CN107540706A - The preparation method of ipragliflozin intermediate - Google Patents
The preparation method of ipragliflozin intermediate Download PDFInfo
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Abstract
The invention discloses the preparation method of ipragliflozin intermediate, including 2 (fluorophenyls of 3 benzos [B] thiophene, 2 ylmethyl 4) 3,4, the alcohol (compound 3) of 5 three trimethylsiloxy group, 6 trimethylsiloxy group methyl oxinane 2 and (1S) 2,3,4,6 four acetoxyl groups 1,5 are dehydrated the specific preparation method of 1 [3 (ylmethyl of 1 benzothiophene 2) 4 fluorophenyls] D D-sorbites (compound 6)；Wherein, it is not higher than in control reacting liquid temperature on the premise of 60 DEG C, n-BuLi should be added dropwise as early as possible, the rate of addition of n-BuLi is faster, the accessory substance of the F ortho positions substitution of compound 3 is fewer, ensures the purity of gained compound 3, and directly affects the yield of last gained compound 6, the amplified no enlarge-effect of the present invention, suitable for industrialized production.
Description
Technical field
The present invention relates to a kind of preparation method of medicine intermediate.Belong to pharmaceutical technology field.
Background technology
Acetoxyl group -1,5- dehydrations-the 1- of (1S) -2,3,4,6- four [3- (1- benzothiophene -2- ylmethyls) -4- fluorobenzene
Base]-D- D-sorbites be synthesize ipragliflozin L-PROLINE (Ipragliflozin L-Proline) key intermediate, after
Person is the important representative drugs of SGLT2 inhibitor, is mainly used in the treatment of diabetes B.
Patent application EP 2105442A1 disclose acetoxyl group -1,5- dehydrations -1- [3- (the 1- benzene of (1S) -2,3,4,6- four
Bithiophene -2- ylmethyls) -4- fluorophenyls]-D- D-sorbites a kind of preparation method, comprise the following steps that：
Problems be present in above-mentioned preparation method：
(1) in prepare compound 3, the accessory substance of substantial amounts of F ortho positions substitution can be produced；
(2) in prepare compound 5, pyridine has been used, toxicity is larger；
(3) trifluoromethanesulfonic acid has been used in demethoxylation prepare compound 6, it is possible to produce Genotoxic, no
Suitable for field of medicaments.
And the purity of compound 6 can directly affect and prepare gained (1S) -1,5- dehydrations -1-C- [3- [(1- benzos in next step
Thiophene -2- bases) methyl] -4- fluorophenyls] and-D- glucitols purity, and then influence end-product bulk drug quality.
The content of the invention
The purpose of the present invention is to overcome above-mentioned the deficiencies in the prior art, there is provided the preparation method of ipragliflozin intermediate.
To achieve the above object, the present invention uses following technical proposals：
2- (3- benzos [B] thiophene -2- ylmethyl -4- fluoro-phenyls) -3,4,5- three-trimethylsiloxy group -6- trimethyl silicanes
The preparation method of epoxide methyl-tetrahydro-pyran -2- alcohol (compound 3), it is by 2- (the bromo- 2- luorobenzyls of 5-) benzothiophene (chemical combination
Thing 1) it is dissolved in organic solvent I, -60~-70 DEG C, under inert gas or nitrogen are protected are cooled to, in control reacting liquid temperature not
On the premise of higher than -60 DEG C, the hexane solution of n-BuLi is added dropwise as early as possible, and 0.5~1 hour is incubated in -60~-70 DEG C,
2,3,4,6- tetra--O- trimethyls silicon substrates-D-Glucose acid lactone (compound 2) is added dropwise afterwards, reaction solution is controlled during dropwise addition
Temperature is not higher than -60 DEG C, -60~-70 DEG C of addition reactions 5~6 hours, produces.Reaction equation is as follows：
Preferably, 2- (the bromo- 2- luorobenzyls of 5-) benzothiophene, n-BuLi and 2,3,4,6- tetra--O- trimethyl silicon substrates-D-
The proportioning of glucolactone is 22g：0.07875mol：36.8g.
Preferably, inert gas is argon gas.
Preferably, organic solvent I is the mixed liquor of tetrahydrofuran and toluene, and both volume ratios are 1：10.
Preferably, the concentration of n-BuLi is 2.5mol/L, and its drop rate is 3 drops/sec.
Preferably, compound 2 is added dropwise after being dissolved in toluene, and the mass volume ratio of compound 2 and toluene is 36.8g：
20mL。
Preferably, the time for adding of compound 2 is 10~60 minutes.
Acetoxyl group -1,5- dehydrations-the 1- of (1S) -2,3,4,6- four [3- (1- benzothiophene -2- ylmethyls) -4- fluorobenzene
Base]-D- D-sorbites preparation method, including step：
(1) 2- (3- benzos [B] thiophene -2- ylmethyl -4- fluoro-phenyls) three-front threes of -3,4,5- are prepared according to preceding method
Base siloxy -6- trimethylsiloxy group methyl-tetrahydro-pyran -2- alcohol (compound 3)；
(2) acidulant is added, 0~10 DEG C is reacted 16~20 hours, 3 acidified reaction of compound, obtains compound 4；
(3) acid binding agent and acetic anhydride are added, 5~15 DEG C are reacted 4~5 hours, and compound 4 obtains chemical combination through acetylization reaction
Thing 5；
(4) organic solvent II and triethyl silicane are added, BFEE, 0~10 DEG C of reaction 3 are added dropwise at -5~5 DEG C
~5 hours, demethoxylation, obtain (1S) -2,3,4,6- tetra- acetoxyl group -1,5- dehydration -1- [3- (1- benzothiophene -2- Ji Jia
Base) -4- fluorophenyls]-D- D-sorbites (compound 6)；Reaction equation is as follows：
Preferably, 2- (the bromo- 2- luorobenzyls of 5-) benzothiophene, n-BuLi, 2,3,4,6- tetra--O- trimethyl silicon substrates-D-
Glucolactone, acidulant, acid binding agent, acetic anhydride, triethyl silicane, the proportioning of BFEE are 22g：
0.07875mol：36.8g：18.8g：41.6g：38.5g：39.8g：34.0g.
Preferably, the acidulant in step (2) is the concentrated sulfuric acid, and specific method is：Using glass reaction kettle, to step (1)
Methanol and the concentrated sulfuric acid are sequentially added in gained reaction system, is to slowly warm up to 0~10 DEG C of reaction；The mass ratio of methanol and the concentrated sulfuric acid
For 87：18.8.
Preferably, the acidulant in step (2) is the concentrated sulfuric acid, and specific method is：(it is adapted to low temperature anti-using stainless steel kettle
Should), methanol and the Part I concentrated sulfuric acid are sequentially added into reaction system obtained by step (1), is to slowly warm up to -5~-15 DEG C,
Enamel still (not low temperature resistant) is transferred to, adds the Part II concentrated sulfuric acid, 0~10 DEG C of reaction；Methanol, the Part I concentrated sulfuric acid and
The mass ratio of the two part concentrated sulfuric acids is 87：4：14.8.
It is further preferred that the mass fraction of the concentrated sulfuric acid is 98%.
Preferably, the acid binding agent in step (3) is triethylamine, and specific method is：Add into reaction system obtained by step (2)
Entering triethylamine, DMAP (DMAP, catalyst) and acetic anhydride, the mass ratio of triethylamine, DMAP and acetic anhydride is
41.6：1.7：38.5.
Preferably, the organic solvent II in step (4) is acetonitrile, and the volume mass ratio of acetonitrile and triethyl silicane is
100mL：39.8g.
Preferably, step (4) also includes purification step, is to add the crude product of gained compound 6 in ethanol, it is heated to 50~
60 DEG C, stir 1 hour, then be cooled to 0~10 DEG C, stir 2 hours, filtering, be dried under reduced pressure at least 6 hours, it is refined to obtain compound 6
Product.
It is further preferred that the mass volume ratio of the crude product of compound 6 and ethanol is 20g：100mL.
It is further preferred that it is 50~60 DEG C, more than vacuum -0.09Mpa to be dried under reduced pressure condition.
Beneficial effects of the present invention：
1st, during step (1), compound 1 and compound 2 react prepare compound 3, the miscellaneous of F ortho positions substitution can be produced
Matter, its structural formula are as follows：
On the premise of control reacting liquid temperature is not higher than -60 DEG C, n-BuLi should be added dropwise as early as possible, its drop rate base
This control is at 3 drops/sec, and drop finishes within 5 minutes or so, and after amplification production, time for adding can proper extension.Generally using n-BuLi
When promoting the addition reaction of carbonyl and halides, the rate of addition of n-BuLi is slower, and reaction effect can be better, but in this hair
In bright, the rate of addition of n-BuLi is faster, and the accessory substance of F ortho positions substitution is fewer on the contrary, overcomes positive fourth to a certain extent
The technology prejudice that base lithium uses.It should be noted that the more inevitable corresponding gainedization of the accessory substance of the F ortho positions substitution of compound 3
The accessory substance of the F ortho positions substitution of compound 4 is more, due to TMS protection groups in compound 3 and unstable, in HPLC detection process
Easy Deprotection, thus in the present invention detection compound 4 HPLC situations, it can directly reflect the purity situation of compound 3.Pass through
, can be by the ratio for the accessory substance that F ortho positions substitute to the HPLC of compound 4 detection it can be found that improving the rate of addition of n-BuLi
Example is down to 2% by 25%.
2nd, step (2), when being acidified prepare compound 4, sulfuric acid-methanol system is have selected, avoids hydrochloric acid-second in the prior art
Acetoacetic ester-methanol system is readily volatilized feeding intake the problem of inaccurate of bringing.
3rd, step (3), during acetylation prepare compound 5, using triethylamine as acid binding agent, toxicity is reduced.
4th, step (4), during de-methoxy reaction prepare compound 6, using BFEE-triethyl silicane system,
Compared with prior art, trifluoromethanesulfonic acid is replaced it is possible to prevente effectively from genetoxic, triethyl silicane using BFEE
Cost can be also reduced instead of t-butyldimethyl silane.
5th, in course of reaction and purification step, the accessory substance of the F ortho positions substitution of generation early stage is gradually refined removing, directly
Connect the yield that have impact on last gained compound 6 so that the yield of compound 6 is relatively low.
6th, the amplified no enlarge-effect of the present invention, suitable for industrialized production.
Brief description of the drawings
Fig. 1 is that the HPLC of the step of embodiment 1 (2) prepare compound 4 schemes；
Fig. 2 is the HPLC figures that embodiment 2 prepares gained compound 6；
Fig. 3 is that the HPLC of the step of comparative example 1 (2) prepare compound 4 schemes；
Fig. 4 is that the HPLC of the step of comparative example 2 (2) prepare compound 4 schemes.
Embodiment
With reference to embodiment, the present invention will be further elaborated, it should explanation, the description below merely to
The present invention is explained, its content is not defined.
Embodiment 1：
Acetoxyl group -1,5- dehydrations-the 1- of (1S) -2,3,4,6- four [3- (1- benzothiophene -2- ylmethyls) -4- fluorobenzene
Base]-D- D-sorbites preparation method, including step：
(1) tetrahydrofuran 22mL, toluene 220mL are added to reaction bulb, under stirring, adds 2- (the bromo- 2- luorobenzyls of 5-) benzene
Bithiophene (compound 1) 22.0g.Reaction solution is cooled to -70 DEG C, the lower hexane solution that n-BuLi is added dropwise of nitrogen protection
(2.5mol/L) 31.5mL, control reacting liquid temperature are not higher than -60 DEG C, and 3 drops/sec of drop rate, about 5min drops finish, -70 DEG C of guarantors
Temperature 1 hour.
2,3,4,6- tetra--O- trimethyls silicon substrates-D-Glucose acid lactone (compound 2) 36.8g is dissolved in toluene 20mL, dripped
It is added in above-mentioned system, control reacting liquid temperature is not higher than -60 DEG C, and about 10min drops finish, and it is small to continue reaction 6 at -70 DEG C of insulation
When, obtain compound 3.
(2) methanol 87g, concentrated sulfuric acid 4.0g are sequentially added into reaction system, is to slowly warm up to -5 DEG C.Add the concentrated sulfuric acid
14.8g, 0 DEG C is incubated, continues reaction 16 hours, obtain compound 4.
Detected (Fig. 1) through HPLC, the by-products content 2% of F ortho positions substitution, the content 67% of compound 4, intermediate state content
30%, unknown impuritie 1%.Wherein, intermediate state is green impurity, if extending the time can continue to be converted into compound 4, if
Do not extend the time, target product can be also converted into subsequent reactions, does not influence ultimate yield.
Ethyl acetate 200mL is added into reaction system, so as to improve effect of extracting, is slow added into sodium bicarbonate solution
(28.8g sodium acid carbonates being dissolved in 400mL water, or saturated solution of sodium bicarbonate), stir about 20 minutes, stand, liquid separation.Have
After machine layer is washed with saturated sodium bicarbonate solution 90mL and saturated aqueous common salt 90mL successively again, liquid separation.It is concentrated under reduced pressure into 60~
80mL (50~60 DEG C, more than vacuum -0.09Mpa).Then toluene 100mL is added, and is concentrated into about 60~80mL, is repeated
Once.Residual solution is cooled to 5 DEG C.
(3) toluene 200mL is added, then sequentially adds triethylamine 41.6g, DMAP 1.7g, acetic anhydride 38.5g, insulation 5
DEG C reaction 5 hours, produce compound 5.
The phosphate aqueous solution 300mL of mass percent 20% (alkali added in washing reaction), stirring are added at 15 DEG C of insulation
20 minutes, stand, liquid separation.Organic layer is washed with saturated sodium bicarbonate solution 180mL, then is washed with saturated aqueous common salt 90mL.Have
Machine is mutually concentrated under reduced pressure into 60~80mL (50~60 DEG C, more than vacuum -0.09Mpa).
(4) acetonitrile 100mL, triethyl silicane 39.8g are added, is cooled to -5~5 DEG C, BFEE 34.0g is added dropwise,
Drop finishes, and 0~10 DEG C of temperature continues reaction 5 hours in control.
(5) sodium bicarbonate solution is added at 0~10 DEG C of temperature control (57.5g sodium acid carbonates to be dissolved in 700mL water, or carbon
Sour hydrogen sodium saturated solution), solid is separated out, filtering, is washed with 55mL water washings, then with 50mL ethanol, obtains compound 6, i.e.,
Acetoxyl group -1,5- dehydrations-the 1- of (1S) -2,3,4,6- four [3- (1- benzothiophene -2- ylmethyls) -4- fluorophenyls]-D- sorbs
Sugar alcohol crude product.
The crude product of compound 6 of ethanol 100mL and gained is added, is heated to 50~60 DEG C, is stirred 1 hour, then it is cooled to 0~
10 DEG C, stir 2 hours, filtering, be dried under reduced pressure at least 6 hours (50~60 DEG C, more than vacuum -0.09Mpa), obtain compound 6
Highly finished product 18.0g, white, purity 98.96%, molar yield 46%.
Embodiment 2：
Acetoxyl group -1,5- dehydrations-the 1- of (1S) -2,3,4,6- four [3- (1- benzothiophene -2- ylmethyls) -4- fluorobenzene
Base]-D- D-sorbites preparation method, including step：
(1) tetrahydrofuran 22mL, toluene 220mL are added to reaction bulb, under stirring, adds 2- (the bromo- 2- luorobenzyls of 5-) benzene
Bithiophene (compound 1) 22.0g.Reaction solution is cooled to -60 DEG C, the lower hexane solution that n-BuLi is added dropwise of nitrogen protection
(2.5mol/L) 31.5mL, control reacting liquid temperature are not higher than -60 DEG C, and 3 drops/sec of drop rate, about 5min drops finish, -60 DEG C of guarantors
Temperature 1 hour.
2,3,4,6- tetra--O- trimethyls silicon substrates-D-Glucose acid lactone (compound 2) 36.8g is dissolved in toluene 20mL, dripped
It is added in above-mentioned system, control reacting liquid temperature is not higher than -60 DEG C, and about 10min drops finish, and it is small to continue reaction 5 at -60 DEG C of insulation
When, obtain compound 3.
(2) methanol 87g, concentrated sulfuric acid 4.0g are sequentially added into reaction system, is to slowly warm up to -15 DEG C.Add the concentrated sulfuric acid
14.8g, 10 DEG C are incubated, continue reaction about 20 hours, obtain compound 4.
Ethyl acetate 200mL is added into reaction system, is slow added into sodium bicarbonate solution (by 28.8g sodium acid carbonates
It is dissolved in 400mL water), stir about 20 minutes, stand, liquid separation.Organic layer uses saturated sodium bicarbonate solution 90mL and saturation successively again
After saline solution 90mL washings, liquid separation.
It is concentrated under reduced pressure into 60~80mL (50~60 DEG C, more than vacuum -0.09Mpa).Then toluene 100mL is added, and
About 60~80mL is concentrated into, is repeated once.Residual solution is cooled to 15 DEG C.
(3) toluene 200mL is added, then sequentially adds triethylamine 41.6g, DMAP 1.7g, acetic anhydride 38.5g, insulation 15
DEG C reaction 5 hours, obtain compound 5.
The phosphate aqueous solution 300mL of mass percent 20% is added at 35 DEG C of insulation, is stirred 20 minutes, is stood, liquid separation.It is organic
Layer is washed with saturated sodium bicarbonate solution 180mL, then is washed with saturated aqueous common salt 90mL.Organic phase is concentrated under reduced pressure into 60~80mL
(50~60 DEG C, more than vacuum -0.09Mpa).
(4) acetonitrile 100mL, triethyl silicane 39.8g are added, is cooled to -5 DEG C, BFEE 34.0g is added dropwise.Drop
Finish, 0 DEG C of temperature continues reaction 4 hours in control.
(5) sodium bicarbonate solution (57.5g sodium acid carbonates are dissolved in 700mL water) is added at 10 DEG C of temperature control, separates out solid.Cross
Filter, washed with 55mL water washings, then with 50mL ethanol, obtain compound 6, i.e. (1S) -2,3,4,6- tetra- acetoxyl groups -1,5- take off
Water -1- [3- (1- benzothiophene -2- ylmethyls) -4- fluorophenyls]-D- D-sorbite crude products.
The crude product of compound 6 of ethanol 100mL and gained is added, is heated to 60 DEG C, is stirred 1 hour, then is cooled to 0 DEG C, is stirred
Mix 2 hours, filter, be dried under reduced pressure at least 6 hours (50~60 DEG C, more than vacuum -0.09Mpa), obtain the highly finished product of compound 6
21g, character is white, purity 98.50% (Fig. 2), molar yield 53%.
Embodiment 3：
Acetoxyl group -1,5- dehydrations-the 1- of (1S) -2,3,4,6- four [3- (1- benzothiophene -2- ylmethyls) -4- fluorobenzene
Base]-D- D-sorbites preparation method, including step：
(1) tetrahydrofuran 2.2L, toluene 22L are added to reaction bulb, under stirring, adds 2- (the bromo- 2- luorobenzyls of 5-) benzo
Thiophene (compound 1) 2200g.Reaction solution is cooled to -70 DEG C, the lower hexane solution that n-BuLi is added dropwise of nitrogen protection
(2.5mol/L) 3150mL, control reacting liquid temperature are not higher than -60 DEG C, and 3 drops/sec of drop rate, drop finishes within about 1 hour, then be incubated -
60 DEG C are reacted 1 hour.
2,3,4,6- tetra--O- trimethyls silicon substrates-D-Glucose acid lactone (compound 2) 3680g is dissolved in toluene 2L, is added dropwise
Into above-mentioned system, control reacting liquid temperature is not higher than -60 DEG C, and drop finishes within about 1 hour, continues reaction 6 hours at -70 DEG C of insulation,
Obtain compound 3.
(2) methanol 8.7kg, concentrated sulfuric acid 400g are sequentially added into reaction system, is to slowly warm up to -5 DEG C.Add the concentrated sulfuric acid
1.5kg, 0 DEG C is incubated, continues reaction about 20 hours, obtain compound 4.
Ethyl acetate 20L is added into reaction system, it is (2.88kg sodium acid carbonates is molten to be slow added into sodium bicarbonate solution
In 40L water), stir about 20 minutes, stand, liquid separation.Organic layer uses saturated sodium bicarbonate solution 9L and saturated aqueous common salt successively again
After 9L washings, liquid separation.
It is concentrated under reduced pressure into 6~8L (50~60 DEG C, more than vacuum -0.09Mpa).Then toluene 10L is added, and is concentrated into
About 6~8L, repeat once.Residual solution is cooled to 15 DEG C.
(3) toluene 20L is added, then sequentially adds triethylamine 4.16kg, DMAP 170g, acetic anhydride 3.85kg, insulation 15
DEG C reaction 5 hours, obtain compound 5.
The phosphate aqueous solution 30L of mass percent 20% is added at 15 DEG C of insulation, is stirred 20 minutes, is stood, liquid separation.Organic layer
Washed with saturated sodium bicarbonate solution 18L, then washed with saturated aqueous common salt 9L.Organic phase is concentrated under reduced pressure into 6~8L (50~60
DEG C, more than vacuum -0.09Mpa).
(4) acetonitrile 10L, triethyl silicane 3.98kg are added, is cooled to -5 DEG C, BFEE 3.40kg is added dropwise.Drop
Finish, 0 DEG C of temperature continues reaction 5 hours in control.
(5) sodium bicarbonate solution (5.75kg sodium acid carbonates are dissolved in 70L water) is added at 0 DEG C of temperature control, separates out solid.Cross
Filter, washed with 5.50L water washings, then with 5L ethanol, obtain compound 6, i.e. (1S) -2,3,4,6- tetra- acetoxyl groups -1,5- take off
Water -1- [3- (1- benzothiophene -2- ylmethyls) -4- fluorophenyls]-D- D-sorbite crude products.
Ethanol 10L is added, the crude product of compound 7, is heated to 60 DEG C, is stirred 1 hour, then is cooled to 0 DEG C, is stirred 2 hours.Cross
Filter, is dried under reduced pressure at least 6 hours (55 DEG C, more than vacuum -0.09Mpa), obtains the highly finished product 2000g of compound 6, character is white
Color, purity 99.1%, molar yield 51%.
Comparative example 1
Acetoxyl group -1,5- dehydrations-the 1- of (1S) -2,3,4,6- four [3- (1- benzothiophene -2- ylmethyls) -4- fluorobenzene
Base]-D- D-sorbites preparation method, including step：
(1) 5.0g 2- (the bromo- 2- luorobenzyls of 5-) benzothiophene (chemical combination is added into 32.5mL toluene and 25mL isopropyl ethers
Thing 1), hexane solution (1.6mol/L) 10mL of -40 DEG C of dropwise addition n-BuLis, (rate of addition is 0.5 drop/sec of drop rate
Embodiment 1~3 1/5), about 30min drops finish, be added dropwise stirring 10min, be cooled to -75 DEG C.By 8.0g 2,3,4,6- tetra--
O- trimethyls silicon substrate-D-Glucose acid lactone (compound 2) is dissolved in 17.5mL toluene, is added dropwise to above-mentioned system, and rear stirring 6 is small
When, obtain compound 3.
(2) 0 DEG C is warming up to, adds methanol 25mL and 4mol/L hydrochloric ethyl acetate solution 7.8mL.Stirring 17 hours,
Obtain compound 4.Detected (Fig. 3) through HPLC, the content of compound 4 is 70%, by-products content 25%, 5% unknown impuritie.
Add the solution of 1.29g potassium carbonate 35mL water, ethyl acetate extraction, liquid separation, aqueous phase 20mL toluene 10mL acetic acid
Ethyl ester extracts.After organic phase merges, 40mL is concentrated into, 25mL toluene is added, is concentrated into 40mL, is repeated once.
7.39g pyridines are added to above-mentioned system at 3 DEG C, 19mg DMAP, 7.94g acetic anhydrides, are stirred 12 hours.
Add 50mL 2mol/L hydrochloric acid solution, liquid separation, the sodium bicarbonate solution of organic phase 75mL mass concentrations 5%
Washing, is then washed with 50mL 25% solution, is then concentrated into 16mL.
(3) 10mL acetonitriles are added, after dissolving, this solution is added to 4.67g trifluoromethanesulfonic acids and the tertiary fourths of 3.62g at 0 DEG C
Base dimethylsilane is dissolved in the solution of 20mL acetonitriles.Stirring 3 hours.Add 70mL tetrahydrofurans, 25mL toluene.2.8g carbonic acid
Potassium, 1.5g sodium chloride are dissolved in 30mL water, add above-mentioned system, and temperature is 5 DEG C.Then heat to 30 DEG C of liquid separations.Organic phase is used
25mL 25% brine It, air-distillation to 55mL, it is cooled to 0 DEG C of stirring and filters for 50 hours, solid is eluted with 5mL*2,
Obtain 2.3g compounds 6, purity 98.1%, molar yield 25.8%.
Comparative example 2
Acetoxyl group -1,5- dehydrations-the 1- of (1S) -2,3,4,6- four [3- (1- benzothiophene -2- ylmethyls) -4- fluorobenzene
Base]-D- D-sorbites preparation method, including step：
(1) tetrahydrofuran 22mL, toluene 220mL are added to reaction bulb, under stirring, adds 2- (the bromo- 2- luorobenzyls of 5-) benzene
Bithiophene (compound 1) 22.0g.Reaction solution is cooled to -70 DEG C or so, the n-hexane of the lower dropwise addition n-BuLi of nitrogen protection is molten
Liquid (2.5mol/L) 31.5mL, control reacting liquid temperature are not higher than -60 DEG C, and (rate of addition is to implement to 0.5 drop/sec of drop rate
Example 1~3 1/5), about 30min drops finish, -70 DEG C or so be incubated 1 hour.
2,3,4,6- tetra--O- trimethyls silicon substrates-D-Glucose acid lactone (compound 2) 36.8g is dissolved in toluene 20mL, dripped
It is added in above-mentioned system, control reacting liquid temperature is not higher than -60 DEG C, and about 10min drops finish, and it is small that -70 DEG C or so of insulation continues reaction 6
When, obtain compound 3.
(2) methanol 87g, concentrated sulfuric acid 4.0g are sequentially added into reaction system, is to slowly warm up to -5~15 DEG C.Add dense sulphur
Sour 14.8g, 0~10 DEG C is incubated, continues reaction about 16 hours, obtain compound 4.Detected (Fig. 4) through HPLC, the content of compound 4 is
86%, by-products content 12%, 2% unknown impuritie.
Ethyl acetate 200mL is added into reaction system, is slow added into sodium bicarbonate solution (by 28.8g sodium acid carbonates
It is dissolved in 400mL water), stir about 20 minutes, stand, liquid separation.Organic layer uses saturated sodium bicarbonate solution 90mL and saturation successively again
After saline solution 90mL washings, liquid separation.
It is concentrated under reduced pressure into 60~80mL (50~60 DEG C, more than vacuum -0.09Mpa).Then toluene 100mL is added, and
About 60~80mL is concentrated into, is repeated once.Residual solution is cooled to 15 DEG C.
(3) toluene 200mL is added, then sequentially adds triethylamine 41.6g, DMAP 1.7g, acetic anhydride 38.5g, insulation 15
DEG C reaction 5 hours, obtain compound 5.
The phosphate aqueous solution 300mL of mass percent 20% is added at 25 DEG C of insulation, is stirred 20 minutes, is stood, liquid separation.It is organic
Layer is washed with saturated sodium bicarbonate solution 180mL, then is washed with saturated aqueous common salt 90mL.Organic phase is concentrated under reduced pressure into 60~80mL
(50~60 DEG C, more than vacuum -0.09Mpa).
(4) acetonitrile 100mL, triethyl silicane 39.8g are added, is cooled to -5 DEG C, BFEE 34.0g is added dropwise.Drop
Finish, 0 DEG C of temperature continues reaction 4 hours in control.
(5) sodium bicarbonate solution (57.5g sodium acid carbonates are dissolved in 700mL water) is added at 10 DEG C of temperature control, separates out solid.Cross
Filter, washed with 55mL water washings, then with 50mL ethanol, obtain compound 6, i.e. (1S) -2,3,4,6- tetra- acetoxyl groups -1,5- take off
Water -1- [3- (1- benzothiophene -2- ylmethyls) -4- fluorophenyls]-D- D-sorbite crude products.
The crude product of compound 6 of ethanol 100mL and gained is added, is heated to 60 DEG C, is stirred 1 hour, then is cooled to 0 DEG C, is stirred
Mix 2 hours, filter, be dried under reduced pressure at least 6 hours (50~60 DEG C, more than vacuum -0.09Mpa), obtain the highly finished product of compound 6
12g, character is white, purity 97.9%, molar yield 30.6%.
Although the above-mentioned embodiment to the present invention is described, not to the limit of the scope of the present invention
System, on the basis of technical scheme, those skilled in the art need not pay creative work can make it is each
Kind modification is deformed still within protection scope of the present invention.
Claims (10)
1.2- (3- benzos [B] thiophene -2- ylmethyl -4- fluoro-phenyls) -3,4,5- three-trimethylsiloxy group -6- trimethyl silica
The preparation method of ylmethyl-ttetrahydro-pyran -2- alcohol, it is characterised in that be to be dissolved in 2- (the bromo- 2- luorobenzyls of 5-) benzothiophene
In organic solvent I, -60~-70 DEG C, under inert gas or nitrogen are protected are cooled to, -60 DEG C are not higher than in control reacting liquid temperature
On the premise of, the hexane solution of n-BuLi is added dropwise as early as possible, and 0.5~1 hour is incubated in -60~-70 DEG C, 2 are added dropwise afterwards,
3,4,6- tetra--O- trimethyls silicon substrates-D-Glucose acid lactone, reacting liquid temperature is controlled during dropwise addition not higher than -60 DEG C, -60
~-70 DEG C of addition reactions 5~6 hours, are produced.
2. preparation method according to claim 1, it is characterised in that 2- (the bromo- 2- luorobenzyls of 5-) benzothiophene, normal-butyl
The proportioning of lithium and the-O- trimethyls silicon substrates of 2,3,4,6- tetra--D-Glucose acid lactone is 22g：0.07875mol：36.8g.
3. preparation method according to claim 1, it is characterised in that organic solvent I is the mixing of tetrahydrofuran and toluene
Liquid, both volume ratios are 1：10.
4. preparation method according to claim 1, it is characterised in that the concentration of n-BuLi is 2.5mol/L, and it is added dropwise
Speed is 3 drops/sec.
5. preparation method according to claim 1, it is characterised in that compound 2 is added dropwise after being dissolved in toluene, compound
2 and the mass volume ratio of toluene be 36.8g：20mL.
Acetoxyl group -1,5- dehydrations-the 1- of (6. 1S) -2,3,4,6- four [3- (1- benzothiophene -2- ylmethyls) -4- fluorophenyls] -
The preparation method of D- D-sorbites, including step：
(1) 2- (3- benzos [B] thiophene -2- ylmethyls -4- are prepared according to preparation method according to any one of claims 1 to 5
Fluoro-phenyl) -3,4,5- three-trimethylsiloxy group -6- trimethylsiloxy group methyl-tetrahydro-pyran -2- alcohol；
(2) acidulant is added, 0~10 DEG C is reacted 16~20 hours, acidified reaction, obtains compound 4；
(3) acid binding agent and acetic anhydride are added, 5~15 DEG C are reacted 4~5 hours, and compound 4 obtains compound 5 through acetylization reaction；
(4) organic solvent II and triethyl silicane are added, BFEE is added dropwise at -5~5 DEG C, 0~10 DEG C of reaction 3~5 is small
When, demethoxylation, obtain (1S) -2,3,4,6- tetra- acetoxyl group -1,5- dehydration -1- [3- (1- benzothiophene -2- ylmethyls) -4-
Fluorophenyl]-D- D-sorbites；Reaction equation is as follows：
7. preparation method according to claim 6, it is characterised in that 2- (the bromo- 2- luorobenzyls of 5-) benzothiophene, normal-butyl
The lithium ,-O- trimethyls silicon substrates of 2,3,4,6- tetra--D-Glucose acid lactone, acidulant, acid binding agent, acetic anhydride, triethyl silicane, three
The proportioning for being fluorinated borate ether is 22g：0.07875mol：36.8g：18.8g：41.6g：38.5g：39.8g：34.0g.
8. preparation method according to claim 6, it is characterised in that the acid binding agent in step (3) is triethylamine, specific side
Method is：Addition triethylamine, DMAP (DMAP, catalyst) and acetic anhydride into reaction system obtained by step (2), three
The mass ratio of ethamine, DMAP and acetic anhydride is 41.6：1.7：38.5.
9. preparation method according to claim 6, it is characterised in that preferable, the organic solvent II in step (4) is second
The volume mass ratio of nitrile, acetonitrile and triethyl silicane is 100mL：39.8g.
10. preparation method according to claim 6, it is characterised in that step (4) also includes purification step, is by gained
The crude product of compound 6 is added in ethanol, is heated to 50~60 DEG C, is stirred 1 hour, then is cooled to 0~10 DEG C, is stirred 2 hours, mistake
Filter, is dried under reduced pressure at least 6 hours, obtains the highly finished product of compound 6.
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| CN105541816A (en) * | 2016-01-20 | 2016-05-04 | 大连理工大学 | Synthetic method of Ipragliflozin |
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| CN101490028A (en) * | 2006-05-19 | 2009-07-22 | 大正制药株式会社 | C-phenyl glycitol compound for the treatment of diabetes |
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