CN109096270A - A kind of canagliflozin 4- position isomer impurity and preparation method thereof - Google Patents
A kind of canagliflozin 4- position isomer impurity and preparation method thereof Download PDFInfo
- Publication number
- CN109096270A CN109096270A CN201810891508.3A CN201810891508A CN109096270A CN 109096270 A CN109096270 A CN 109096270A CN 201810891508 A CN201810891508 A CN 201810891508A CN 109096270 A CN109096270 A CN 109096270A
- Authority
- CN
- China
- Prior art keywords
- formula
- preparation
- compound
- reaction
- organic solvent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 229960001713 canagliflozin Drugs 0.000 title claims abstract description 24
- VHOFTEAWFCUTOS-TUGBYPPCSA-N canagliflozin hydrate Chemical compound O.CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1.CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1 VHOFTEAWFCUTOS-TUGBYPPCSA-N 0.000 title claims abstract description 24
- 239000012535 impurity Substances 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 239000003513 alkali Substances 0.000 claims abstract description 13
- -1 bromo- 2- methylbenzyl Chemical group 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 11
- 239000002253 acid Substances 0.000 claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 8
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims abstract description 3
- 238000006482 condensation reaction Methods 0.000 claims abstract description 3
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 3
- 150000002596 lactones Chemical class 0.000 claims abstract description 3
- 238000006722 reduction reaction Methods 0.000 claims abstract description 3
- 239000007858 starting material Substances 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 150000001875 compounds Chemical class 0.000 claims description 20
- 239000003960 organic solvent Substances 0.000 claims description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 9
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 9
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- 235000019441 ethanol Nutrition 0.000 claims description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000003638 chemical reducing agent Substances 0.000 claims description 6
- 239000012046 mixed solvent Substances 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 239000002841 Lewis acid Substances 0.000 claims description 4
- 150000007517 lewis acids Chemical class 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- 229930192474 thiophene Natural products 0.000 claims description 4
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical group CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 claims description 4
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- 239000000376 reactant Substances 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- KWEKXPWNFQBJAY-UHFFFAOYSA-N (dimethyl-$l^{3}-silanyl)oxy-dimethylsilicon Chemical compound C[Si](C)O[Si](C)C KWEKXPWNFQBJAY-UHFFFAOYSA-N 0.000 claims description 2
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 230000009471 action Effects 0.000 claims description 2
- 230000008859 change Effects 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 239000011541 reaction mixture Substances 0.000 claims description 2
- 229910000077 silane Inorganic materials 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000000758 substrate Substances 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 3
- 125000006179 2-methyl benzyl group Chemical group [H]C1=C([H])C(=C(C([H])=C1[H])C([H])([H])*)C([H])([H])[H] 0.000 claims 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims 1
- 230000008569 process Effects 0.000 abstract description 3
- 239000006227 byproduct Substances 0.000 abstract description 2
- 239000000047 product Substances 0.000 abstract description 2
- 230000035484 reaction time Effects 0.000 abstract description 2
- 229940125782 compound 2 Drugs 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 14
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 7
- 239000002585 base Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000006356 dehydrogenation reaction Methods 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- PURJRGMZIKXDMW-UHFFFAOYSA-N 2-(4-fluorophenyl)thiophene Chemical compound C1=CC(F)=CC=C1C1=CC=CS1 PURJRGMZIKXDMW-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 229910015900 BF3 Inorganic materials 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010018473 Glycosuria Diseases 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001207 fluorophenyl group Chemical group 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical compound C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 description 1
- 229940094989 trimethylsilane Drugs 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a kind of canagliflozin 4- position isomer impurity and preparation method thereof; its structural formula is shown in formula I; preparation method is using 2- (the bromo- 2- methylbenzyl of 4-) -5- (4- fluorophenyl) thiophene as starting material; with Formula II compound 2; 3; 4,6- tetra--O- trimethyl silicon substrates-D-Glucose acid lactone carry out condensation reaction, deprotection reaction, carry out acetyl group protection reaction again, reduction reaction, last be deprotected in the presence of alkali obtain canagliflozin 4- position isomer impurity shown in Formulas I；
Description
Technical field
The present invention relates to field of medicinal chemistry, and in particular to (1R) -1,5- dehydrogenation -1- [4- [[5- (4- fluorophenyl) -2- thiophene
Pheno base] methyl] -3- aminomethyl phenyl]-D-Glucose alcohol (canagliflozin 4- position isomer impurity) and preparation method thereof.
Background of invention
Canagliflozin (Canagliflozin), entitled (1R) -1,5- dehydrogenation -1- [3- [[5- (4- the fluorophenyl) -2- of chemistry
Thienyl] methyl] -4- aminomethyl phenyl]-D-Glucose alcohol, structural formula is as follows:
Canagliflozin is the oral diabetes drug of drugmaker of Johnson & Johnson exploitation, for treating the II type glycosuria of adult patients
Disease is first SGLT2 inhibitor, and the glucose in renal tubule can be prevented to enter blood from smooth reabsorption and arrange with urine
Out, to reduce blood sugar concentration.
Yuan Yan house journal WO2005012326A1 reports a kind of synthetic route of canagliflozin, and this method is card at present
Lattice arrange the main method synthesized only, specific as follows:
During synthesizing canagliflozin, the inventors discovered that canagliflozin 4- position isomer impurity is that main technique is miscellaneous
Matter structural formula is as follows:
The 4- position isomer impurity is not easy to remove in subsequent processes, and the content of the impurity is to the quality of canagliflozin
Control has important influence.Currently without the structure and preparation method of the document report impurity,
The present invention provides a kind of method of controlled syntheses canagliflozin 4- position isomer impurity, quick, convenient, efficient
It is significant to the quality control of canagliflozin bulk pharmaceutical chemicals to impurity reference substance.
Summary of the invention
An aspect of of the present present invention provides a kind of canagliflozin 4- position isomer impurity, and structure is as shown in Equation 1:
On the other hand a kind of easy to operate, low-cost synthesis (1R) -1,5- dehydrogenation -1- [3- [[5- (4- fluorine is provided
Phenyl) -2- thienyl] methyl] -4- aminomethyl phenyl]-D-Glucose alcohol method.
Method includes the following steps:
A) using 2- (the bromo- 2- methylbenzyl of 4-), thiophene is starting material to -5- (4- fluorophenyl), under the action of butyl lithium,
Condensation reaction is carried out in organic solvent with 2,3,4,6- tetra--O- trimethyl silicon substrate of Formula II compound-D-Glucose acid lactone, then
Acid progress deprotection reaction is added in obtained reaction mixture and obtains formula III compound；
B) then in the presence of alkali, acetyl group protection is carried out with acetic anhydride to react to obtain formula IV compound；
C) then in the presence of a lewis acid, carry out reduction reaction in organic solvent with reducing agent and obtain Formula V chemical combination
Object；
D) finally Formula V compound is deprotected in the presence of alkali in organic solvent and obtains canagliflozin shown in Formulas I
4- position isomer impurity.
Wherein, the organic solvent in step a) is one of toluene, tetrahydrofuran, ether or its mixed solvent；It is described
Acid be methanesulfonic acid, p-methyl benzenesulfonic acid or trifluoroacetic acid.
The mass ratio of consumption of organic solvent and 2- (the bromo- 2- methylbenzyl of 4-) -5- (4- fluorophenyl) thiophene in step a)
For 5.0:1~20:1, preferably 6:1~15:1；The sour dosage and 2- (the bromo- 2- methylbenzyl of 4-) -5- (4- fluorophenyl)
The molar ratio of thiophene is 1:1~6:1, preferably 1.2:1~4:1；The dosage and 2- (the bromo- 2- methyl benzyl of 4- of the butyl lithium
Base) -5- (4- fluorophenyl) thiophene molar ratio be 1:1~2.5:1, preferably 1.1:1~1.5:1；The dosage of Formula II reactant
Molar ratio with 2- (the bromo- 2- methylbenzyl of 4-) -5- (4- fluorophenyl) thiophene is 1:1~2.5:1, preferably 1.1:1~1.5:
1。
Alkali in step b) is triethylamine, N-methylmorpholine or tri-n-butylamine；The dosage of the alkali is rubbed with formula III compound
You are than being 4:1~15:1, preferably 6:1~10:1.
Organic solvent in step c) is one of methylene chloride, toluene, chloroform, carbon tetrachloride or its mixed solvent；
The lewis acid is alchlor, trifluoroacetic acid or boron trifluoride ether solution；The reducing agent be triethylsilane,
Pheiiyldimetliyl silane or 1,1,3,3- tetramethyl disiloxane；Wherein the dosage of the reducing agent and formula III compound rub
You are than being 1:1~5:1, preferably 2.5:1~3.5:1；The lewis acidic dosage and the molar ratio of formula III compound are 1:
1~5:1, preferably 2.5:1~3.5:1.
Reaction organic solvent in step d) is tetrahydrofuran, water, ethyl alcohol, one kind of methanol or its mixed solvent；It is described
Alkali be sodium hydroxide, potassium hydroxide, sodium ethoxide, sodium methoxide or potassium tert-butoxide；Reaction consumption of organic solvent therein and Formula V
The mass ratio for closing object is 10:1~30:1, preferably 15:1~20:1；The dosage of the alkali and the molar ratio of Formula V compound are 4:
1~15:1, preferably 7:1~10:1.
Synthetic route of the present invention has reaction condition mild, and simple process, the reaction time is short, and by-product is few, and yield is good,
The advantages that capable of obtaining high-purity product.
Specific embodiment
The present invention is further elaborated below with reference to embodiment, but these examples do not constitute any limit to the present invention
System.
Embodiment 1:
(3R, 4S, 5S, 6R) -2- (4- ((5- (4- fluorophenyl) thiophene -2- base) methyl) -3- aminomethyl phenyl) -6- (hydroxyl first
Base) -2- methoxyl group tetrahydro -2H- pyrans -3,4,5- triol (formula III compound) synthesis:
Under nitrogen protection, into the there-necked flask of 500mL, 2- (the bromo- 2- methylbenzyl of 4-) -5- (4- fluorophenyl) is sequentially added
Thiophene (36.1g, 0.10mol), 120g toluene, 120g tetrahydrofuran, stirring are cooled to -90~-70 DEG C, and butyl lithium is added dropwise
(27.5mL, 0.11mol) continues to stir 0.5h after being added dropwise, is added dropwise Formula II reactant (56.0g, 0.12mol), drips
Continue to stir 1h after finishing, methanesulfonic acid (26.4g, 0.12mol) and 300g methyl alcohol mixed liquor is added dropwise, drips off and be warming up to 15~30 DEG C and stir
15h is mixed, saturated sodium bicarbonate solution 600g, liquid separation is added dropwise, water phase is extracted with 800g ethyl acetate, is merged organic phase, is evaporated.Make
Residue is dried with vacuum oven, faint yellow solid 40.1g can be obtained, HPLC purity: 90%, yield 85%.
Embodiment 2:
(2R, 3R, 4R, 5S, 6S) -2- (acetoxymethyl ester base) -6- (4- ((5- (4- fluorophenyl) thiophene -2- base) methyl) -3-
Aminomethyl phenyl) tetrahydro -2H- pyrans -3,4,5- acetic acid three ester (Formula V compound) synthesis:
Under nitrogen protection, into the there-necked flask of 500mL, the formula III compound prepared according to embodiment 1 is sequentially added
(46.0g, 0.10mol), the methylene chloride of 1150g, stirring are cooled to 0~10 DEG C, be added N-methylmorpholine (98.0g,
0.97mol), acetic anhydride (98.9g, 0.97mol) is added, is warming up to 20~30 DEG C, react 12h, 700g water is added, stir 1h,
Liquid separation, water phase are extracted with 200g methylene chloride, merge organic phase, add 500g saturated common salt water washing, and trimethyl silane is added
(34.8g, 0.30mol) is cooled to 0~10 DEG C, is added dropwise boron trifluoride ether (42.6g, 0.30mol), rises to 15~25 DEG C, instead
8h is answered, 700g water is added, stirs 1h, liquid separation.It is evaporated organic phase, residue adds 100g isopropanol to stir 2h, filters out filtrate, protects
Filter cake is stayed, is dried using vacuum oven, white solid 46.5g can be obtained, HPLC purity: 99%, yield 76%.
Embodiment 3:
(1R) -1,5- dehydrogenation -1- [4- [[5- (4- fluorophenyl) -2- thienyl] methyl] -3- aminomethyl phenyl]-D-Glucose
The synthesis of alcohol (canagliflozin 4- position isomer impurity):
Into the there-necked flask of 500mL, Formula V compound (61.3g, 0.10mol), 600g tetrahydrofuran, 600g are sequentially added
Methanol, stir 20min after, be added potassium hydroxide (56g, 1.0mol), 20~30 DEG C, react 5h.300g is added in solvent evaporated
Water stirs 1h, and filtering dries filter cake using vacuum oven, can obtain white solid 35.6g, HPLC purity: 99%, yield
80%.
1H NMR(DMSO-d6)δ2.28(s,3H),3.21-3.23(m,3H),3.29(m,1H),3.47(m,1H),3.72
(m,1H),3.97(d,1H),4.11(s,2H),4.49(t,1H),4.81(d,1H),5.00(d,1H),5.04(d,1H),6.82
(d,1H),7.16-7.19(m,5H),7.28(d,1H),7.59(d,2H)；13C NMR(DMSO-d6)δ19.2,33.1,61.5,
70.5,74.6,78.6,81.3,81.4,115.9,123.5,125.9,126.5,127.0,128.7,129.8,130.6,
135.1,137.4,138.9,140.3,143.7,161.4.MS-ESI(m/z):[M+H]+445.1.
Embodiment 4:
(1R) -1,5- dehydrogenation -1- [4- [[5- (4- fluorophenyl) -2- thienyl] methyl] -3- aminomethyl phenyl]-D-Glucose
The synthesis of alcohol (canagliflozin 4- position isomer impurity):
It into the there-necked flask of 500mL, sequentially adds Formula V compound (61.3g, 0.10mol), the methanol of 1000g, stirs
After 20min, it is added sodium methoxide (54g, 1.0mol), 15~30 DEG C of reaction 4h.500g water is added in solvent evaporated, stirs 1h, mistake
Filter dries filter cake using vacuum oven, can obtain white solid 34.7g, HPLC purity: 99%, yield 78%.
1H NMR(DMSO-d6)δ2.28(s,3H),3.21-3.23(m,3H),3.29(m,1H),3.47(m,1H),3.72
(m,1H),3.97(d,1H),4.11(s,2H),4.49(t,1H),4.81(d,1H),5.00(d,1H),5.04(d,1H),6.82
(d,1H),7.16-7.19(m,5H),7.28(d,1H),7.59(d,2H)；13C NMR(DMSO-d6)δ19.2,33.1,61.5,
70.5,74.6,78.6,81.3,81.4,115.9,123.5,125.9,126.5,127.0,128.7,129.8,130.6,
135.1,137.4,138.9,140.3,143.7,161.4.MS-ESI(m/z):[M+H]+445.1.
Embodiment 5:
(1R) -1,5- dehydrogenation -1- [4- [[5- (4- fluorophenyl) -2- thienyl] methyl] -3- aminomethyl phenyl]-D-Glucose
The synthesis of alcohol (canagliflozin 4- position isomer impurity):
It into the there-necked flask of 500mL, sequentially adds Formula V compound (61.3g, 0.10mol), the methanol of 1200g, stirs
After 20min, the solution that potassium hydroxide (56g, 1.0mol) and 200g water are prepared is added, 20~30 DEG C, reacts 5h.Methanol is boiled off,
300g water is added, stirs 1h, filtering dries filter cake using vacuum oven, can obtain white solid 32.0g, HPLC purity:
99%, yield 72%.
1H NMR(DMSO-d6)δ2.28(s,3H),3.21-3.23(m,3H),3.29(m,1H),3.47(m,1H),3.72
(m,1H),3.97(d,1H),4.11(s,2H),4.49(t,1H),4.81(d,1H),5.00(d,1H),5.04(d,1H),6.82
(d,1H),7.16-7.19(m,5H),7.28(d,1H),7.59(d,2H)；13C NMR(DMSO-d6)δ19.2,33.1,61.5,
70.5,74.6,78.6,81.3,81.4,115.9,123.5,125.9,126.5,127.0,128.7,129.8,130.6,
135.1,137.4,138.9,140.3,143.7,161.4.MS-ESI(m/z):[M+H]+445.1.
A kind of canagliflozin 4- position isomer impurity proposed by the present invention and preparation method thereof is carried out by embodiment
Description, related technical personnel obviously can not depart from the content of present invention, in spirit and scope to canagliflozin 4- as described herein
Position isomer impurity and preparation method thereof is modified or appropriate changes and combinations, to realize the technology of the present invention.Especially need to refer to
Out, all similar replacements and change are apparent to those skilled in the art, they are considered as wrapping
It includes in spirit of the invention, range and content.
Claims (10)
1. a kind of canagliflozin 4- position isomer impurity, structure are as shown in Equation 1:
2. a kind of method for preparing canagliflozin 4- position isomer impurity as described in claim 1, this method includes following step
It is rapid:
A) using 2- (the bromo- 2- methylbenzyl of 4-), thiophene is starting material to -5- (4- fluorophenyl), under the action of butyl lithium, with formula
2,3,4,6- tetra--O- trimethyl silicon substrate of II compound-D-Glucose acid lactone carries out condensation reaction in organic solvent, then is obtaining
To reaction mixture in be added acid carry out deprotection reaction obtain formula III compound；
B) then in the presence of alkali, acetyl group protection is carried out with acetic anhydride to react to obtain formula IV compound；
C) then in the presence of a lewis acid, carry out reduction reaction in organic solvent with reducing agent and obtain Formula V compound；
D) finally Formula V compound is deprotected in the presence of alkali in organic solvent and obtains shown in Formulas I canagliflozin 4-
Isomer impurities；
3. preparation method according to claim 2, which is characterized in that the organic solvent in step a) is toluene, tetrahydro furan
It mutters, one of ether or its mixed solvent；The acid is methanesulfonic acid, p-methyl benzenesulfonic acid or trifluoroacetic acid.
4. preparation method according to claim 2, which is characterized in that the alkali in step b) is triethylamine, N-methylmorpholine
Or tri-n-butylamine.
5. preparation method according to claim 2, which is characterized in that the organic solvent in step c) is methylene chloride, first
One of benzene, chloroform, carbon tetrachloride or its mixed solvent；The lewis acid is alchlor, trifluoroacetic acid or trifluoro
Change borate ether solution；The reducing agent is triethylsilane, pheiiyldimetliyl silane or 1,1,3,3- tetramethyl disiloxane.
6. preparation method according to claim 2, which is characterized in that the reaction organic solvent in step d) is tetrahydro furan
It mutters, one kind of water, ethyl alcohol, methanol or its mixed solvent；The alkali be sodium hydroxide, potassium hydroxide, sodium ethoxide, sodium methoxide or
Potassium tert-butoxide.
7. preparation method according to claim 2, which is characterized in that (4- is bromo- with 2- for the consumption of organic solvent in step a)
2- methylbenzyl) -5- (4- fluorophenyl) thiophene mass ratio be 5.0:1~20:1, preferably 6:1~15:1；The acid is used
Amount and the molar ratio of 2- (the bromo- 2- methylbenzyl of 4-) -5- (4- fluorophenyl) thiophene are 1:1~6:1, preferably 2:1~4:1；Institute
The molar ratio of the dosage and 2- (the bromo- 2- methylbenzyl of 4-) -5- (4- fluorophenyl) thiophene of stating butyl lithium is 1:1~2.5:1, preferably
For 1.1:1~1.5:1；The dosage of Formula II reactant and the molar ratio of 2- (the bromo- 2- methylbenzyl of 4-) -5- (4- fluorophenyl) thiophene
For 1:1~2.5:1, preferably 1.1:1~1.5:1.
8. preparation method according to claim 2, which is characterized in that the dosage and formula III of the alkali in step b)
The molar ratio for closing object is 4:1~15:1, preferably 6:1~10:1.
9. preparation method according to claim 2, which is characterized in that the dosage and formula of the reducing agent in step c)
The molar ratio of III compound is 1:1~5:1, preferably 2.5:1~3.5:1；The lewis acidic dosage and formula III chemical combination
The molar ratio of object is 1:1~5:1, preferably 2.5:1~3.5:1.
10. preparation method according to claim 2, which is characterized in that reaction consumption of organic solvent and Formula V in step d)
The mass ratio of compound is 10:1~30:1, preferably 15:1~20:1；The dosage of the alkali and the molar ratio of Formula V compound are
4:1~15:1, preferably 7:1~10:1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810891508.3A CN109096270A (en) | 2018-08-07 | 2018-08-07 | A kind of canagliflozin 4- position isomer impurity and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810891508.3A CN109096270A (en) | 2018-08-07 | 2018-08-07 | A kind of canagliflozin 4- position isomer impurity and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109096270A true CN109096270A (en) | 2018-12-28 |
Family
ID=64848692
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810891508.3A Pending CN109096270A (en) | 2018-08-07 | 2018-08-07 | A kind of canagliflozin 4- position isomer impurity and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109096270A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115028616A (en) * | 2022-05-24 | 2022-09-09 | 上海予君生物科技发展有限公司 | Canagliflozin impurity, preparation process and application thereof, and preparation process of compounds of formula II and formula III |
-
2018
- 2018-08-07 CN CN201810891508.3A patent/CN109096270A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115028616A (en) * | 2022-05-24 | 2022-09-09 | 上海予君生物科技发展有限公司 | Canagliflozin impurity, preparation process and application thereof, and preparation process of compounds of formula II and formula III |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105061373B (en) | A kind of synthetic method of Dapagliflozin isomer impurities | |
| DK2324002T3 (en) | Methods of making of sglt2 inhibitors | |
| TWI488861B (en) | Process for the preparation of β-c-aryl glucosides | |
| EA021373B1 (en) | Process for the preparation of compounds useful as inhibitors of sodium-dependent glucose transporter (sglt) | |
| CN101238112A (en) | Crystalline forms of 1-chloro-4-(beta-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benzene, methods for its preparation and the use thereof for preparing medicaments | |
| CN104402946B (en) | Canagliflozin intermediate and its unbodied preparation method | |
| US20170114051A1 (en) | Process for preparation of canagliflozin | |
| CN100516063C (en) | Production method of nifuratel | |
| CN106458857A (en) | Crystalline free acid, hemicalcium salt and alfa-phenylethylamine salt of ahu-377 as well as preparation method therefor and application thereof | |
| US8952139B2 (en) | Process for the preparation of β-C-aryl glucosides | |
| CN104059042B (en) | C-triaryl glucoside SGLT-2 inhibitor | |
| CN109180662A (en) | A kind of preparation method of canagliflozin | |
| CN104327027B (en) | One class novel C aryl glucoside SGLT2 inhibitor | |
| CN108892659A (en) | A kind of canagliflozin impurity and preparation method thereof | |
| CN111560004A (en) | Preparation method of high-purity canagliflozin intermediate | |
| WO2017206808A1 (en) | Process for preparing dapagliflozin eutectic matter | |
| CN104744449A (en) | Preparation method of canagliflozin hemihydrate and monocrystal thereof | |
| CN109096270A (en) | A kind of canagliflozin 4- position isomer impurity and preparation method thereof | |
| CN110655517A (en) | Preparation method of doriravir open-loop impurities and impurities thereof | |
| CN104744390A (en) | Preparation method of ezetimibe internmediate ketone | |
| CN107501222B (en) | Scutellarin aglycone derivative as well as preparation method and application thereof | |
| CN108218928B (en) | Bicyclic derivatives of glucoside, preparation method and application thereof | |
| CN108864084B (en) | Apixaban related substances and preparation method thereof | |
| CN109438448A (en) | A kind of indoles and compounds with 7-member cycle and its preparation method and application | |
| CN109516938A (en) | A kind of Alfacalcidol derivative and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20181228 |