：In a steps, the mol ratio of acylating reagent and reaction substrate used is 1.5:1—3.5:1.
- 4. a kind of preparation method of new SGLT2 inhibitor medicine canagliflozin according to claim 1, its feature exist In：In the b step, acylating reagent used is thionyl chloride, oxalyl chloride, and lewis acid used is alchlor or zinc chloride, Solvent for use is dichloromethane, toluene, DMF or ether or wherein any mixture of two or more.
- 5. a kind of preparation method of new SGLT2 inhibitor medicine canagliflozin according to claim 1 or 4, its feature It is：In the b step, the bromo- 2- methyl benzoic acids of the 5- and 2-（4- fluorophenyls）The mol ratio of thiophene is 1:1.0-1: 2.5。
- 6. a kind of preparation method of new SGLT2 inhibitor medicine canagliflozin according to claim 1, its feature exist In：In the step c, super base used is n-BuLi, tert-butyl lithium, hexamethyldisilane amine base potassium or hexamethyldisilane Amido sodium, solvent for use are tetrahydrofuran, toluene, DMF, ether or methanol or wherein any mixture of two or more.
- 7. a kind of preparation method of new SGLT2 inhibitor medicine canagliflozin according to claim 1 or 6, its feature It is：In the step c, the mol ratio of reaction substrate and super base is：1:1.05-1:3.05.
- 8. a kind of preparation method of new SGLT2 inhibitor medicine canagliflozin according to claim 1, its feature exist In：In the Step d, the reducing agent of reducing carbonyl is sodium borohydride, lithium borohydride or potassium borohydride, and demethoxylation reducing agent is Triethyl silicane and BFEE or triethyl silicane and boron trifluoride methyl ether, solvent for use are dichloromethane, toluene, four Hydrogen furans, ether, DMF, methanol or methyl tertiary butyl ether(MTBE) or wherein any mixture of two or more.
- 9. a kind of preparation method of new SGLT2 inhibitor medicine canagliflozin according to claim 1 or 8, its feature It is：In the Step d, the mol ratio of substrate and reducing agent is：1:2.5-1:5.5.
- 10. a kind of preparation method of new SGLT2 inhibitor medicine canagliflozin according to claim 1, its feature exist In：In the step e, alkali used is lithium hydroxide, potassium hydroxide or sodium hydroxide, and solvent for use is tetrahydrofuran, methanol, different The mol ratio of propyl alcohol or water or wherein any mixture of two or more, reaction substrate and alkali is：1:0.5-1:3.5.
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| CN111592515B (en) * | 2020-06-22 | 2022-02-08 | 广州市力鑫药业有限公司 | Preparation method of SGLT2 inhibitor for reducing blood sugar |
| CN113214041A (en) * | 2021-04-29 | 2021-08-06 | 河北唯达生物医药产业技术研究有限公司 | Novel method for preparing 3-iodine-2 bromotoluene |
| CN113429379A (en) * | 2021-06-28 | 2021-09-24 | 江苏法安德医药科技有限公司 | LH-1801 intermediate and preparation method and application thereof |
| CN116162945B (en) * | 2022-11-28 | 2023-08-04 | 安庆奇创药业有限公司 | Method for continuously and electrically synthesizing canagliflozin intermediate by utilizing micro-reaction device |
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