CN106938998B - Synthetic method of the canagliflozin in relation to substance - Google Patents
Synthetic method of the canagliflozin in relation to substance Download PDFInfo
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- 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 in relation to substance, belong to Drug-related Substances synthesis field.It is an object of the present invention to provide a kind of synthetic method of canagliflozin in relation to substance, the related substance is canagliflozin impurity I and canagliflozin impurity II, synthetic method of the invention in relation to substance canagliflozin impurity I and canagliflozin impurity II, it is to first pass through raw material A canagliflozin impurity I is prepared, canagliflozin impurity II is further then prepared using canagliflozin impurity I again.Canagliflozin impurity I and canagliflozin impurity II are determined as by nuclear-magnetism and mass spectrum, the quality control prepared available for canagliflozin bulk pharmaceutical chemicals 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 in relation to substance, 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.It expects 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, special
Point is chronic hyperglycemia, with hypoinsulinism and/or insulin action obstacle, leads to carbohydrate, fat and egg
The metabolic disorder of white matter ultimately causes the chronic injury and dysfunction of a variety of organs.The international parting master to diabetes at present
If the teiology based on diabetes, WHO consultation reports (WHO/NCD/NCS/99.2) and International Diabetes Federation
Diabetes were divided into four types by (International Diabetes Federation, IDF) committee of Xi Tai areas in 1999,
That is the 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 drug of first acquisition U.S. FDA approval that department and Johson ＆ Johnson develop jointly, is total to 2 type sodium glucose
Transport protein (SGLT2) is the oral hypoglycemic of target.The target site and mechanism of SGLT-2 and existing oral hypoglycemic agents
Different with antidiabetic, creativeness opens hypoglycemic new route.Its mechanism of action does not depend on beta Cell of islet, therefore drug effect
It is not influenced by islet beta cell function.And because its mechanism of action is independent of insulin, in any stage of diabetes B
It may be applied.Therefore, SGLT-2 inhibitor has good prospect for the treatment of diabetes B.Faced by existing
Bed experiment confirms validity and the safety of the medicine.It is applied alone or is used in combination with melbine, sulfonylurea drugs, Ke Yixian
Write reduce diabetes B patient HbA1c and fasting blood-glucose, adverse reaction rate is similar to placebo, risk of hypoglycemia compared with
It is low, it can significantly mitigate the scale of construction.In order to improve the quality of bulk pharmaceutical chemicals, the related substance studied in building-up process is of great significance.
The Yuan Yan companies of canagliflozin are military field, and patent CN102264714 is to the synthetic route of canagliflozin at home
It has been reported, its method is as follows for the main method of domestic canagliflozin synthesis at present at present：
Its in the synthesis process, since compound B quality controllabilities are not high and step 1 grignard reaction, reaction condition compare
Harshness needs to carry out in the environment of low-temperature anhydrous anaerobic, so in reaction process, is readily incorporated special related substance.
In the prior art, since impurity is unknown, the quality of synthesis finished product can not be effectively controlled, the present inventor passes through
The methods of enrichment impurity, destructive testing, column chromatography purifying, is prepared, and pass through structural identification means, its structure is carried out
Verification and parsing, so that it is determined that two major impurities of canagliflozin are respectively canagliflozin impurity I, canagliflozin impurity
Ⅱ.I molecular formula of canagliflozin impurity is C52H50F2O9S2, molecular weight 921.07.II molecular formula of canagliflozin impurity 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 pharmaceutical chemicals are arranged, new direction is provided to improve bulk pharmaceutical chemicals.
Invention content
Technical problem solved by the invention is to provide a kind of synthetic method of canagliflozin in relation to substance, present invention synthesis
The related substance that method is prepared is canagliflozin impurity I and canagliflozin impurity II, is the by-product under main reaction route,
In this approach still based on the synthetic reaction route of canagliflozin, adjust certain reaction condition, and pass through enrichment with
And the method for column chromatography purifies related substance, obtains target compound canagliflozin impurity I and canagliflozin impurity II.
In the present invention：
Compound A：D-Glucose acid lactone, molecular formula C6H10O6, molecular weight 178.14.
Compound B：2,3,4,6- tetra--O- acetyl-D-glucose acid lactones, molecular formula C14H18O10, molecular weight is
346.29。
Compound C：I precursor of canagliflozin impurity, molecular formula C52H50F2O10S2, molecular weight 937.07.
Synthetic line of the invention in relation to substance canagliflozin impurity I and canagliflozin impurity II is as follows：
Synthetic method of the invention in relation to substance 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 includes the following steps：
Step 1：Compound A is dissolved in solvent, adds in catalyst, and stirring at normal temperature, which is reacted to reaction, to be completed to obtain compound
B。
Step 2：Iodo object or bromo-derivative are dissolved in reaction dissolvent, add in Grignard Reagent or lithium reagent under low temperature, react 1-
3 hours (preferably 2 hours), which add in reaction solution in the solution of compound B, reacts, and reaction is quenched in acetic acid solution after the completion of reaction, directly
It connects and is evaporated to obtain crude Compound C and be directly used in react in next step.
Step 3：Crude Compound C is dissolved in solvent, adds in reducing agent silane reagent, lewis acid under low temperature, room temperature is anti-
It should be completed to reaction, add in sodium bicarbonate solution and reaction is quenched, extraction and separation, organic phase is directly evaporated, and obtains crude product Ka Gelie
Net impurity I, column chromatography purifying, eluant, eluent is ethyl acetate, petroleum ether, volume ratio 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 1
To three with canagliflozin impurity I synthetic method, difference lies in：
Step 4：Canagliflozin impurity I is dissolved in reaction dissolvent, adds in alkali and is deprotected, and normal-temperature reaction is completed to reacting.
It adds in acetic acid and reaction is quenched, be then added to the water reaction solution, solid is precipitated, filtering obtains canagliflozin impurity II.
In above-mentioned technical proposal, catalyst described in step 1 is trifluoroacetic acid, and the molar 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 1 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 room temperature described in step 1 is 15-35 DEG C.
In above-mentioned technical proposal, the reaction time described in step 1 is 2-10h, preferably 2-3h.Reaction end is usually root
Reach reaction end according to the judgement of 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 dosage is that the mass ratio of iodo object and solvent is 1:1~5；It is preferred that 1:2~3.Reaction dissolvent is preferred described in step 2
Toluene；Toluene dosage is that the mass ratio of iodo object 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, Grignard Reagent 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 object described in step 2 is 1 with the molar ratio of lithium reagent or Grignard Reagent:1~5；It is excellent
Select 1:1~2.
In above-mentioned technical proposal, the starting material iodo object described in step 2 can also be replaced with bromo-derivative, then bromo-derivative with
The molar ratio of lithium reagent or Grignard Reagent is 1:1~5；It is preferred that 1:1~2.
Iodo object：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
It reacts in above-mentioned technical proposal, described in step 2 and carries out under inert atmosphere conditions.Preferably, the inert atmosphere
For nitrogen or argon gas.
In above-mentioned technical proposal, iodo object or bromo-derivative described in step 2 are dissolved in reaction dissolvent, and grignard examination is added under low temperature
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, the reaction condition that compound B is added in reaction solution described in step 2 is：Reaction temperature for-
20~-78 DEG C, preferably -40~-50 DEG C.
In above-mentioned technical proposal, reaction, a concentration of 5%- of the acetic acid solution is quenched with acetic acid solution described in step 2
10%, acetic acid solution dosage 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.Since 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 is using tri isopropyl silane, triethylsilane, three
Methyl-monosilane etc., it is preferred to use tri isopropyl silane；The molar 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 is using boron trifluoride ether, boron trifluoride tetrahydrofuran, chlorine
Change zinc, aluminium chloride, iron chloride etc., preferably boron trifluoride ether；Compound C is 1 with lewis acidic molar 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
Reach reaction end according to the judgement of TLC tracking and monitorings.
In above-mentioned technical proposal, a concentration of 10% of sodium bicarbonate solution described in step 3, it is quenched instead using sodium bicarbonate
Should, the dosage 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 preferably using methanol, second
The mass ratio of alcohol, tetrahydrofuran etc., canagliflozin impurity I and reaction dissolvent is 1:3~10；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 is completed to reach reaction end with the judgement of TLC tracking and monitorings.
In above-mentioned technical proposal, described in step 4 add in alkali be deprotected, the alkali select sodium methoxide, sodium ethoxide,
Lithium hydroxide, sodium hydroxide, potassium hydroxide etc., preferably sodium methoxide.The molar ratio of canagliflozin impurity I and alkali is 1:0.5~5；
Preferably 1:1~2.The molar ratio of canagliflozin impurity I and sodium methoxide is 1:0.5~5；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 dosage 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 determined 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 pharmaceutical chemicals and research, are fixed
Property quantitative test card lattice row provide a kind of new selection only.
Specific embodiment
Technical scheme of the present invention is clearly and completely described below in conjunction with embodiment, it is clear that described reality
It is only part of the embodiment of the present invention to apply example, instead of all the embodiments.Based on the embodiments of the present invention, this field is general
Logical technical staff all other embodiments obtained without creative efforts belong to what the present invention protected
Range.
Embodiment 1
Formula
Glucolactone 10g, add in 100mL drying three-necked bottle in, be added with stirring acetic anhydride 90g, be cooled to 0 DEG C~
10 DEG C, trifluoroacetic acid 29.3g (heat release when trifluoroacetic acid adds in) is added in, adition process control system temperature is at 15 DEG C~35 DEG C.
25 DEG C~30 DEG C 3~4h of insulation reaction after addition, until reaction solution is clarified substantially, TLC is monitored to reaction solution substantially without Portugal
Grape saccharic acid lactone, reaction are completed.Above-mentioned reaction solution, 70 DEG C~80 DEG C reduced pressures, until no liquid flows out, obtains amber transparent
Oily thick liquid compound B about 25g (yields：About 117%).
Embodiment 2
Formula
Glucolactone 150g is added in 1000mL drying three-necked bottles, is added with stirring acetic anhydride 900g, is cooled to 0
DEG C~10 DEG C, trifluoroacetic acid 29.3g (heat release when trifluoroacetic acid adds in) is added in, adition process control system temperature is 15 DEG C~25
℃.25 DEG C~30 DEG C insulation reaction 6h after addition, until reaction solution is clarified substantially, TLC is monitored to reaction solution substantially without Portugal
Grape saccharic acid lactone, reaction are completed.Above-mentioned reaction solution, 70 DEG C~80 DEG C reduced pressures, until no liquid flows out, obtains amber transparent
Oily thick liquid compound B about 360g (yields：About 113%).
Embodiment 3
Formula
In 100mL drying three-necked bottles, toluene 15g is added in, iodo object 15g is added with stirring, is cooled to 0 under nitrogen protection
DEG C~-10 DEG C, the tetrahydrofuran solution 50mL of trimethyl silicon substrate lithium is added with stirring, temperature is controlled to be 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 Grignard Reagent prepared is added in equipped with toluene 30g
In the 250mL three-necked bottles of compound B25g.It is cooled to -20 DEG C under nitrogen protection hereinafter, insulation reaction 4h.Reaction is completed
Afterwards, -20 DEG C are maintained the temperature at hereinafter, being slowly added to 10% acetic acid solution under stirring, it is 5~6 to survey system pH.It adds in and completes
Afterwards, 30min is stirred, 20~30 DEG C of stirring 15min is warming up to, stands 30~40min, discard water phase (lower floor), organic phase is with pure
Change washing 2 times, stir 30min every time, discard water phase (lower floor).Organic to be added to anhydrous magnesium sulfate, filtering, 50 DEG C~60 DEG C subtract
Solvent evaporated to no liquid is pressed to flow out, obtains midbody compound C, is directly used in and reacts in next step.
Embodiment 4
Formula
Acetonitrile 100g and midbody compound C obtained in the previous step is added in 250mL three-necked bottles, adds in triethylsilane
28g is stirred to dissolve, and under nitrogen protection, is cooled to 0 DEG C, adds in boron trifluoride ether, 10.4g, adition process temperature control to 0 DEG C,
After addition, 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 in
Solution, make pH value of solution for 7~8 (, -5 DEG C of adition process temperature control~0 DEG C, stir 30min, detach water phase, organic phase is eaten with saturation
Salt is washed 2 times, discards water phase.It is organic to be added to anhydrous magnesium sulfate drying, it filters, solvent evaporated obtains crude product canagliflozin impurity
I, column chromatography purifying, eluant, eluent ratio is (ethyl acetate:Petroleum ether=1:1) component, is collected, is concentrated and dried, obtains faint yellow
I 2.2g of solid pure product canagliflozin impurity (two step yields be 10.2%)
ES-MS(m/z):943.2760[M+Na]+；
1H-NMR(DMSO-d6,BrukerAV-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
In 500mL drying three-necked bottles, toluene 75g is added in, iodo object 75g is added with stirring, is cooled to 0 under nitrogen protection
DEG C~-10 DEG C, isopropylmagnesium chloride lithium chloride tetrahydrofuran solution 250mL (1.3mol/L) is added with stirring, 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 Grignard Reagent prepared is added
Enter in the 2000mL three-necked bottles equipped with toluene 150g and compound B-11 25g.It is cooled to -20 DEG C under nitrogen protection hereinafter, heat preservation
React 4h.After the completion of reaction, -20 DEG C are maintained the temperature at hereinafter, being slowly added to 10% acetic acid solution under stirring, surveying system pH is
5~6.After the completion of addition, stir 30min, be warming up to 20~30 DEG C stirring 15min, stand 30~40min, discard water phase (under
Layer), organic phase purifying washing 2 times stirs 30min, discards water phase (lower floor) every time.It is organic to be added to anhydrous magnesium sulfate, mistake
Filter, 50 DEG C~60 DEG C evaporated under reduced pressure solvents to no liquid flow out, and obtain midbody compound C, are directly used in and react in next step.
Embodiment 6
Formula
Dichloromethane 133g and midbody compound C obtained in the previous step is added in 250mL three-necked bottles, adds in triethyl group
Silane 20g, is stirred to dissolve, and under nitrogen protection, is cooled to 0 DEG C, adds in boron trifluoride ether, 6.7g, adition process temperature control to 0
DEG C, after addition, 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 in
Acid sodium solution, make pH value of solution for 7~8 (, -5 DEG C of adition process temperature control~0 DEG C, stir 30min, detach water phase, organic phase is with full
It is washed 2 times with salt, discards water phase.It is organic to be added to anhydrous magnesium sulfate drying, it filters, solvent evaporated obtains crude product canagliflozin
Impurity I, column chromatography purifying, eluant, eluent ratio are (ethyl acetate:Petroleum ether=1:1) component, is collected, is concentrated and dried, obtains light
I 3.2g of solid pure product canagliflozin impurity of yellow (two step yields are 14.8%).
Embodiment 7
Formula
In 50mL drying three-necked bottles, methanol 10g is added in, I 0.8g of canagliflozin impurity is added with stirring, is slowly added to methanol
Sodium 0.18g, 20 DEG C~30 DEG C of adition process temperature control, the reaction was complete for lower reaction 1~3h, the TLC monitoring of 25 DEG C~30 DEG C stirrings of temperature control
(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 is slowly added to, 20 DEG C~25 DEG C stirring 2h are filtered, dry, are obtained II 450mg of off-white color canagliflozin impurity and (are received
70%) rate is.
ES-MS(m/z):775.2344[M+Na]+；
1H-NMR(DMSO-d6,BrukerAV-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
In 50mL drying three-necked bottles, methanol 10g is added in, I 1.6g of canagliflozin impurity is added with stirring, 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
(until the complete dissolved clarification of mixture) entirely.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 are filtered, dry, obtain II 750mg of off-white color canagliflozin impurity
(yield 61%).
Embodiment 9
Formula
In 50mL drying three-necked bottles, methanol 10g is added in, I 1.5g of canagliflozin impurity is added with stirring, 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
(until the complete dissolved clarification of mixture) entirely.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 are filtered, dry, obtain II 1.1g of off-white color canagliflozin impurity
(yield 89.7%).
It is the canagliflozin impurity I and the progress qualitative and quantitative detection of canagliflozin impurity II prepared using the present invention 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 without the situation of this 2 kinds of impurity：1) as miscellaneous without canagliflozin
Matter I, in canagliflozin preparation process the quality control of intermediate K3 cannot then provide the specific impurities of the intermediate well
Content, this can reduce the controllability of the quality of the subsequent preparation process of canagliflozin；2) as without canagliflozin impurity II, then blocked
The net related substance control of lattice row can only provide the limit of a total impurities, this in control of the bulk pharmaceutical chemicals in relation to substance for seeming
It is inaccurate and careful.In recent years, raw materials of compound medicine is the weight of domestic drug research and development work in relation to object Quality Research and control
Point.In China, the variation of Control of Impurities theory：" Pureness control " → " Control of Impurities " → " control of impurity spectrum ", wherein " impurity is composed
I.e. " the impurity spectrum analysis " to be done of control " --- establish the analysis method of specific aim control specific impurities.Therefore, it is related specific miscellaneous
Drug research and development requirement is complied in the quantitative analysis control of matter.
The method being detected below using impurity provided by the invention to intermediate K3 and canagliflozin finished product.
First, the detection method of canagliflozin intermediate K3
K3 is the intermediate in canagliflozin preparation process, and chemical formula is：Acetic acid -3 (R), 4 (R), 5 (S)-triacetyls
Oxygroup -6 (S)-[3- [5- (4- fluorophenyls)-thiophene -2- benzyls] -4- methylphenyls]-oxinane -2 (R)-base methyl esters.
Structural formula is as follows：
K3：C32H33FO9S molecular weight 612.66：
【Character】K3 is off-white color to pale yellow powder or particle.
【It checks】Moisture：This product is taken, is surveyed according to aquametry (four general rules of Chinese Pharmacopoeia version in 2015,0,832 first method A)
Fixed, aqueous should must not cross is 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 tune 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 be 1.0ml per minute, Detection wavelength 290nm, 35 DEG C of column temperature.
Measuring method takes canagliflozin intermediate K3 samples about 10mg, accurately weighed, puts in 50ml measuring bottles, adds acetonitrile appropriate,
Shaking makes dissolving in 10 minutes, is diluted to scale, shakes up, as test sample liquid.It is another to take canagliflozin impurity I appropriate, add acetonitrile molten
It solves and quantifies dilution and the respectively solution containing about 10ug is made in every 1ml, as impurity reference substance solution；According to high performance liquid chromatography
(two V D of annex of Chinese Pharmacopoeia version in 2010) are measured.It is each that precision measures blank solvent, test 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 " of the invention is then the exclusive impurity of K3, and K3 is detected using canagliflozin impurity I
Control can effectively improve the quality of production.
2nd, the detection method of canagliflozin finished product【Related substance】
【It checks】Related substance takes canagliflozin sample appropriate, accurately weighed, 45% acetonitrile is added to dissolve and dilute be made it is every
Solution of the 1ml containing about 0.5mg, as test sample liquid.Precision measures in right amount, is made in every lml about in addition stating solvent and quantitatively diluting
Solution containing 0.5ug, as contrast solution.It separately takes II reference substance of canagliflozin impurity appropriate, acetonitrile is added to dissolve and quantifies dilution
The solution containing about 50ug in every 1ml is made, as impurity reference substance storing solution；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, it puts in same 100ml measuring bottles, 45% acetonitrile is added to dissolve and is diluted to scale, is shaken
It is even, as system suitability solution.It is tested according to high performance liquid chromatography, with octadecylsilane chemically bonded silica (Agilent TC-
C18,4.6 × 250mm, 5 μm) it is filler；Using acetonitrile as mobile phase A；Water (with phosphoric acid tune pH value to 2.0) is Mobile phase B, is pressed
Following table carries out gradient elution；
Detection wavelength is 290mn；Column temperature is 35 DEG C, flow velocity 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 contrast solution, test solution, each 20u1 of blank solvent, notes people's liquid respectively
Chromatography, record chromatogram was to 60 minutes.Except in addition to the chromatographic peak of blank solvent same position, in test solution chromatogram
If any impurity peaks listed in Table, single impurity peak area is not greater than contrast solution main peak area by the calculated by peak area after correction
1 times (0.1%), other single impurity peak areas are not greater than contrast solution main peak area 1 times (0.1%), other each impurity
5 times (0.5%) peak area and that be not greater than contrast solution main peak area.It is less than contrast solution in test solution chromatogram
It ignores 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, it can quickly and accurately having in qualitative and quantitative detection raw material
Impurity is closed, is conducive to quickly determine final product quality in process of production, it is ensured that the quality of bulk pharmaceutical chemicals.
Claims (33)
1. the synthetic method of canagliflozin impurity I, it is characterised in that：Include the following steps：
Step 1：Compound A is dissolved in solvent, adds in catalyst, and stirring at normal temperature, which is reacted to reaction, to be completed to obtain compound B；
Step 2：Iodo object or bromo-derivative are dissolved in reaction dissolvent, and Grignard Reagent or lithium reagent are added under low temperature, and reaction 1-3 is small
When, reaction solution is added in the solution of compound B and is reacted, reaction is quenched in acetic acid solution after the completion of reaction, is directly evaporated to obtain thick
Product compound C is directly used in react in next step；
Step 3：Crude Compound C is dissolved in solvent, adds in reducing agent silane reagent, lewis acid under low temperature, normal-temperature reaction is extremely
Reaction is completed, and adds in sodium bicarbonate solution and reaction is quenched, extraction and separation, organic phase is directly evaporated, and it is miscellaneous to obtain crude product canagliflozin
Matter I, column chromatography purifying, eluant, eluent is ethyl acetate, petroleum ether, volume ratio 1：1, obtain sterling canagliflozin impurity I；
Wherein, the structural formula of the compound A is：
The structural formula of the compound B is：
The structural formula of the compound C is：
The structural formula of the canagliflozin impurity I is：
Catalyst described in step 1 is trifluoroacetic acid；
Solvent described in step 1 is acetic anhydride；
The temperature of room temperature described in step 1 is 15-35 DEG C；
The condition that Grignard Reagent or lithium reagent are added under low temperature described in step 2 is -10~10 DEG C；
Reducing agent silane reagent is added under low temperature described in step 3, lewis acidic condition is 0 DEG C；
The reaction temperature of normal-temperature reaction described in step 3 is 10~20 DEG C.
2. the synthetic method of canagliflozin impurity I according to claim 1, it is characterised in that：At least meet following arbitrary
One：
The molar ratio of step 1 compound A and catalyst is 1:1~5；
The mass ratio of step 1 compound A and acetic anhydride is 1:5~1:9；
Reaction time described in step 1 is 2-10h.
3. the synthetic method of canagliflozin impurity I according to claim 2, it is characterised in that：A is with urging for step 1 compound
The molar ratio of agent is 1:2~3.
4. the synthetic method of canagliflozin impurity I according to claim 2, it is characterised in that：Step 1 compound A and second
The mass ratio of acid anhydrides is 1:5~1:6.
5. the synthetic method of canagliflozin impurity I according to claim 2, it is characterised in that：Reaction described in step 1
Time is 2-3h.
6. the synthetic method of canagliflozin impurity I according to claim 1, it is characterised in that：At least meet following arbitrary
One：
It is 2 hours that step 2, which adds in Grignard Reagent 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 dosage of reaction dissolvent described in step 2 is that the mass ratio of iodo object and solvent is 1:1~5；
The water content of reaction dissolvent described in step 2 is less than 5/1000ths；
Grignard Reagent described in step 2 or lithium reagent using trimethyl silicon substrate lithium, n-BuLi, isopropylmagnesium chloride lithium chloride,
Sec-butyl magnesium chloride lithium chloride；
Iodo object described in step 2 is 1 with the molar ratio of lithium reagent or Grignard Reagent:1~5；The iodo object is 2- (4- fluorobenzene
Base) -5- [(the iodo- 2- aminomethyl phenyls of 5-) methyl] thiophene；
Starting material bromo-derivative and the molar ratio of lithium reagent or Grignard Reagent described in step 2 are 1:1~5；The bromo-derivative：
2- (4- fluorophenyls) -5- [(the bromo- 2- aminomethyl phenyls of 5-) methyl] thiophene；
It reacts described in step 2 and carries out under inert atmosphere conditions；
Iodo object or bromo-derivative described in step 2 are dissolved in reaction dissolvent, and Grignard Reagent is added under low temperature or the low temperature of lithium reagent is anti-
The condition is answered to be：Reaction temperature is 0~10 DEG C；
It is by the reaction condition of compound B addition reaction solutions described in step 2：Reaction temperature is -20~-78 DEG C；
Reaction, a concentration of 5%-10% of the acetic acid solution is quenched with acetic acid solution described in step 2；Acetic acid solution dosage with
The pH value for controlling reaction solution is 6~7；
The reaction time of step 2 reaction is 3-8h.
7. the synthetic method of canagliflozin impurity I according to claim 6, it is characterised in that：Reaction is molten described in step 2
The solvent dosage of agent is that the mass ratio of iodo object and solvent is 1:2~3.
8. the synthetic method of canagliflozin impurity I according to claim 6, it is characterised in that：Reaction is molten described in step 2
Agent is toluene.
9. the synthetic method of canagliflozin impurity I according to claim 8, it is characterised in that：Toluene dosage is iodo object
Mass ratio with toluene is 1:1~5.
10. the synthetic method of canagliflozin impurity I according to claim 9, it is characterised in that：Toluene dosage is iodo object
Mass ratio with toluene is 1:2~3.
11. the synthetic method of canagliflozin impurity I according to claim 6, it is characterised in that：Iodo object described in step 2
It is 1 with the molar ratio of lithium reagent or Grignard Reagent:1~2.
12. the synthetic method of canagliflozin impurity I according to claim 6, it is characterised in that：Starting described in step 2
Material bromo-derivative is 1 with the molar ratio of lithium reagent or Grignard Reagent:1~2.
13. the synthetic method of canagliflozin impurity I according to claim 6, it is characterised in that：The inert atmosphere is nitrogen
Gas or argon gas.
14. the synthetic method of canagliflozin impurity I according to claim 6, it is characterised in that：By chemical combination described in step 2
Object B add in reaction solution reaction condition be：Reaction temperature is -40~-50 DEG C.
15. the synthetic method of canagliflozin impurity I according to claim 6, it is characterised in that：The reaction of step 2 reaction
Time is 2-3h.
16. the synthetic method of canagliflozin impurity I according to claim 1, it is characterised in that：At least meet following arbitrary
One：
Solvent described in step 3 is halogenated hydrocarbon reagent；
Reducing agent silane reagent described in step 3 is using tri isopropyl silane, triethylsilane, trimethyl silane；
The molar ratio of compound C and reducing agent silane reagent is 1:1~10；
Lewis acid described in step 3 is using boron trifluoride ether, boron trifluoride tetrahydrofuran, zinc chloride, aluminium chloride, iron chloride；
Compound C is 1 with lewis acidic molar ratio:1~10；
The molar ratio of compound C and boron trifluoride ether is 1:1~10；
Reaction time described in step 3 is 3-12h；
A concentration of 10% of sodium bicarbonate solution described in step 3；
Reaction is quenched using sodium bicarbonate in step 3, and the dosage of sodium bicarbonate solution ensures that reacting liquid pH value is 7-8.
17. the synthetic method of canagliflozin impurity I according to claim 16, it is characterised in that：Halogen described in step 3
Dichloromethane, chloroform, toluene or acetonitrile are used for hydro carbons reagent；The mass ratio of crude Compound C and solvent is 1:1~
10。
18. the synthetic method of canagliflozin impurity I according to claim 17, it is characterised in that：Solvent uses dichloromethane
Alkane, chloroform, toluene；The mass ratio of crude Compound C and solvent is 1:6~10.
19. the synthetic method of canagliflozin impurity I according to claim 17, it is characterised in that：Solvent uses acetonitrile；Slightly
The mass ratio of product compound C and solvent is 1:3~5.
20. the synthetic method of canagliflozin impurity I according to claim 16, it is characterised in that：Reduction described in step 3
Agent uses tri isopropyl silane.
21. the synthetic method of canagliflozin impurity I according to claim 16, it is characterised in that：Compound C and reducing agent
The molar ratio of silane reagent is 1:2~3.
22. the synthetic method of canagliflozin impurity I according to claim 16, it is characterised in that：Compound C and Louis
The molar ratio of acid is 1:1~2.
23. the synthetic method of canagliflozin impurity I according to claim 16, it is characterised in that：Louis described in step 3
This acid uses boron trifluoride ether.
24. the synthetic method of canagliflozin impurity I according to claim 16, it is characterised in that：Compound C with it is borontrifluoride
The molar ratio of borate ether is 1:1~2.
25. the synthetic method of canagliflozin impurity I according to claim 16, it is characterised in that：It is anti-described in step 3
It is 4-6h between seasonable.
26. the synthetic method of canagliflozin impurity II, it is characterised in that：Include the following steps：
Step 1 to three with canagliflozin impurity I synthetic method；
Step 4：Canagliflozin impurity I is dissolved in reaction dissolvent, adds in alkali and is deprotected, and normal-temperature reaction is completed to reacting；It adds in
Reaction is quenched in acetic acid, is then added to the water reaction solution, and solid is precipitated, and filtering obtains canagliflozin impurity II；
Wherein, the reaction temperature of normal-temperature reaction described in step 4 is 15~35 DEG C；
The structural formula of the canagliflozin impurity I is：
The structural formula of the canagliflozin impurity II is：
27. the synthetic method of canagliflozin impurity II according to claim 26, it is characterised in that：At least meet following appoint
Meaning one：
Reaction dissolvent described in step 4 uses alcohols solvent；
The mass ratio of canagliflozin impurity I and reaction dissolvent is 1:3~10；
The reaction temperature of normal-temperature reaction described in step 4 is 20~25 DEG C；
It adds in alkali described in step 4 to be deprotected, the alkali selects sodium methoxide, sodium ethoxide, lithium hydroxide, sodium hydroxide, hydrogen
Potassium oxide；
The molar ratio of canagliflozin impurity I and alkali is 1:0.5~5；
The molar ratio of canagliflozin impurity I and sodium methoxide is 1:0.5~5；
Reaction is quenched using acetic acid described in step 4；
The dosage of acetic acid ensures that reacting liquid pH value is 6-7.
28. the synthetic method of canagliflozin impurity II according to claim 27, it is characterised in that：Alcohols described in step 4
Solvent is using methanol, ethyl alcohol, tetrahydrofuran.
29. the synthetic method of canagliflozin impurity II according to claim 27, it is characterised in that：Lattice arrange net impurity I with
The mass ratio of reaction dissolvent is 1:5~7.
30. the synthetic method of canagliflozin impurity II according to claim 27, it is characterised in that：Canagliflozin impurity I
Molar ratio with alkali is 1:1~2.
31. the synthetic method of canagliflozin impurity II according to claim 27, it is characterised in that：Alkali is described in step 4
Sodium methoxide.
32. the synthetic method of canagliflozin impurity II according to claim 27, it is characterised in that：Canagliflozin impurity I
Molar ratio with sodium methoxide is 1:1~2.
33. the synthetic method of canagliflozin impurity II according to claim 27, it is characterised in that：The acetic acid is using pure
Glacial acetic acid.
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