CN106938998A - Synthetic method of the canagliflozin about material - Google Patents
Synthetic method of the canagliflozin about material Download PDFInfo
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- CN106938998A CN106938998A CN201710224890.8A CN201710224890A CN106938998A CN 106938998 A CN106938998 A CN 106938998A CN 201710224890 A CN201710224890 A CN 201710224890A CN 106938998 A CN106938998 A CN 106938998A
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- BBYLJZYITJEIQG-VZMBAYEOSA-N CC(O[C@H](C1)C1([C@H]([C@@H](C1)OC(C)=O)OC(C)=O)OC1c1ccc(C)c(Cc2ccc(-c(cc3)ccc3F)[s]2)c1)=O Chemical compound CC(O[C@H](C1)C1([C@H]([C@@H](C1)OC(C)=O)OC(C)=O)OC1c1ccc(C)c(Cc2ccc(-c(cc3)ccc3F)[s]2)c1)=O BBYLJZYITJEIQG-VZMBAYEOSA-N 0.000 description 1
Classifications
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- 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
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
Abstract
The present invention relates to synthetic method of the canagliflozin about material, belong to Drug-related Substances synthesis field.It is an object of the present invention to provide a kind of synthetic method of canagliflozin about material, the relevant material is canagliflozin impurity I and canagliflozin impurity II, synthetic method of the present invention about material canagliflozin impurity I and canagliflozin impurity II, it is to first pass through raw material A to prepare canagliflozin impurity I, canagliflozin impurity II is further then prepared using canagliflozin impurity I again.Canagliflozin impurity I and canagliflozin impurity II are defined as by nuclear-magnetism and mass spectrum, the quality control prepared available for canagliflozin bulk drug and the standard items of research provide a kind of new selection for qualitative and quantitative detection canagliflozin.
Description
Technical field
The present invention relates to synthetic method of the canagliflozin about material, belong to Drug-related Substances synthesis field.
Background technology
Diabetes are a kind of chronic disease in the serious puzzlement whole world, according to incompletely statistics, existing 21.3 hundred million sugar in the whole world
Urinate patient.Expect 2025, the whole world will have 31.5 hundred million diabetics.The World Health Organization (World in 1999
Health Organization, WHO) diabetes are defined as：Diabetes are the metabolic disorders as caused by Different types of etiopathogenises, and it is special
Point is chronic hyperglycemia, with hypoinsulinism and/or insulin action obstacle, causes carbohydrate, fat and egg
The metabolic disorder of white matter, ultimately causes the chronic injury and dysfunction of a variety of organs.The current international parting master to diabetes
If the teiology based on diabetes, WHO consultation reports (WHO/NCD/NCS/99.2) and IDF
Diabetes were divided into four types by (International Diabetes Federation, IDF) committee of Xi Tai areas in 1999,
That is diabetes of type 1 diabetes, diabetes B, gestational diabetes and other specific types.Therefore, to diabetes medicament
Correlative study and exploitation have important theory significance and practical value.
Canagliflozin, English name：Canagliflozin, chemical name：(1S) -1,5- dehydrogenations -1-C- [3- [[5- (4- fluorobenzene
Base) -2- thienyls] methyl] -4- aminomethyl phenyls]-D-Glucose alcohol semihydrate.Canagliflozin is public by the pharmacy of Tian Bian Mitsubishis
The SGLT2 inhibitor class medicine for the first acquisition U.S. FDA approval that department and Johson ＆ Johnson develop jointly, it is common with 2 type sodium glucose
Transport protein (SGLT2) is the oral hypoglycemic of target.SGLT-2 target site and mechanism and existing OHA
Different with antidiabetic, creativeness opens hypoglycemic new route.Its mechanism of action is independent of beta Cell of islet, therefore drug effect
Do not influenceed by islet beta cell function.And because its mechanism of action is independent of insulin, in any stage of diabetes B
It may be employed.Therefore, SGLT-2 inhibitor is used for the treatment of diabetes B with good prospect.Faced by existing
Bed experiment confirms the validity and security of the medicine.Its is alone or is used in combination with melbine, sulfonylurea drugs, Ke Yixian
Write the HbA1c and fasting blood-glucose of reduction diabetes B patient, adverse reaction rate is similar to placebo, risk of hypoglycemia compared with
It is low, it can significantly mitigate the scale of construction.It is significant to improve the relevant material in the quality of bulk drug, research building-up process.
The Yuan Yan companies of canagliflozin are military field, its synthetic routes of patent CN102264714 to canagliflozin at home
Have been reported, its current method is as follows for the main method of domestic canagliflozin synthesis at present：
It is in building-up process, and due to compound B quality controllabilities not high and step one grignard reaction, reaction condition compares
Harshness needs to carry out in the environment of low-temperature anhydrous anaerobic, so in course of reaction, being readily incorporated special relevant material.
In the prior art, because impurity is unknown, it is impossible to which effectively control synthesizes the quality of finished product, the present inventor passes through
Prepared by the methods such as enrichment impurity, destructive testing, column chromatography purifying, and by structural identification means, its structure is carried out
Checking and parsing, so that it is determined that two major impurities of canagliflozin are respectively canagliflozin impurity I, canagliflozin impurity
Ⅱ.The molecular formula of canagliflozin impurity I is C52H50F2O9S2, molecular weight 921.07.The molecular formula of canagliflozin impurity II is
C44H42F2O5S2, molecular weight 752.93.Structural formula is：
The present inventor synthesizes the standard items of the relative substance of canagliflozin by preparation, further applies card lattice
Quality control and research prepared by net bulk drug are arranged, new direction is provided to improve bulk drug.
The content of the invention
Technical problem solved by the invention is to provide a kind of synthetic method of canagliflozin about material, present invention synthesis
The relevant material that method is prepared is canagliflozin impurity I and canagliflozin impurity II, is the accessory substance under main reaction route,
In this approach still based on the synthetic reaction route of canagliflozin, adjust certain reaction condition, and by be enriched with
And the method for column chromatography is purified to relevant material, target compound canagliflozin impurity I and canagliflozin impurity II are obtained.
In the present invention：
Compound A：D-Glucose acid lactone, molecular formula is C6H10O6, molecular weight is 178.14.
Compound B：- O- acetyl-D-glucose the acid lactones of 2,3,4,6- tetra-, molecular formula is C14H18O10, molecular weight is
346.29。
Compound C：The precursor of canagliflozin impurity I, molecular formula is C52H50F2O10S2, molecular weight is 937.07.
The present invention is as follows about the synthetic line of material canagliflozin impurity I and canagliflozin impurity II：
The present invention, about the synthetic method of material canagliflozin impurity I and canagliflozin impurity II, is the raw material A system that first passes through
It is standby to obtain canagliflozin impurity I, canagliflozin impurity II is further then prepared using canagliflozin impurity I again.
The synthetic method of canagliflozin impurity I comprises the following steps：
Step one：Compound A is dissolved in solvent, adds catalyst, and stirring at normal temperature, which is reacted to reaction completion, obtains compound
B。
Step 2：Iodo thing or bromo-derivative, which are dissolved under reaction dissolvent, low temperature, adds RMgBr or lithium reagent, reacts 1-
3 hours (preferably 2 hours) add reaction solution reacts in compound B solution, and reaction is quenched in acetic acid solution after the completion of reaction, directly
Connect be evaporated obtain crude Compound C be directly used in next step reaction.
Step 3：Crude Compound C is dissolved under solvent, low temperature and adds reducing agent silane reagent, lewis acid, normal temperature is anti-
It should be completed to reaction, add sodium bicarbonate solution and reaction is quenched, extract and separate, organic phase is directly evaporated, and obtains crude product Ka Gelie
Net impurity I, column chromatography purifying, eluant, eluent is ethyl acetate, petroleum ether, and its volume ratio is 1：1, obtain sterling canagliflozin impurity
Ⅰ。
The synthetic method of canagliflozin impurity II is to prepare canagliflozin impurity II using canagliflozin impurity I：Step one
To three synthetic methods with canagliflozin impurity I, difference is：
Step 4：Canagliflozin impurity I is dissolved in reaction dissolvent, adds alkali and is deprotected, and normal-temperature reaction is to reacting completion.
Add acetic acid and reaction is quenched, be then added to the water reaction solution, separate out solid, filtering obtains canagliflozin impurity II.
In above-mentioned technical proposal, catalyst described in step one is trifluoroacetic acid, and the mol ratio of compound A and catalyst is 1:
1~5；It is preferred that 1:2~3 equivalents.
In above-mentioned technical proposal, solvent described in step one is acetic anhydride, and the mass ratio of compound A and acetic anhydride is 1:5~
1:9；It is preferred that 1:5~1:6 equivalents.
In above-mentioned technical proposal, the temperature of normal temperature described in step one is 15-35 DEG C.
In above-mentioned technical proposal, the reaction time described in step one is 2-10h, preferably 2-3h.Reaction end is usually root
Judge to reach reaction end according to TLC tracking and monitorings.
In above-mentioned technical proposal, reaction dissolvent described in step 2 is toluene, tetrahydrofuran, ether, n-hexane, Isosorbide-5-Nitrae-dioxy
Six rings；Solvent load is that the mass ratio of iodo thing and solvent is 1:1~5；It is preferred that 1:2~3.Reaction dissolvent is preferred described in step 2
Toluene；Toluene consumption is that the mass ratio of iodo thing and toluene is 1:1~5；It is preferred that 1:2~3.
In above-mentioned technical proposal, the water content of reaction dissolvent described in step 2 is less than 5/1000ths.
In above-mentioned technical proposal, RMgBr described in step 2 or lithium reagent using trimethyl silicon substrate lithium, n-BuLi,
The reagents such as isopropylmagnesium chloride lithium chloride, sec-butyl magnesium chloride lithium chloride.
In above-mentioned technical proposal, iodo thing described in step 2 is 1 with the mol ratio of lithium reagent or RMgBr:1~5；It is excellent
Select 1:1~2.
In above-mentioned technical proposal, the starting material iodo thing described in step 2 can also be replaced with bromo-derivative, then bromo-derivative with
The mol ratio of lithium reagent or RMgBr is 1:1~5；It is preferred that 1:1~2.
Iodo thing：2- (4- fluorophenyls) -5- [(the iodo- 2- aminomethyl phenyls of 5-) methyl] thiophene
Bromo-derivative：2- (4- fluorophenyls) -5- [(the bromo- 2- aminomethyl phenyls of 5-) methyl] thiophene
React and carry out under inert atmosphere conditions in above-mentioned technical proposal, described in step 2.It is preferred that, the inert atmosphere
For nitrogen or argon gas.
In above-mentioned technical proposal, iodo thing or bromo-derivative described in step 2, which are dissolved under reaction dissolvent, low temperature, adds grignard examination
The low-temp reaction condition of agent or lithium reagent is：Reaction temperature is -10~10 DEG C, preferably 0~10 DEG C.
In above-mentioned technical proposal, it is by the compound B reaction conditions for adding reaction solution described in step 2：Reaction temperature for-
20~-78 DEG C, preferably -40~-50 DEG C.
In above-mentioned technical proposal, reaction is quenched described in step 2 with acetic acid solution, the concentration of the acetic acid solution is 5%-
10%, acetic acid solution consumption is to control the pH value of reaction solution as 6~7.
In above-mentioned technical proposal, the reaction time of step 2 reaction is 3-8h, preferably 2-3h.Because this step reaction can not
With the means identification terminal such as thin layer, so being provided with time range, it is fully able within 3-8 hours ensure the reaction of various dosage
Completely.
In above-mentioned technical proposal, the solvent described in step 3 is halogenated hydrocarbon reagent, and the halogenated hydrocarbon reagent uses two
The mass ratio of chloromethanes, chloroform, toluene or acetonitrile etc., crude Compound C and solvent is 1:1~10；Solvent uses dichloro
Methane, chloroform, toluene preferably 1:6~10；Solvent uses acetonitrile preferably 1:3~5.
In above-mentioned technical proposal, reducing agent silane reagent described in step 3 uses tri isopropyl silane, triethyl silicane, three
Methyl-monosilane etc., it is preferred to use tri isopropyl silane；The mol ratio of compound C and silane reagent is 1:1~10；It is preferred that 1:2~
3。
In above-mentioned technical proposal, lewis acid described in step 3 uses BFEE, boron trifluoride tetrahydrofuran, chlorine
Change zinc, aluminium chloride, iron chloride etc., preferably BFEE；Compound C is 1 with lewis acidic mol ratio:1~10；It is preferred that
1:1~2.
In above-mentioned technical proposal, the reaction temperature of normal-temperature reaction described in step 3 is 10~20 DEG C.
In above-mentioned technical proposal, the reaction time described in step 3 is 3-12h, preferably 4-6h.Reaction end is usually root
Judge to reach reaction end according to TLC tracking and monitorings.
In above-mentioned technical proposal, the concentration of sodium bicarbonate solution described in step 3 is 10%, is quenched instead using sodium acid carbonate
Should, the consumption of sodium bicarbonate solution ensures that reacting liquid pH value is 7-8.
In above-mentioned technical proposal, reaction dissolvent described in step 4 uses alcohols solvent, and alcohols solvent is preferred to use methanol, second
Alcohol, tetrahydrofuran etc., canagliflozin impurity I are 1 with the mass ratio of reaction dissolvent:3~10；It is preferred that 1:5~7.
In above-mentioned technical proposal, the reaction temperature of normal-temperature reaction described in step 4 is 15~35 DEG C, and preferable reaction temperature is
20~25 DEG C.
In above-mentioned technical proposal, reaction described in step 4 completes to judge to reach reaction end with TLC tracking and monitorings.
In above-mentioned technical proposal, described in step 4 alkali is added to be deprotected, described alkali select sodium methoxide, caustic alcohol,
Lithium hydroxide, NaOH, potassium hydroxide etc., preferably sodium methoxide.Canagliflozin impurity I is 1 with the mol ratio of alkali:0.5~5；
Preferably 1:1~2.Canagliflozin impurity I is 1 with the mol ratio of sodium methoxide:0.5~5；Preferably 1:1~2.
In above-mentioned technical proposal, reaction is quenched using acetic acid described in step 4, acetic acid uses pure glacial acetic acid, the consumption of acetic acid
Guarantee reacting liquid pH value is 6-7.
The relative substance of canagliflozin can be prepared by the above method, Ka Gelie is defined as by nuclear-magnetism and mass spectrum
The standard items of net impurity I and canagliflozin impurity II, the quality control prepared available for canagliflozin bulk drug and research, are fixed
Property quantitative test card lattice row provide a kind of new selection only.
Embodiment
Technical scheme is clearly and completely described below in conjunction with embodiment, it is clear that described reality
It is only a part of embodiment of the invention to apply example, rather than whole embodiments.Based on the embodiment in the present invention, this area is general
The every other embodiment that logical technical staff is obtained under the premise of creative work is not made, belongs to what the present invention was protected
Scope.
Embodiment 1
Formula
Glucolactone 10g, adds 100mL and dries in three-necked bottle, and stirring is lower to add acetic anhydride 90g, be cooled to 0 DEG C~
10 DEG C, trifluoroacetic acid 29.3g (heat release when trifluoroacetic acid is added) is added, adition process control system temperature is at 15 DEG C~35 DEG C.
Addition finishes rear 25 DEG C~30 DEG C 3~4h of insulation reaction, is clarified substantially to reaction solution, TLC is monitored to reaction solution substantially without Portugal
Grape saccharic acid lactone, reaction is completed.Above-mentioned reaction solution, 70 DEG C~80 DEG C are concentrated under reduced pressure, and to no liquid outflow, obtain amber transparent
Oily thick liquid compound B about 25g (yields：About 117%)
Embodiment 2
Formula
Glucolactone 150g, adds 1000mL and dries in three-necked bottle, and stirring is lower to add acetic anhydride 900g, is cooled to 0
DEG C~10 DEG C, trifluoroacetic acid 29.3g (heat release when trifluoroacetic acid is added) is added, adition process control system temperature is 15 DEG C~25
℃.Addition finishes rear 25 DEG C~30 DEG C insulation reaction 6h, is clarified substantially to reaction solution, TLC is monitored to reaction solution substantially without Portugal
Grape saccharic acid lactone, reaction is completed.Above-mentioned reaction solution, 70 DEG C~80 DEG C are concentrated under reduced pressure, and to no liquid outflow, obtain amber transparent
Oily thick liquid compound B about 360g (yields：About 113%)
Embodiment 3
Formula
100mL is dried in three-necked bottle, adds toluene 15g, and stirring is lower to add iodo thing 15g, and 0 is cooled under nitrogen protection
DEG C~-10 DEG C, the lower tetrahydrofuran solution 50mL for adding trimethyl silicon substrate lithium of stirring, control temperature is added at 0 DEG C~-5 DEG C,
In -5 DEG C of -0 DEG C of insulation reaction 2-3h.The grignard reagent prepared.The RMgBr prepared is added toluene 30g is housed
In compound B25g 250mL three-necked bottles.Less than -20 DEG C, insulation reaction 4h are cooled under nitrogen protection.Reaction is completed
Afterwards, maintain the temperature at and 10% acetic acid solution is slowly added under less than -20 DEG C, stirring, it is 5~6 to survey system pH.Add and complete
Afterwards, 30min is stirred, 20~30 DEG C of stirring 15min are warming up to, 30~40min is stood, aqueous phase discarded (lower floor), organic phase is with pure
Change washing 2 times, 30min, aqueous phase discarded (lower floor) are stirred every time.It is organic to be added to anhydrous magnesium sulfate, filter, 50 DEG C~60 DEG C subtract
Press solvent evaporated to no liquid to flow out, obtain midbody compound C, be directly used in next step reaction.
Embodiment 4
Formula
Acetonitrile 100g and midbody compound C obtained in the previous step is added in 250mL three-necked bottles, triethyl silicane is added
28g, is stirred to dissolve, and under nitrogen protection, is cooled to 0 DEG C, adds BFEE, 10.4g, adition process temperature control to 0 DEG C,
After addition is finished, about 4h is reacted at 10 DEG C~20 DEG C, TLC is monitored to reaction and completed.After the completion of reaction, 10% sodium carbonate is added
Solution, make pH value of solution for 7~8 (, -5 DEG C of adition process temperature control~0 DEG C, stir 30min, separate aqueous phase, organic phase is eaten with saturation
Salt is washed 2 times, aqueous phase discarded.Organic to be added to anhydrous magnesium sulfate drying, filtering, solvent evaporated obtains crude product canagliflozin impurity
I, column chromatography purifying, eluant, eluent ratio is (ethyl acetate:Petroleum ether=1:1) component, is collected, concentrate drying obtains faint yellow
The 2.2g of solid pure product canagliflozin impurity I (two step yields be 10.2%)
ES-MS(m/z):943.2760[M+Na]+；
1H-NMR(DMSO-d6,Bruker AV-400MHz；)
1.46 (d, J=5.6Hz, 3H)；1.62 (d, J=4.4Hz, 3H)；1.90(S,3H)；1.94(d,3H)；2.00(S,
3H)；2.21,2.19 (dd, J=2Hz, 3.6Hz, 6H)；3.99-4.13(m,8H)；4.605,4.585 (dd, J=1.6Hz,
2Hz,1H)；4.93-4.97(m,1H)；5.01-5.04(m,1H)；5.33 (t, J=7.6Hz, 1H)；6.74-6.76(m,1H)；
6.817 (d, J=5.6Hz, 1H)；6.94-6.97(m,2H)；7.06-7.07(m,1H)；7.11-7.18(m,7H)；7.18-
7.27(m,3H)；7.55-7.58(m,2H).
Embodiment 5
Formula
500mL is dried in three-necked bottle, adds toluene 75g, and stirring is lower to add iodo thing 75g, and 0 DEG C~-10 are cooled under nitrogen protection
DEG C, stirring is lower to add isopropylmagnesium chloride lithium chloride tetrahydrofuran solution 250mL (1.3mol/L), and control temperature is 0 DEG C~-5
DEG C add, in -5 DEG C of -0 DEG C of insulation reaction 2-3h.The grignard reagent prepared.The RMgBr prepared is added and is equipped with
In toluene 150g and compound B-11 25g 2000mL three-necked bottles.Less than -20 DEG C, insulation reaction 4h are cooled under nitrogen protection.
After the completion of reaction, maintain the temperature at and 10% acetic acid solution is slowly added under less than -20 DEG C, stirring, it is 5~6 to survey system pH.Plus
After the completion of entering, 30min is stirred, 20~30 DEG C of stirring 15min is warming up to, stands 30~40min, aqueous phase discarded (lower floor) is organic
Mutually with purifying washing 2 times, 30min, aqueous phase discarded (lower floor) are stirred every time.It is organic to be added to anhydrous magnesium sulfate, filter, 50 DEG C~
60 DEG C of evaporated under reduced pressure solvents to no liquid flows out, and obtains midbody compound C, is directly used in next step reaction.
Embodiment 6
Formula
Dichloromethane 133g and midbody compound C obtained in the previous step is added in 250mL three-necked bottles, triethyl group is added
Silane 20g, is stirred to dissolve, and under nitrogen protection, is cooled to 0 DEG C, adds BFEE, 6.7g, adition process temperature control to 0
DEG C, after addition is finished, about 4h is reacted at 10 DEG C~20 DEG C, TLC is monitored to reaction and completed.After the completion of reaction, 10% carbon is added
Acid sodium solution, make pH value of solution for 7~8 (, -5 DEG C of adition process temperature control~0 DEG C, stir 30min, separate aqueous phase, organic phase is with full
Washed 2 times with salt, aqueous phase discarded.Organic to be added to anhydrous magnesium sulfate drying, filtering, solvent evaporated obtains crude product canagliflozin
Impurity I, column chromatography purifying, eluant, eluent ratio is (ethyl acetate:Petroleum ether=1:1) component, is collected, concentrate drying obtains light
The 3.2g of solid pure product canagliflozin impurity I of yellow (two step yields are 14.8%)
Embodiment 7
50mL is dried in three-necked bottle, adds methanol 10g, and stirring is lower to add the 0.8g of canagliflozin impurity I, is slowly added to methanol
Sodium 0.18g, 20 DEG C~30 DEG C of adition process temperature control, lower reaction 1~3h, the TLC monitoring reactions of 25 DEG C~30 DEG C stirrings of temperature control are complete
(until the complete dissolved clarification of mixture).After the completion of reaction, 0~5 DEG C of addition glacial acetic acid is cooled to, survey system pH is 6-7.Thereto
Purified water 30g, 20 DEG C~25 DEG C stirring 2h are slowly added to, filters, dries, obtain the 450mg of off-white color canagliflozin impurity II (receipts
70%) rate is.
ES-MS(m/z):775.2344[M+Na]+；
1H-NMR(DMSO-d6,Bruker AV-400MHz；)
1.46 (d, J=5.6Hz, 3H)；2.21(S,3H)；3.12-3.16(m,3H)；3.19-3.22(m,1H)；3.69
(d, J=8.4Hz, 1H)；3.95 (d, J=7.6Hz, 1H)；4.00-4.09(m,5H)；6.74-6.75(m,1H)；6.86(d,J
=2.8Hz, 1H)；6.95-6.96(m,2H)；7.06-7.07(m,2H)；7.10-7.20(m,6H)；7.25-7.28(m,3H)；
7.55-7.58(m,2H)
Embodiment 8
Formula
50mL is dried in three-necked bottle, adds methanol 10g, and stirring is lower to add the 1.6g of canagliflozin impurity I, is slowly added to hydrogen-oxygen
Change lithium 0.078g, 20 DEG C~30 DEG C of adition process temperature control, lower reaction 1~3h, the TLC monitoring of 25 DEG C~30 DEG C stirrings of temperature control has been reacted
Entirely (until the complete dissolved clarification of mixture).After the completion of reaction, 0~5 DEG C of addition glacial acetic acid is cooled to, survey system pH is 6-7.Xiang Qi
In be slowly added to purified water 30g, 20 DEG C~25 DEG C stirring 2h, filter, dry, obtain the 750mg of off-white color canagliflozin impurity II
(yield is 61%).
Embodiment 9
Formula
50mL is dried in three-necked bottle, adds methanol 10g, and stirring is lower to add the 1.5g of canagliflozin impurity I, is slowly added to hydrogen-oxygen
Change sodium 0.098g, 20 DEG C~30 DEG C of adition process temperature control, lower reaction 1~3h, the TLC monitoring of 25 DEG C~30 DEG C stirrings of temperature control has been reacted
Entirely (until the complete dissolved clarification of mixture).After the completion of reaction, 0~5 DEG C of addition glacial acetic acid is cooled to, survey system pH is 6-7.Xiang Qi
In be slowly added to purified water 30g, 20 DEG C~25 DEG C stirring 2h, filter, dry, obtain the 1.1g of off-white color canagliflozin impurity II
(yield is 89.7%).
It is that the canagliflozin impurity I and canagliflozin impurity II prepared using the present invention carries out qualitative and quantitative detection below
Method.Using 2 kinds of impurity that inventor has found and prepares can make intermediate K3 in canagliflozin preparation process and
The quality testing of canagliflozin finished product is more accurate, controllable.If the situation without this 2 kinds of impurity：1) as miscellaneous without canagliflozin
Intermediate K3 quality control can not then provide the specific impurities of the intermediate well in matter I, canagliflozin preparation process
Content, this can reduce the controllability of the quality of the follow-up preparation process of canagliflozin；2) as without canagliflozin impurity II, then blocked
The net relevant material control of lattice row can only provide the limit of a total impurities, and this is for bulk drug about seeming in the control of material
It is not accurate and careful enough.In recent years, raw materials of compound medicine is the weight of domestic drug research and development work about thing Quality Research and control
Point.In China, the change of Control of Impurities theory：" Pureness control " → " Control of Impurities " → " control of impurity spectrum ", wherein " impurity is composed
Control " i.e. " the impurity analysis of spectrum " to be done --- set up the analysis method that specific aim controls specific impurities.Therefore, it is related specific miscellaneous
Drug research and development requirement is complied with the quantitative analysis control of matter.
The method that the impurity provided below using the present invention is detected to intermediate K3 and canagliflozin finished product.
First, canagliflozin intermediate K3 detection method
K3 is the intermediate in canagliflozin preparation process, and its chemical formula is：Acetic acid -3 (R), 4 (R), 5 (S)-triacetyls
Epoxide -6 (S)-[3- [5- (4- fluorophenyls)-thiophene -2- benzyls] -4- methylphenyls]-oxinane -2 (R)-base methyl esters.
Structural formula is as follows：
【Character】K3 is off-white color to pale yellow powder or particle.
【Check】Moisture：This product is taken, is surveyed according to aquametry (the method A of four general rules of Chinese Pharmacopoeia version in 2015 0832 first)
It is fixed, it is aqueous should to cross as 0.5%.
【Purity】Chromatographic condition is filler (Agilent with octadecylsilane chemically bonded silica with system suitability
TC-C18,4.6 × 250mm, 5 μm), using acetonitrile as mobile phase A；Water (phosphoric acid adjusts pH value to 2.0) is Mobile phase B, carries out gradient
Elution, elution program see the table below.
Gradient elution program table
Flow velocity is 1.0ml per minute, and Detection wavelength is 290nm, 35 DEG C of column temperature.
Determination method takes canagliflozin intermediate K3 samples about 10mg, accurately weighed, puts in 50ml measuring bottles, plus appropriate acetonitrile,
Shaking makes dissolving in 10 minutes, is diluted to scale, shakes up, is used as test sample liquid.It is another to take canagliflozin impurity I in right amount, plus acetonitrile is molten
Solve and quantify dilution and each solution containing about 10ug in every 1ml is made, be used as impurity reference substance solution；According to high performance liquid chromatography
(two D of annex V of Chinese Pharmacopoeia version in 2010) are determined.It is each that precision measures blank solvent, need testing solution, canagliflozin impurity I
20 μ l, inject liquid chromatograph, record chromatogram.Blank solvent interference is deducted, is calculated by area normalization method, purity must not be low
In 99.0%, canagliflozin impurity I must not cross 0.3%.
" canagliflozin impurity I " is then K3 exclusive impurity to the present invention, utilizes the detecting to K3 of canagliflozin impurity I
Control can effectively improve the quality of production.
2nd, the detection method of canagliflozin finished product【Relevant material】
【Check】Relevant material takes canagliflozin sample appropriate, accurately weighed, plus 45% acetonitrile dissolves and diluted and is made often
Solution of the 1ml containing about 0.5mg, is used as test sample liquid.Precision is measured in right amount, is added to state solvent and quantitatively dilute and is made in every lml about
Solution containing 0.5ug, is used as contrast solution.It is another to take the reference substance of canagliflozin impurity II in right amount, plus acetonitrile dissolves and quantifies dilution
The solution containing about 50ug in every 1ml is made, impurity reference substance storing solution is used as；It is another to take canagliflozin reference substance about 50mg, and essence
It is close to measure above-mentioned impurity reference substance storing solution 1ml, put in same 100ml measuring bottles, plus 45% acetonitrile dissolves and is diluted to scale, shakes
It is even, it is used as system suitability solution.According to high performance liquid chromatography experiment, with octadecylsilane chemically bonded silica (Agilent TC-
C18,4.6 × 250mm, 5 μm) it is filler；Using acetonitrile as mobile phase A；Water (adjusting pH value to 2.0 with phosphoric acid) is Mobile phase B, is pressed
Following table carries out gradient elution；
Detection wavelength is 290mn；Column temperature is 35 DEG C, and flow velocity is 1.0ml/min.
Precision measures system suitability solution 20u1, injects liquid chromatograph, records chromatogram, and peak sequence is followed successively by card
Lattice row are net, canagliflozin impurity II,.Precision measures each 20u1 of contrast solution, need testing solution, blank solvent, and people's liquid is noted respectively
Chromatography, record chromatogram was to 60 minutes.Except with addition to the chromatographic peak of blank solvent same position, in need testing solution chromatogram
If any impurity peaks listed in Table, single impurity peak area cannot be greater than contrast solution main peak area by the calculated by peak area after correction
1 times (0.1%), other single impurity peak areas cannot be greater than 1 times of contrast solution main peak area (0.1%), other each impurity
5 times (0.5%) peak area and that cannot be greater than contrast solution main peak area.It is less than contrast solution in need testing solution chromatogram
Ignore at the peak that 0.2 times of main peak area.
| Compound | Classification | Correction factor |
| Canagliflozin impurity II | Process contaminants | 1.4 |
Canagliflozin is detected by above-mentioned detection method, can quickly and accurately having in qualitative and quantitative detection raw material
Impurity is closed, is conducive to quickly determining final product quality in process of production, it is ensured that the quality of bulk drug.
Claims (6)
1. the synthetic method of canagliflozin impurity I, it is characterised in that：Comprise the following steps：
Step one：Compound A is dissolved in solvent, adds catalyst, and stirring at normal temperature, which is reacted to reaction completion, obtains compound B；
Step 2：Iodo thing or bromo-derivative, which are dissolved under reaction dissolvent, low temperature, adds RMgBr or lithium reagent, and reaction 1-3 is small
When, reaction solution is added to reaction in compound B solution, reaction is quenched in acetic acid solution after the completion of reaction, be directly evaporated and obtain thick
Product compound C is directly used in next step reaction；
Step 3：Crude Compound C is dissolved under solvent, low temperature and adds reducing agent silane reagent, lewis acid, normal-temperature reaction is extremely
Reaction is completed, and adds sodium bicarbonate solution and reaction is quenched, extract and separate, organic phase is directly evaporated, and obtains crude product canagliflozin miscellaneous
Matter I, column chromatography purifying, eluant, eluent is ethyl acetate, petroleum ether, and its volume ratio is 1：1, obtain sterling canagliflozin impurity I.
2. the synthetic method of canagliflozin impurity I according to claim 1, it is characterised in that：At least meet following any
One：
Catalyst described in step one is trifluoroacetic acid, and the mol ratio of compound A and catalyst is 1:1~5；It is preferred that 1:2~3 work as
Amount；
Solvent described in step one is acetic anhydride, and the mass ratio of compound A and acetic anhydride is 1:5~1:9；It is preferred that 1:5~1:6；
The temperature of normal temperature described in step one is 15-35 DEG C；
Reaction time described in step one is 2-10h, preferably 2-3h.
3. the synthetic method of canagliflozin impurity I according to claim 1, it is characterised in that：At least meet following any
One：
It is 2 hours that step 2, which adds RMgBr or the reaction time of lithium reagent reaction,；
Reaction dissolvent described in step 2 is toluene, tetrahydrofuran, ether, n-hexane, Isosorbide-5-Nitrae-dioxane；
The solvent load of reaction dissolvent described in step 2 is that the mass ratio of iodo thing and solvent is 1:1~5；It is preferred that 1:2~3；
The preferred toluene of reaction dissolvent described in step 2；Toluene consumption is that the mass ratio of iodo thing and toluene is 1:1~5；It is preferred that 1:2
~3；
The water content of reaction dissolvent described in step 2 is less than 5/1000ths；
RMgBr described in step 2 or lithium reagent using trimethyl silicon substrate lithium, n-BuLi, isopropylmagnesium chloride lithium chloride,
The reagents such as sec-butyl magnesium chloride lithium chloride；
Iodo thing described in step 2 is 1 with the mol ratio of lithium reagent or RMgBr:1~5；It is preferred that 1:1~2；The iodo thing
For 2- (4- fluorophenyls) -5- [(the iodo- 2- aminomethyl phenyls of 5-) methyl] thiophene；
Starting material bromo-derivative and the mol ratio of lithium reagent or RMgBr described in step 2 are 1:1~5；It is preferred that 1:1~2；
The bromo-derivative：2- (4- fluorophenyls) -5- [(the bromo- 2- aminomethyl phenyls of 5-) methyl] thiophene；
React and carry out under inert atmosphere conditions described in step 2；
It is further preferred that the inert atmosphere is nitrogen or argon gas；
The low temperature that iodo thing or bromo-derivative described in step 2 are dissolved in addition RMgBr or lithium reagent under reaction dissolvent, low temperature is anti-
The condition is answered to be：Reaction temperature is -10~10 DEG C, preferably 0~10 DEG C；
It is by the compound B reaction conditions for adding reaction solution described in step 2：Reaction temperature be -20~-78 DEG C, preferably -40~-
50℃；
Reaction is quenched described in step 2 with acetic acid solution, the concentration of the acetic acid solution is 5%-10%；Acetic acid solution consumption with
The pH value for controlling reaction solution is 6~7；
The reaction time of step 2 reaction is 3-8h, preferably 2-3h.
4. the synthetic method of canagliflozin impurity I according to claim 1, it is characterised in that：At least meet following any
One：
Solvent described in step 3 is halogenated hydrocarbon reagent；
It is preferred that, the halogenated hydrocarbon reagent described in step 3 uses dichloromethane, chloroform, toluene or acetonitrile；
It is preferred that, the mass ratio of crude Compound C and solvent is 1:1~10；
It is further preferred that solvent uses dichloromethane, chloroform, toluene preferably 1:6~10；
It is further preferred that solvent uses acetonitrile preferably 1:3~5；
Reducing agent silane reagent described in step 3 uses tri isopropyl silane, triethyl silicane, trimethyl silane；
It is preferred that, reducing agent uses tri isopropyl silane described in step 3；
Compound C is 1 with the mol ratio of reducing agent silane reagent:1~10；It is preferred that 1:2~3；
Lewis acid described in step 3 uses BFEE, boron trifluoride tetrahydrofuran, zinc chloride, aluminium chloride, iron chloride；
Compound C is 1 with lewis acidic mol ratio:1~10；It is preferred that 1:1~2；
Lewis acid is preferred to use BFEE described in step 3；
The mol ratio of compound C and BFEE is 1:1~10；It is preferred that 1:1~2；
The reaction temperature of normal-temperature reaction described in step 3 is 10~20 DEG C；
Reaction time described in step 3 is 3-12h, preferably 4-6h；
The concentration of sodium bicarbonate solution described in step 3 is 10%；
Reaction is quenched using sodium acid carbonate in step 3, and the consumption of sodium bicarbonate solution ensures that reacting liquid pH value is 7-8.
5. the synthetic method of canagliflozin impurity II, it is characterised in that：Comprise the following steps：
Step one is to three synthetic methods with canagliflozin impurity I；
Step 4：Canagliflozin impurity I is dissolved in reaction dissolvent, adds alkali and is deprotected, and normal-temperature reaction is to reacting completion；Add
Reaction is quenched in acetic acid, is then added to the water reaction solution, separates out solid, and filtering obtains canagliflozin impurity II.
6. the synthetic method of canagliflozin impurity II according to claim 5, it is characterised in that：At least meet following any
One：
Reaction dissolvent uses alcohols solvent described in step 4；
Alcohols solvent described in step 4 is preferred to use methanol, ethanol, tetrahydrofuran；
Canagliflozin impurity I is 1 with the mass ratio of reaction dissolvent:3~10；It is preferred that 1:5~7；
The reaction temperature of normal-temperature reaction described in step 4 is 15~35 DEG C, and preferable reaction temperature is 20~25 DEG C；
Add alkali described in step 4 to be deprotected, described alkali selects sodium methoxide, caustic alcohol, lithium hydroxide, NaOH, hydrogen
Potassium oxide；
Canagliflozin impurity I is 1 with the mol ratio of alkali:0.5~5；Preferably 1:1~2；
The preferred sodium methoxide of alkali described in step 4；
Canagliflozin impurity I is 1 with the mol ratio of sodium methoxide:0.5~5；Preferably 1:1~2；
Reaction is quenched using acetic acid described in step 4；
The acetic acid uses pure glacial acetic acid；
The consumption of acetic acid ensures that reacting liquid pH value is 6-7.
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