CN107488156A - A kind of synthetic method of unformed glucitol - Google Patents
A kind of synthetic method of unformed glucitol Download PDFInfo
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- 0 CCOc1ccc(Cc2cc(*)ccc2Cl)cc1 Chemical compound CCOc1ccc(Cc2cc(*)ccc2Cl)cc1 0.000 description 4
- GDOPTJXRTPNYNR-UHFFFAOYSA-N CC1CCCC1 Chemical compound CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 1
- WQEWCQSGRZDTSN-ADAARDCZSA-N CCOC1=CC=C(Cc2cc([C@@H]([C@@H]([C@H]3O)O)O[C@H](CO)[C@H]3O)ccc2Cl)CC1 Chemical compound CCOC1=CC=C(Cc2cc([C@@H]([C@@H]([C@H]3O)O)O[C@H](CO)[C@H]3O)ccc2Cl)CC1 WQEWCQSGRZDTSN-ADAARDCZSA-N 0.000 description 1
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- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention discloses the synthetic method that one kind unformed (1S) 1,5 is dehydrated 1 [4 chlorine 3 [(4 ethoxyl phenenyl) methyl] phenyl] D glucitols, its reaction equation are as follows：
Description
Technical field
The present invention relates to a kind of synthetic method of pharmaceutical grade compound, and in particular to and a kind of unformed (1S) -1,5- dehydrations -
The synthetic method of 1- [the chloro- 3- of 4- [(4- ethoxyl phenenyls) methyl] phenyl]-D-Glucose alcohol (Dapagliflozin).
Background technology
One of ten disease before America Diabetes are lethal ranking.About 25,000,000 people suffer from diabetes, and this number
Word is gradually increasing due to aging and the influence of obesity.The whole world there are about 3.82 hundred million people and suffer from diabetes at present, there is tables of data
Bright, by 2035, this numeral will be expected to be changed into 5.92 hundred million people, account for the 10% of whole world total population.
2 type sodium-glucose collaboration operating albumen 2 (SGLT2) is a novel targets for treating diabetes, and it is by 672 ammonia
Base acid composition.SGLT2 is distributed in kidney, is the major protein that control absorbs the glucose in crude urine, and return it to blood
In liquid.Therefore, the excretion of glucose in urine can just be increased so as to reducing blood sugar concentration by suppressing SGLT2 activity.
Dapagliflozin (Dapagliflozin, DGZ), entitled (1S) -1,5- dehydrations -1- [4- chloro- 3- [(the 4- ethoxies of chemistry
Base phenyl) methyl] phenyl]-D-Glucose alcohol, No. CAS is 461432-26-8, and chemical structural formula is shown in formula 1.At present, its medicinal crystalline substance
Type is Dapagliflozin S-1,2- propane diols monohydrate, is by Bristol-Myers Squibb Co. (BMS) and Astrazeneca AB
(AstraZeneca) develop jointly, obtain European drug administration (EMA) approval listing in November, 2012, be first to be approved to list
White 2 (SGLT2) inhibitor of sodium glucose co-transporter 2 for treating diabetes B.By suppressing the SGLT2 in kidney
Passage, renal tubule blood glucose reabsorption is reduced, glucose is discharged through urine, reaching reduces blood glucose and glycosylated hemoglobin
(HbA1c) purpose.SGLT2 inhibitor can apply to any stage of diabetes independent of insulin, be sent out newly
Raw diabetic and using having identical hypoglycemic effect in the patient of insulin.U.S. FDA is ratified it in January, 2014
For the treatment of diabetes B, trade name Farxiga.
DGZ has the characteristics of stable, reversible, high selectivity.Relative to the transport protein of glucose reabsorption in small intestine
SGLT1, DGZ are far above DGZ to SGLT1 selectivity to SGLT2 selectivity, and the former is 1000~3000 times of the latter.Base
Mainly played a role in SGLT2 in kidney, in other organs and be not found glucose or other carbohydrate and occur
Transhipment or reabsorption, therefore DGZ reduces the side effect to other organs.TGZ can also improve internal hemoglobin (HbA1c)
Content.Glucose excretion in urine depends primarily on the glucose amount being filtered across in kidney.The glucose amount being filtered across
Depending on being by the glucose amount and the filter effect of glomerulus in blood plasma.Therefore, DGZ hypoglycemic effect depends on the base of patient
Plinth blood glucose and renal function, the β cell functions independent of patient and the sensitiveness to insulin, so as to reduce patient's production
The risk of raw hypoglycemia.In addition, DGZ produces suppression to transhipment of the sodium glucose in proximal convoluted tubule, therefore, DGZ has slight
Diuresis, it is more suitable for the treatment of diabetes B.
, in the prior art, can be former by different startings shown in following reaction equation 1 for the synthesis technique of Dapagliflozin 6
Material obtains compound 3 by condensation reaction, and compound 3 obtains 4 through reduction reaction, then compound 4 is carried out into hydroxyl protection, through second
Compound 5-2 is obtained after alcohol recrystallization, after compound 5-2 basic hydrolysis, disperses to obtain target compound 6 through free.Due at it
Impurity 5-2,6-1,6-2,6-3 and 6-4 as shown in chemical formula 2 can be produced in technique, these impurity are difficult to remove completely again, are added
Current medicinal crystal-form be Dapagliflozin S-1,2- propane diols monohydrates.Therefore, the Da Gelie obtained in the prior art
Net 6, used typically as a kind of intermediate, its quality is extremely difficult to medicinal standard.
Reaction equation 1
Chemical formula 2
2003, the synthetic method of patent US6515117B2 reports was exactly to use this technique synthesising target compound 6, its
Method is：1) synthesis of compound 3；Under argon gas protection, to dry tetrahydrofuran/toluene (volume ratio 1 dissolved with 1:2) mixed liquor
In, 2.5M n-BuLi hexane solution is added dropwise in -78 DEG C, continues to stir 30min after dripping off, is then added by conduit
Enter to having cooled in -78 DEG C of 2 toluene solution, control charging rate, reacting liquid temperature is maintained at less than -70 DEG C, add
Reacted after complete in -78 DEG C of insulated and stirred 30min, the methanol solution for then adding methanesulfonic acid (1-1.88 equivalents) with being quenched.Reaction
After liquid is warmed to room temperature, it is stirred overnight.After the completion of reaction, reaction, the sodium bicarbonate aqueous solution of addition is quenched in sodium bicarbonate aqueous solution
It should make reaction solution that alkalescent be presented.After be diluted with water, ethyl acetate extract 3 times, merge organic phase, salt washing after, anhydrous slufuric acid
Sodium is dried, filtering, filtrate concentration, after concentration raffinate is using hot toluene dissolving, is added in hexane solution, solid separates out, mistake
Filter, filter cake n-hexane wash 2 times, are dried to obtain compound 3.2) compound 5-2 synthesis is worked as under the conditions of -10 DEG C to dissolved with 1
Dichloromethane/acetonitrile (volume ratio 1 of amount 3:1) in solution, the triethyl silicane of 2 equivalents is added, is then added dropwise the three of 1.5 equivalents
Borate ether is fluorinated, keeps reaction temperature -10~-5 DEG C.Drip off and react 5h after less than 0 DEG C.After the completion of reaction, saturated carbon is used
Reaction is quenched in sour hydrogen sodium water solution.Resulting solution directly rotates, and removes easy volatile solvent, add in residue ethyl acetate and
Water, after layering, aqueous phase makes to be extracted with ethyl acetate 2 times, merges organic phase, then washes, salt water washing, dries, and filtering and concentrating obtains
To yellow foaming material 4, it is dissolved in dichloromethane solution, uses pyridine/acetic anhydride and catalyst DMAP (4- dimethylaminos
Pyridine) in the presence of acetylation, after the completion of reaction, carry out that reaction is quenched using water.After layering, aqueous phase is extracted using dichloromethane
2 times, merge organic phase, washed 2 times using diluted hydrochloric acid aqueous solution, then dried with salt water washing 1 time, anhydrous magnesium sulfate, filtering is dense
Contracting, absolute ethyl alcohol obtain target compound 5-2 after recrystallizing.3) synthesis of compound 6 to tetrahydrofuran/methanol dissolved with 5-2/
Water (volume ratio 2:3:1) lithium hydroxide monohydrate of 1.16 equivalents is added in solution, 20 DEG C are stirred overnight in room temperature.React
Cheng Hou, rotate and remove solvent, after residue is using ethyl acetate dissolving, salt solution washed once, and then uses and contains 5% potassium acid sulfate
The aqueous solution washed once, then with salt water washing, anhydrous sodium sulfate drying, filter, revolving, and removing the grease obtained after solvent makes
Dissolved with minimal amount of dichloromethane, and dried under vacuum, finally obtain the foaming material containing compound 6, purity 94%.
Another process route is also reported in patent US6515117B2：After compound 3 is obtained, first acetylation is protected
Hydroxyl is protected, triethyl silicane/BFEE is reused and is reduced, post-treated to obtain grease, it is then at 70 DEG C
Dissolved in ethyl acetate/hexane solution, obtain compound 5-2 through cooling crystallization, compound 5-2 obtains through lithium hydrate again
Compound 6.
The compound 6 obtained in patent US6515117B2, used because it is intended only as a kind of intermediate, and it is synthesized
During impurity again be difficult be completely removed, therefore, its product quality is extremely difficult to drug standard.In addition, technique road
Line will be through perhydroxyl radical protection and deprotection reaction, route is longer, yield it is relatively low (inventor by its technique through many experiments, its
Total recovery is 7.57%~16.8%), it is unfavorable for industrialized production.
2012, the synthetic method of patent CN102627676B reports was similar with the method that patent US6515117B2 is reported,
Process route is also required to protection and deprotection reaction through perhydroxyl radical, and route is longer, and yield is relatively low, is unfavorable for industrialized production,
And compound 6 is also to be used as a kind of intermediate, product quality is extremely difficult to medicinal standard.
2015, patent CN104496952A report synthetic method be：At -78 DEG C of low temperature, using n-BuLi just
Hexane solution, halo benzene derivative is prepared into copper lithium reagent or RMgBr, then it is again with 2,3,4,6- tetra- acetoxyl groups-
α-D- glucopyranoses bromide occurs condensation reaction and obtains compound 5-1, and it is through being recrystallized to give compound 5-2, finally, then
Compound 6 is obtained through lithium hydroxide basic hydrolysis.Process avoids the triethyl silicane/boron trifluoride used in general literature to urge
The reduction reaction of change and the acetylization reaction of hydroxyl, reactions steps are shortened, but the compound 6 that the technique finally obtains is one
Individual intermediate product, its quality do not reach medicinal standard far.Process route is shown in following reaction equation 3
Reaction equation 3
In summary, the 6 of prior art acquisition are essentially all to be obtained by methods of the acetylate 5-2 Jing Guo basic hydrolysis
, total recovery is relatively low, is unfavorable for industrialized production, and 6 quality finally obtained is extremely difficult to medicinal standard.Therefore, urgently
Need to provide a kind of easy industrialized production, and easily obtain unformed 6 synthesis technique of medicinal standard, that is, need offer a kind of low
Cost, environmental protection, yield is high and meets unformed 6 production technology of medicinal standard.
The content of the invention
The present invention is intended to provide a kind of synthetic method of unformed glucitol, particularly unformed (1S) -1,5- dehydrations -
The synthetic method of 1- [the chloro- 3- of 4- [(4- ethoxyl phenenyls) methyl] phenyl]-D-Glucose alcohol (Dapagliflozin).
A kind of synthetic method of unformed glucitol, its reaction equation are as follows：
Comprise the following steps：
1) compound 1 obtains compound 3 with compound 2 through condensation reaction；
2) compound 3 obtains compound 4 through reduction reaction；
3) crude product 5 is obtained after S-1,2- propane diols and water reaction are added into compound 4；
4) crude product 5 is refining to obtain compound 5 through 2 times；
5) compound 5 is dissociated through toluene and water, and obtaining three-phase system, (upper strata is toluene phase, and middle level is aqueous phase, lower floor
To be material bed), lower floor's material is obtained after layering；
6) lower floor's material is after good solvent dissolves, then scrubbed and scattered obtain amorphous compound 6；
Characterized in that,
In step 5), described compound 5 is dissociated through toluene and aqueous systems, and layering obtains lower floor's material；
In step 6), lower floor's material is after good solvent dissolves and washes, then through being concentrated under reduced pressure to give foaming material；
Foaming material is dissolved using good solvent, and is added dropwise under inert gas shielding in poor solvent；In inert gas
Protection is lower to filter, and filter cake obtains amorphous compound 6 after drying.
Preferably, described good solvent is ethers, esters or chlorinated hydrocarbon, it is preferable that described good solvent is first
Base tertbutyl ether, 2- methyltetrahydrofurans, ethyl acetate, butyl acetate, dichloromethane or chloroform；
Preferably, described good solvent dosage is the every g of compound 5 of 1~5ml, and preferably 2~4ml is per g of compound 5.
Preferably, the poor solvent is normal heptane, n-hexane, pentane；The poor solvent dosage is that 8~15ml is every
G of compound 5.
Preferably, during described 3 reduction reaction of compound, by BFEE, triethyl silicane and solvent dichloromethane
Alkane is added in reactor in the lump, and the dichloromethane solution of compound 3 is then added dropwise, rear insulated and stirred is dripped off, after the completion of reaction
The use of saturated aqueous sodium carbonate regulation solution ph is neutrality.
Preferably, in described reduction reaction, reaction temperature be -20 DEG C~20 DEG C, preferably -15 DEG C~10 DEG C, more preferably -
10 DEG C~-5 DEG C；The mol ratio of reactant is：Compound 3:BFEE:Triethyl silicane=1:(2~7):(1~3),
Preferably, compound 3:BFEE:Triethyl silicane=1:(4~6.5):(1.5~2.5).
Preferably, step 3), S-1,2- propane diols and water are added into compound 4, heated, after dissolved clarification, Slow cooling, analysis
Crude product 5 is obtained after crystalline substance, compound 5 is obtained after 2 recrystallizations of methyl tertiary butyl ether(MTBE).
After toluene and the free layering of aqueous systems, gained lower floor is material bed to be dissolved compound 5 using good solvent, then is washed
2 times, the concentration of gained organic phase removes solvent, and toluene band steams 1 time, obtains foaming material, then is dissolved with good solvent, is then added drop-wise to not
In good solvent.
Compound 5 is subjected to free temperature as 5 DEG C~60 DEG C, preferably 10 DEG C~45 DEG C using toluene and water, more preferably
15 DEG C~35 DEG C, mixing time of dissociating is 0.5~1h；
Separatory funnel layering is transferred to, divides three layers, upper strata is toluene, and middle level is water, and lower floor is feed liquid；In the guarantor of inert gas
Under shield, feed liquid is dissolved using good solvent, is added dropwise in poor solvent, 0.5~1h is stirred after dripping off, inert gas shielding was descended
Filter, is drained, in 30~50 DEG C of vacuum drying；
Preferably, described toluene and water consumption are respectively 10~20ml per every gram of chemical combination of g of compound 5 and 10~20ml
Thing 5.
Wherein, this method specifically comprises the following steps：
1) synthesis of compound 3；In tetrahydrofuran/toluene mixture liquid, in less than -70 DEG C, initiation material 1 first with positive fourth
Base lithium reacts, and then carries out condensation reaction with initiation material 2 again, and after the completion of condensation reaction, the methanesulfonic acid first prepared in advance is added dropwise
Alcoholic solution, drip off and reacted after at 20-30 DEG C, it is post-treated to obtain grease crude product 3 after the completion of reaction, without curing process,
It is directly used in the next step；
2) synthesis of compound 4；In dichloromethane solution, crude product 3 is gone back using triethyl silicane/BFEE
Original, reaction finish, and reaction is quenched using saturated aqueous sodium carbonate, and resulting solution is directly concentrated under reduced pressure, and remove low boiling point solvent
Afterwards, water and ethyl acetate dissolving are added, and the pH value of reaction solution is adjusted to 7, after liquid separation using saturated aqueous sodium carbonate, water
Mutually make to be extracted with ethyl acetate 3 times, merge organic phase, and with saturated common salt water washing 3 times, gained organic phase is concentrated under reduced pressure, and obtains
Yellow blister solid 4；
3) preparation of two fine work 5；(S)-(+) -1,2-PD and pure water are added into yellow blister solid 4, heating is molten
Cooled down again after clear and can obtain crude product 5；Crude product 5 obtains two fine work 5 after methyl tertiary butyl ether(MTBE) refines twice；The fine work 5 of gained two
Purity is more than 99.8%, and list is miscellaneous to be less than 0.1%, and always miscellaneous to be less than 0.2%, ignition residue is less than 0.1%；
4) two fine work 5 is free；Toluene and water are added into two fine work 5,0.5~1h is stirred at 5 DEG C~60 DEG C, is transferred to
In separatory funnel, stratification (upper strata is toluene phase, and middle level is aqueous phase, and lower floor is 6 viscous shape liquid), after layering, middle level water layer
And upper toluene layer discards；Lower floor's sticky matter material uses good solvent (methyl tertiary butyl ether(MTBE), 2- methyltetrahydrofurans, acetic acid second
Ester, butyl acetate, dichloromethane and chloroform etc.) dissolving after, drinking pure water wash 3 times, gained organic phase is removed through being concentrated under reduced pressure
After removing solvent, add q. s. toluene band and steam 1 time, finally obtain foaming material 6；
5) unformed 6 preparation；Use good solvent (methyl tertiary butyl ether(MTBE), 2- methyltetrahydrofurans, ethyl acetate, second
Acid butyl ester, dichloromethane and chloroform etc.) foaming material 6 is dissolved.Under conditions of inert gas shielding and stirring, in -15~15
It is added drop-wise at DEG C in poor solvent (normal heptane, n-hexane, pentane etc.), drips off follow-up continuous insulated and stirred 20-30min, then,
Filtered under inert gas shielding, after draining, filter cake is positioned in 40~50 DEG C of vacuum drying chamber and is dried under reduced pressure 24~
48h, unformed 6 being obtained, purity more than 99.8%, list is miscellaneous to be less than 0.1%, and always miscellaneous to be less than 0.2%, ignition residue is less than 0.1%,
Meet drug standard.
The positive effect of the present invention is：Compared with the existing technology for preparing unformed 6, present invention reduces reaction
Step, protection and the deprotection reaction of hydroxyl are needed not move through, be directly recrystallized to give the (HPLC of two fine work 5 by 2 times by crude product 5
For content more than 99.8%, list is miscellaneous to be less than 0.1%, always miscellaneous to be less than 0.2%), and two fine work 5 can be prepared by by free, scattered again
Unformed the 6 of high-purity.This preparation technology reaction condition is gentle, easy to operate, is suitable for industrialized production；Product total recovery compared with
Height, 43~53%, be easy to get to pharmaceutical grade unformed 6 (HPLC contents more than 99.8%, it is single it is miscellaneous is less than 0.1%, it is total miscellaneous to be less than
0.2%, its ignition residue, molten residual, moisture content etc. meet medicinal standard).
Embodiment
The experimental method of unreceipted actual conditions in the following example, generally according to normal condition or according to institute of manufacturer
It is recommended that condition.In following preparation embodiments, nuclear magnetic resonance is by Varian Inova-400 type nmr determinations, TMS
For internal standard, chemical shift unit is ppm；HPLC is determined by Waters1525 high performance liquid chromatographs.
Wherein in synthetic method, specific step is as follows,
Embodiment 1. prepare unformed (1S) -1,5- dehydrations -1- [the chloro- 3- of 4- [(4- ethoxyl phenenyls) methyl] phenyl] -
D-Glucose alcohol
1), the synthesis of compound 3
Under nitrogen protection, successively by toluene (500.0ml), tetrahydrofuran (400.0ml) and compound 1 (200.00g,
614.19mmol) it is added in reaction bulb, liquid nitrogen is cooled to less than -70 DEG C, and 2.5M n-BuLi hexane solution is added dropwise
(270.25ml, 675.61mmol), after dripping off, insulated and stirred 10min, compound 2 (344.10g, 737.03mmol) is added dropwise
Toluene solution (500.0ml), drip off follow-up continuous insulated and stirred 30-60min, TLC monitoring reactions.After the completion of reaction, it is added dropwise advance
Methanol (500.0ml) solution of the methanesulfonic acid (80.0ml, 1.23mol) of preparation, drips off and is reacted after at 20-30 DEG C.TLC is monitored
Reaction, after the completion of reaction, reaction solution pH >=7 are adjusted using saturated aqueous sodium carbonate or sodium bicarbonate aqueous solution.After layering, water
Mutually make to be extracted with ethyl acetate 3 times, extract merges with organic phase, is concentrated under reduced pressure.Concentration raffinate is dissolved using ethyl acetate, is satisfied
With sodium-chloride water solution wash 2 times, gained organic phase is directly concentrated under reduced pressure, obtain grease crude product 3 (283.00g,
536.92mmol), [the HPLC normalization methods of HPLC contents 83.27%：The chromatographic column Agilent SB-C18 (μ of 250 × 4.6mm 5
m)；Mobile phase, with acetonitrile-water-trifluoracetic acid (30：70：0.025) it is mobile phase A, with acetonitrile-water-trifluoracetic acid (90：10：
0.025) it is Mobile phase B, gradient elution (0 → 20min：A 100% → 70%, 20 → 40min：A 70% → 10%, 40 →
50min：A 10%, 50 → 50.1min：A 100%, 50.1 → 60min：A 100%) Detection wavelength 220nm；30 DEG C of column temperature；
Flow velocity, 1.0ml/min], yield 87.42%.Without curing process, the next step is directly used in.
2), the synthesis of compound 4
Under nitrogen protection, successively by dichloromethane (730ml), triethyl silicane (210.9ml, 1.32mol) and borontrifluoride
Borate ether (412.7ml, 1.58mol) is added in reaction bulb, is cooled to -10 to -0 DEG C, be added dropwise 3 (282.50g,
Dichloromethane solution (340ml) 535.97mmol), after dripping off, insulated and stirred 1.5h, uses saturated aqueous sodium carbonate
Reaction is quenched in (282.5ml), and resulting solution is directly concentrated under reduced pressure, and after removing low boiling point solvent, adds water (250.0ml) and acetic acid
Ethyl ester (500.0ml) stirring and dissolving, reuses saturated aqueous sodium carbonate and the pH value of reaction solution is adjusted into 7, after liquid separation, aqueous phase makes
It is extracted with ethyl acetate 2 times, using ethyl acetate 150ml/ times, extract merges with organic phase, uses saturated common salt water washing 3
Secondary, 100ml/ times, gained organic phase is concentrated under reduced pressure, and obtains yellow blister solid 4 (220.00g, 435.83mmol), HPLC contents
80.23% [HPLC normalization methods：Chromatographic column Agilent SB-C18 (5 μm of 250 × 4.6mm)；Mobile phase, with acetonitrile-water-three
Fluorine acetic acid (30：70：0.025) it is mobile phase A, with acetonitrile-water-trifluoracetic acid (90：10：0.025) it is Mobile phase B, gradient is washed
De- (0 → 20min：A 100% → 70%, 20 → 40min：A 70% → 10%, 40 → 50min：A 10%, 50 →
50.1min：A 100%, 50.1 → 60min：A 100%) Detection wavelength 220nm；30 DEG C of column temperature；Flow velocity, 1.0ml/min],
Yield 80.54%.
3), the preparation of two fine work 5
(S)-(+) -1,2-PD (399.2ml) is added into yellow blister solid 4 (219.50g, 434.84mmol)
And pure water (1170.0ml), heating stirring, Slow cooling after dissolved clarification, stirring and crystallizing, drain to obtain crude product 5 after filtering
(284.0g)；Crude product 5 is directly recrystallized using methyl tertiary butyl ether(MTBE) (1600ml) without drying, drains to obtain an essence after filtering
Product 5 (240.0g)；Without drying, methyl tertiary butyl ether(MTBE) (1600ml) secondary recrystallization is reused, is filtered, filter cake uses appropriate
Methyl tertiary butyl ether(MTBE) elutes 2 times, drains after being dried in 45-50 DEG C of air dry oven, obtain two fine work 5 (160.00g,
318.04mmol), [the HPLC normalization methods of HPLC purity 99.98%：The chromatographic column Agilent SB-C18 (μ of 250 × 4.6mm 5
m)；Mobile phase, with acetonitrile-water-trifluoracetic acid (30：70：0.025) it is mobile phase A, with acetonitrile-water-trifluoracetic acid (90：10：
0.025) it is Mobile phase B, gradient elution (0 → 20min：A 100% → 70%, 20 → 40min：A 70% → 10%, 40 →
50min：A 10%, 50 → 50.1min：A 100%, 50.1 → 60min：A 100%) Detection wavelength 220nm；30 DEG C of column temperature；
Flow velocity, 1.0ml/min], yield 73.14%.
4), two fine work 5 is free
Two fine work 5 (70.50g, 140.14mmol) are added to and fill the anti-of toluene (500.0ml) and water (500.0ml)
Answer in bottle, 30min is stirred at 25 DEG C, then, being transferred to stratification in separatory funnel, (upper strata is toluene phase, and middle level is
Aqueous phase, lower floor are 6 viscous shape liquid), after layering, middle level water layer and upper toluene layer discard；Lower floor's sticky matter material uses methyl- tert
After butyl ether (500ml) dissolving, drinking pure water washs 3 times, and gained organic phase adds suitable after being concentrated under reduced pressure and removing solvent
Measure toluene band to steam 1 time, finally obtain foaming material 6.
5) unformed (1S) -1,5- dehydrations -1- [the chloro- 3- of 4- [(4- ethoxyl phenenyls) methyl] phenyl]-D- grapes, are prepared
Sugar alcohol (6)
After using methyl tertiary butyl ether(MTBE) (200.0ml), foaming material 6 is dissolved, in the condition of inert gas shielding and stirring
Under, it is added drop-wise at -15~15 DEG C in normal heptane, follow-up continuous insulated and stirred 20-30min is dripped off, then, in inert gas shielding
Lower filtering, after draining, filter cake is positioned in 40~50 DEG C of vacuum drying chamber and is dried under reduced pressure 24~48h, obtain unformed 6
(53.94g, 131.87mmol), [the HPLC normalization methods of HPLC contents 99.96%：Chromatographic column Agilent SB-C18 (250 ×
4.6mm 5μm)；Mobile phase, with acetonitrile-water-trifluoracetic acid (30：70：0.025) it is mobile phase A, with acetonitrile-water-trifluoracetic acid
(90：10：0.025) it is Mobile phase B, gradient elution (0 → 20min：A 100% → 70%, 20 → 40min：A 70% →
10%, 40 → 50min：A 10%, 50 → 50.1min：A 100%, 50.1 → 60min：A 100%) Detection wavelength 220nm；
30 DEG C of column temperature；Flow velocity, 1.0ml/min], ESI-MS (m/z)：431.0 [M+Na]+, 1H NMR (400MHz, CDCl3) δ：7.22
(d, J=8.2Hz, 1H), 7.16-7.04 (m, 2H), 6.97 (d, J=8.6Hz, 2H), 6.69 (d, J=8.6Hz, 2H), 5.27
(s, 1H), 5.03 (s, 1H), 4.06 (s, 1H), 3.90 (t, J=8.3Hz, 2H), 3.85-3.78 (m, 2H), 3.65 (s, 2H),
3.58-3.39 (m, 2H), 3.39-3.10 (m, 4H), 1.28 (t, J=7.0Hz, 3H).Yield 94.08%.
Embodiment 2. prepare unformed (1S) -1,5- dehydrations -1- [the chloro- 3- of 4- [(4- ethoxyl phenenyls) methyl] phenyl] -
D-Glucose alcohol (Dapagliflozin)
1), the synthesis of compound 3
Under nitrogen protection, successively by toluene (430.0ml), tetrahydrofuran (400.0ml) and compound 1 (200.00g,
614.19mmol) it is added in reaction bulb, liquid nitrogen is cooled to less than -70 DEG C, and 2.5M n-BuLi hexane solution is added dropwise
(294.81ml, 737.03mmol), after dripping off, insulated and stirred 10min, compound 2 (344.10g, 737.03mmol) is added dropwise
Toluene solution (370.0ml), drip off follow-up continuous insulated and stirred 30-60min, TLC monitoring reactions.After the completion of reaction, it is added dropwise advance
Methanol (600.0ml) solution of the methanesulfonic acid (80.0ml, 1.23mol) of preparation, drips off and is reacted after at 20-30 DEG C.TLC is monitored
Reaction, after the completion of reaction, reaction solution pH >=7 are adjusted using saturated aqueous sodium carbonate or sodium bicarbonate aqueous solution.After layering, water
Mutually make to be extracted with ethyl acetate 3 times, extract merges with organic phase, is concentrated under reduced pressure.Concentration raffinate is dissolved using ethyl acetate, is satisfied
With sodium-chloride water solution wash 2 times, gained organic phase is directly concentrated under reduced pressure, obtain grease crude product 3 (307.22g,
568.73mmol), [the HPLC normalization methods of HPLC contents 81.25%：The chromatographic column Agilent SB-C18 (μ of 250 × 4.6mm 5
m)；Mobile phase, with acetonitrile-water-trifluoracetic acid (30：70：0.025) it is mobile phase A, with acetonitrile-water-trifluoracetic acid (90：10：
0.025) it is Mobile phase B, gradient elution (0 → 20min：A 100% → 70%, 20 → 40min：A 70% → 10%, 40 →
50min：A 10%, 50 → 50.1min：A 100%, 50.1 → 60min：A 100%) Detection wavelength 220nm；30 DEG C of column temperature；
Flow velocity, 1.0ml/min], yield 92.60%.Without curing process, the next step is directly used in.
2), the synthesis of compound 4
Nitrogen protection under, successively by dichloromethane (750.0ml), triethyl silicane (136.69ml, 855.80mmol) and
BFEE (267.51ml, 997.07mmol) is added in reaction bulb, is cooled to -10 to -0 DEG C, is added dropwise 3
The dichloromethane solution (340ml) of (189.46g, 350.74mmol), after dripping off, insulated and stirred 1.5h, uses saturated sodium carbonate
Reaction is quenched in the aqueous solution (200.0ml), and resulting solution is directly concentrated under reduced pressure, and after removing low boiling point solvent, adds water (200.0ml)
And ethyl acetate (500.0ml) stirring and dissolving, reuse saturated aqueous sodium carbonate and the pH value of reaction solution be adjusted to 7, after liquid separation,
Aqueous phase makes to be extracted with ethyl acetate 2 times, and using ethyl acetate 100ml/ times, extract merges with organic phase, uses saturated common salt
Water washing 3 times, 100ml/ times, gained organic phase is concentrated under reduced pressure, and obtains yellow blister solid 4 (131.80g, 295.17mmol),
[the HPLC normalization methods of HPLC contents 91.57%：Chromatographic column Agilent SB-C18 (5 μm of 250 × 4.6mm)；Mobile phase, with second
Nitrile-water-trifluoracetic acid (30：70：0.025) it is mobile phase A, with acetonitrile-water-trifluoracetic acid (90：10：0.025) it is mobile phase
B, gradient elution (0 → 20min：A 100% → 70%, 20 → 40min：A 70% → 10%, 40 → 50min：A 10%, 50
→50.1min：A 100%, 50.1 → 60min：A 100%) Detection wavelength 220nm；30 DEG C of column temperature；Flow velocity, 1.0ml/
Min], yield 84.16%.
3), the preparation of two fine work 5
(S)-(+) -1,2-PD (296.0ml) is added into yellow blister solid 4 (131.77g, 295.11mmol)
And pure water (866.0ml), heating stirring, Slow cooling after dissolved clarification, stirring and crystallizing, drain to obtain crude product 5 after filtering；Crude product 5 is not
Through drying, directly recrystallized using methyl tertiary butyl ether(MTBE) (900ml), drain to obtain a fine work 5 after filtering；Without drying, again
Using methyl tertiary butyl ether(MTBE) (900ml) secondary recrystallization, filtering, filter cake is eluted 2 times using appropriate methyl tertiary butyl ether(MTBE), after draining
Dried in 45-50 DEG C of air dry oven, obtain two fine work 5 (116.37g, 231.22mmol), HPLC purity 99.94%
[HPLC normalization methods：Chromatographic column Agilent SB-C18 (5 μm of 250 × 4.6mm)；Mobile phase, with acetonitrile-water-trifluoracetic acid
(30：70：0.025) it is mobile phase A, with acetonitrile-water-trifluoracetic acid (90：10：0.025) it is Mobile phase B, gradient elution (0 →
20min：A 100% → 70%, 20 → 40min：A 70% → 10%, 40 → 50min：A 10%, 50 → 50.1min：A
100%, 50.1 → 60min：A 100%) Detection wavelength 220nm；30 DEG C of column temperature；Flow velocity, 1.0ml/min], yield
78.35%.
4), two fine work 5 is free
Two fine work 5 (70.50g, 140.14mmol) are added to and fill the anti-of toluene (500.0ml) and water (500.0ml)
Answer in bottle, 30min is stirred at 30 DEG C, being then transferred to stratification in separatory funnel while hot, (upper strata is toluene phase, and middle level is water
Phase, lower floor are 6 viscous shape liquid), after layering, middle level water layer and upper toluene layer discard；Lower floor's sticky matter material uses methyl- tert fourth
After base ether (500ml) dissolving, drinking pure water washs 3 times, and gained organic phase adds appropriate after being concentrated under reduced pressure and removing solvent
Toluene band steams 1 time, finally obtains foaming material 6.
5) unformed (1S) -1,5- dehydrations -1- [the chloro- 3- of 4- [(4- ethoxyl phenenyls) methyl] phenyl]-D- grapes, are prepared
Sugar alcohol (6)
After using methyl tertiary butyl ether(MTBE) (150.0ml), foaming material 6 is dissolved, in the condition of inert gas shielding and stirring
Under, it is added drop-wise at -15~15 DEG C in normal heptane, follow-up continuous insulated and stirred 20-30min is dripped off, then, in inert gas shielding
Lower filtering, after draining, filter cake is positioned in 40~50 DEG C of vacuum drying chamber and is dried under reduced pressure 24~48h, obtain unformed 6
(56.6g, 138.35mmol), [the HPLC normalization methods of HPLC contents 99.94%：Chromatographic column Agilent SB-C18 (250 ×
4.6mm 5μm)；Mobile phase, with acetonitrile-water-trifluoracetic acid (30：70：0.025) it is mobile phase A, with acetonitrile-water-trifluoracetic acid
(90：10：0.025) it is Mobile phase B, gradient elution (0 → 20min：A 100% → 70%, 20 → 40min：A 70% →
10%, 40 → 50min：A 10%, 50 → 50.1min：A 100%, 50.1 → 60min：A 100%) Detection wavelength 220nm；
30 DEG C of column temperature；Flow velocity, 1.0ml/min], yield 98.70%.
Embodiment 3. prepare unformed (1S) -1,5- dehydrations -1- [the chloro- 3- of 4- [(4- ethoxyl phenenyls) methyl] phenyl] -
D-Glucose alcohol
1), the synthesis of compound 3
Under nitrogen protection, successively by toluene (500.0ml), tetrahydrofuran (400.0ml) and compound 1 (200.00g,
614.19mmol) it is added in reaction bulb, liquid nitrogen is cooled to less than -70 DEG C, and 2.5M n-BuLi hexane solution is added dropwise
(270.25ml, 675.61mmol), after dripping off, insulated and stirred 10min, compound 2 (344.10g, 737.03mmol) is added dropwise
Toluene solution (500.0ml), drip off follow-up continuous insulated and stirred 30-60min, TLC monitoring reactions.After the completion of reaction, it is added dropwise advance
Methanol (500.0ml) solution of the methanesulfonic acid (80.0ml, 1.23mol) of preparation, drips off and is reacted after at 20-30 DEG C.TLC is monitored
Reaction, after the completion of reaction, reaction solution pH >=7 are adjusted using saturated aqueous sodium carbonate or sodium bicarbonate aqueous solution.After layering, water
Mutually make to be extracted with ethyl acetate 3 times, extract merges with organic phase, is concentrated under reduced pressure.Concentration raffinate is dissolved using ethyl acetate, is satisfied
With sodium-chloride water solution wash 2 times, gained organic phase is directly concentrated under reduced pressure, obtain grease crude product 3 (298.73g,
597.05mmol), [the HPLC normalization methods of HPLC contents 87.72%：The chromatographic column Agilent SB-C18 (μ of 250 × 4.6mm 5
m)；Mobile phase, with acetonitrile-water-trifluoracetic acid (30：70：0.025) it is mobile phase A, with acetonitrile-water-trifluoracetic acid (90：10：
0.025) it is Mobile phase B, gradient elution (0 → 20min：A 100% → 70%, 20 → 40min：A 70% → 10%, 40 →
50min：A 10%, 50 → 50.1min：A 100%, 50.1 → 60min：A 100%) Detection wavelength 220nm；30 DEG C of column temperature；
Flow velocity, 1.0ml/min], yield 97.21%.Without curing process, the next step is directly used in.
2), the synthesis of compound 4
Under nitrogen protection, successively by dichloromethane (750.0ml), triethyl silicane (250.0ml, 1.57mmol) and trifluoro
Change borate ether (470.0ml, 1.75mol) to be added in reaction bulb, be cooled to -10 to -0 DEG C, be added dropwise 3 (298.50g,
Dichloromethane solution (340ml) 596.59mmol), after dripping off, insulated and stirred 1.5h, uses saturated aqueous sodium carbonate
Reaction is quenched in (200.0ml), and resulting solution is directly concentrated under reduced pressure, and after removing low boiling point solvent, adds water (200.0ml) and acetic acid
Ethyl ester (500.0ml) stirring and dissolving, reuses saturated aqueous sodium carbonate and the pH value of reaction solution is adjusted into 7, after liquid separation, aqueous phase makes
It is extracted with ethyl acetate 2 times, using ethyl acetate 100ml/ times, extract merges with organic phase, uses saturated common salt water washing 3
Secondary, 100ml/ times, gained organic phase is concentrated under reduced pressure, and obtains yellow blister solid 4 (240.38g, 539.99mmol), HPLC contents
91.85% [HPLC normalization methods：Chromatographic column Agilent SB-C18 (5 μm of 250 × 4.6mm)；Mobile phase, with acetonitrile-water-three
Fluorine acetic acid (30：70：0.025) it is mobile phase A, with acetonitrile-water-trifluoracetic acid (90：10：0.025) it is Mobile phase B, gradient is washed
De- (0 → 20min：A 100% → 70%, 20 → 40min：A 70% → 10%, 40 → 50min：A 10%, 50 →
50.1min：A 100%, 50.1 → 60min：A 100%) Detection wavelength 220nm；30 DEG C of column temperature；Flow velocity, 1.0ml/min],
Yield 90.51%.
3), the preparation of two fine work 5
(S)-(+) -1,2-PD (546.0ml) is added into yellow blister solid 4 (240.10g, 537.81mmol)
And pure water (1400.0ml), heating stirring, Slow cooling after dissolved clarification, stirring and crystallizing, drain to obtain crude product 5 after filtering；Crude product 5 is not
Through drying, directly recrystallized using methyl tertiary butyl ether(MTBE) (1050ml), drain to obtain a fine work 5 after filtering；Without drying, again
Using methyl tertiary butyl ether(MTBE) (1050ml) secondary recrystallization, filtering, filter cake is eluted 2 times using appropriate methyl tertiary butyl ether(MTBE), is drained
After being dried in 45-50 DEG C of air dry oven, two fine work 5 (174.21g, 346.25mmol), HPLC purity 99.97% are obtained
[HPLC normalization methods：Chromatographic column Agilent SB-C18 (5 μm of 250 × 4.6mm)；Mobile phase, with acetonitrile-water-trifluoracetic acid
(30：70：0.025) it is mobile phase A, with acetonitrile-water-trifluoracetic acid (90：10：0.025) it is Mobile phase B, gradient elution (0 →
20min：A 100% → 70%, 20 → 40min：A 70% → 10%, 40 → 50min：A 10%, 50 → 50.1min：A
100%, 50.1 → 60min：A 100%) Detection wavelength 220nm；30 DEG C of column temperature；Flow velocity, 1.0ml/min], yield
64.38%.
4), two fine work 5 is free
Two fine work 5 (70.50g, 140.12mmol) are added to and fill the anti-of toluene (500.0ml) and water (500.0ml)
Answer in bottle, 30min is stirred at 35 DEG C, being then transferred to stratification in separatory funnel while hot, (upper strata is toluene phase, and middle level is water
Phase, lower floor are 6 viscous shape liquid), after layering, middle level water layer and upper toluene layer discard；Lower floor's sticky matter material uses methyl- tert fourth
After base ether (500ml) dissolving, drinking pure water washs 3 times, and gained organic phase adds appropriate after being concentrated under reduced pressure and removing solvent
Toluene band steams 1 time, finally obtains foaming material 6.
5) unformed (1S) -1,5- dehydrations -1- [the chloro- 3- of 4- [(4- ethoxyl phenenyls) methyl] phenyl]-D- grapes, are prepared
Sugar alcohol (6)
After using methyl tertiary butyl ether(MTBE) (150.0ml), foaming material 6 is dissolved, in the condition of inert gas shielding and stirring
Under, it is added drop-wise at -15~15 DEG C in normal heptane, follow-up continuous insulated and stirred 20-30min is dripped off, then, in inert gas shielding
Lower filtering, after draining, filter cake is positioned in 40~50 DEG C of vacuum drying chamber and is dried under reduced pressure 24~48h, obtain unformed 6
(55.92g, 136.71mmol), [the HPLC normalization methods of HPLC contents 99.96%：Chromatographic column Agilent SB-C18 (250 ×
4.6mm 5μm)；Mobile phase, with acetonitrile-water-trifluoracetic acid (30：70：0.025) it is mobile phase A, with acetonitrile-water-trifluoracetic acid
(90：10：0.025) it is Mobile phase B, gradient elution (0 → 20min：A 100% → 70%, 20 → 40min：A 70% →
10%, 40 → 50min：A 10%, 50 → 50.1min：A 100%, 50.1 → 60min：A 100%) Detection wavelength 220nm；
30 DEG C of column temperature；Flow velocity, 1.0ml/min], yield 97.57%.
Although the present invention is disclosed as above with preferred embodiment, it is not for limiting the present invention, any this area
Technical staff without departing from the spirit and scope of the present invention, may be by the methods and technical content of the disclosure above to this hair
Bright technical scheme makes possible variation and modification, therefore, every content without departing from technical solution of the present invention, according to the present invention
Any simple modifications, equivalents, and modifications made to above example of technical spirit, belong to technical solution of the present invention
Protection domain.
Claims (9)
1. a kind of synthetic method of unformed glucitol, its reaction equation are as follows：
Comprise the following steps：
1) compound 1 obtains compound 3 with compound 2 through condensation reaction；
2) compound 3 obtains compound 4 through reduction reaction；
3) crude product 5 is obtained after S-1,2- propane diols and water reaction are added into compound 4；
4) crude product 5 is refining to obtain compound 5 through 2 times；
5) compound 5 is dissociated through toluene and water, obtains three-phase system, wherein, upper strata is toluene phase, and middle level is aqueous phase, under
Layer is material bed, and lower floor's material is obtained after layering；
6) lower floor's material is after good solvent dissolves, then scrubbed and scattered obtain amorphous compound 6；
Characterized in that,
In step 5), described compound 5 is dissociated through toluene and aqueous systems, and layering obtains lower floor's material；
In step 6), lower floor's material is after good solvent dissolves and washes, then through being concentrated under reduced pressure to give foaming material；
Foaming material is dissolved using good solvent, and is added dropwise under inert gas shielding in poor solvent, in inert gas shielding
Lower filtering, filter cake obtain amorphous compound 6 after drying.
2. synthetic method according to claim 1, it is characterised in that described good solvent is ethers, esters or chloro
Hydro carbons, it is preferable that described good solvent is methyl tertiary butyl ether(MTBE), 2- methyltetrahydrofurans, ethyl acetate, butyl acetate, two
Chloromethanes or chloroform；
Described good solvent dosage is the every g of compound 5 of 1~5ml, and preferably 2~4ml is per g of compound 5.
3. synthetic method according to claim 1, it is characterised in that the poor solvent is normal heptane, n-hexane or just
Pentane；The poor solvent dosage is 8~15ml per g of compound 5.
4. synthetic method according to claim 1, it is characterised in that, will be borontrifluoride during described 3 reduction reaction of compound
Borate ether, triethyl silicane and methylene chloride are added in reactor in the lump, and the dichloromethane that compound 3 is then added dropwise is molten
Liquid, rear insulated and stirred is dripped off, solution ph is adjusted using saturated aqueous sodium carbonate as neutrality after the completion of reaction.
5. synthetic method according to claim 4, it is characterised in that in described reduction reaction, reaction temperature is -20 DEG C
~20 DEG C, preferably -15 DEG C~10 DEG C, more preferably -10 DEG C~-5 DEG C；The mol ratio of reactant is：Compound 3:Boron trifluoride second
Ether:Triethyl silicane=1:(2~7):(1~3), it is preferable that compound 3:BFEE:Triethyl silicane=1:(4~
6.5):(1.5~2.5).
6. synthetic method according to claim 1, it is characterised in that in step 3), S-1,2- third are added into compound 4
Glycol and water, heating, after dissolved clarification, Slow cooling, crude product 5 are obtained after crystallization, is changed after 2 recrystallizations of methyl tertiary butyl ether(MTBE)
Compound 5.
7. according to the synthetic method described in claim any one of 1-3, it is characterised in that compound 5 is swum through toluene and aqueous systems
After layering, gained lower floor is material bed to be dissolved using good solvent, then is washed 2 times, and the concentration of gained organic phase removes solvent, toluene
Band steams 1 time, obtains foaming material, then is dissolved with good solvent, is then added drop-wise in poor solvent.
8. synthetic method according to claim 7, it is characterised in that described toluene and good solvent dosage be 10~
For 20ml per g of compound 5, each water consumption is 0.3~1 times of toluene or good solvent used.
9. synthetic method according to claim 7, it is characterised in that
It is 5 DEG C~60 DEG C that compound 5 is carried out into free temperature using toluene and water, preferably 10 DEG C~45 DEG C, more preferably 15 DEG C
~35 DEG C, mixing time of dissociating is 0.5~1h；
Separatory funnel layering is transferred to, divides three layers, upper strata is toluene phase, and middle level is aqueous phase, and lower floor is feed liquid layer；In inert gas
Under protection, feed liquid is dissolved using good solvent, is added dropwise in poor solvent, 0.5~1h is stirred after dripping off, under inert gas shielding
Filtering, is drained, in 30~50 DEG C of vacuum drying；
Preferably, described toluene and water consumption are respectively 10~20ml per g of compound 5 and 10~20ml is per g of compound 5.
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