CN103980261B - The A crystal formation of canagliflozin and crystallization preparation method thereof - Google Patents
The A crystal formation of canagliflozin and crystallization preparation method thereof Download PDFInfo
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- CN103980261B CN103980261B CN201410129786.7A CN201410129786A CN103980261B CN 103980261 B CN103980261 B CN 103980261B CN 201410129786 A CN201410129786 A CN 201410129786A CN 103980261 B CN103980261 B CN 103980261B
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- 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
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Abstract
The invention discloses the A crystal formation of a kind of canagliflozin and crystallization preparation method thereof, its X-ray powder diffraction in the angle of diffraction 2 θ=3.7 ± 0.1,3.9 ± 0.1,7.7 ± 0.1,7.9 ± 0.1,11.5 ± 0.1,13.1 ± 0.1,13.5 ± 0.1,14.3 ± 0.1,15.5 ± 0.1,17.3 ± 0.1,18.8 ± 0.1,19.3 ± 0.1,20.3 ± 0.1,22.5 ± 0.1,22.7 there is characteristic peak at ± 0.1,23.2 ± 0.1 and 23.4 ± 0.1 degree of places.Operating procedure of the present invention is simple to operation, consuming time short, power consumption is few.The product stability prepared is good, purity higher than 99%, yield about 90%, after product stores 100 days under room temperature, drying condition, product purity, color, form do not change.
Description
Technical field
The invention belongs to fine chemistry industry and application, particularly to novel crystal forms and the crystallization preparation method thereof of a kind of canagliflozin.
Background technology
The chemistry of canagliflozin (canagliflozin) is called 1-(β-D-glycopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene, and molecular formula is C24H25FO5S, molecular weight is 444.52, structural formula such as formula (I).Canagliflozin is as a kind of sodium dependent glucose operating albumen (SGLT) inhibitor, food and drug administration (FDA) ratifies its tablet and coordinates with diet and motion on March 29th, 2013, it can make the glucose in renal tubules can not heavily be absorbed into blood smoothly and discharge with urine, thus reducing blood sugar concentration, control blood glucose for adults with type 2 diabetes.
Diabetes are a kind of chronic diseases perplexing the whole world, and the current whole world there are about 2.3 hundred million patients, and 35-40 year after be the type 2 diabetes mellitus multiple phase, make a definite diagnosis diabetics and account for more than 90%.Long term hyperglycemia can increase risk severe complication occur, including heart disease, blind, neural and kidney damage.In recent years the trend of rising is also had along with the sickness rate in growth in the living standard child.Having reported that hyperglycemia is relevant with the morbidity of diabetes and Progressive symmetric erythrokeratodermia damage, chronic hyperglycemia may result in insulin secretion and reduces and reduce insulin sensitivity further, and resulting in blood sugar concentration increases so that diabetes are self-exacerbated.Therefore, by treating hyperglycemia, above-mentioned self-exacerbating cycle can be blocked so that prevention and treatment diabetes are possibly realized.
Although Diet Therapy and exercise therapy are required in the treatment of diabetes, but when these therapies are not enough to control disease, then need other insulin injection or oral antidiabetic thing.At present, have as diabetes: biguanide compound, sulphonyl urea compound, insulin resistance improving agent and alpha-glucosidase inhibitor.But, these antidiabetics have various side effect.Such as, biguanide compound can cause lactic acidosis, sulphonyl urea compound that hypoglycemia, insulin resistance improving agent significantly can be caused to cause edema, heart failure, and alpha-glucosidase inhibitor can cause abdominal distention and diarrhoea.In this case it is necessary to develop for treating diabetes and not there is the new drug of these side effect.
One of method as treatment hyperglycemia, medically makes excessive glucose directly to drain and makes blood sugar concentration normalization in urine.Such as, by suppressing the sodium dependent glucose operating albumen being positioned at renal proximal kidney convoluted tubule can suppress the kidney re-absorption to glucose, thereby promote that glucose is drained and make into urine blood sugar level reduce.It is true that have proven to the phlorhizin to the continuous subcutaneous administration of diabetes animal model with SGLT inhibitory activity, hyperglycemia normalization can be made and make its blood sugar level remain normal in a long time, thus improving insulin secretion and insulin resistant.
Being solid under canagliflozin compound normal temperature and pressure, it is first disclosed as in Chinese patent CN200480022007.8, day Honda limit Co., Ltd. propose.Its commodity are called Invokana(canagliflozin) tablet, the Janssen Pharmaceutica of New Jersey Titusville manufacture.Invokana tablet coordinates diet and motion to control blood glucose for adults with type 2 diabetes.Invokana can block kidney and glucose re-absorption, increase glucose are drained and reduce blood sugar in diabetic patients level.Invokana cannot be used for type 1 diabetes, hematuria ketone increases (diabetic ketoacidosis) or severe renal functional defect, End-stage renal disease or at dialysis patient.
Patent CN200780043154.7, WO2008069327A1 disclose canagliflozin semihydrate crystal formation and method for crystallising, this method for crystallising crystallization time is longer, is typically in more than 20 hours.
Patent CN200880106239.X, WO2012154812A1 disclose compound crystal form and the method for crystallising thereof of canagliflozin, and the method for crystallising step described in the document is more, and need to carry out when argon shield.
Patent WO2013064909A2 discloses canagliflozin and L-PROLINE, D-PROLINE, the eutectic of L-phenylalanine and amorphous canagliflozin, eutectic that the canagliflozin that this patent mainly describes and other various adjuvant are formed and method for crystallising thereof.
Summary of the invention
The invention discloses the crystal formation of a kind of new canagliflozin crystal, its X-ray powder diffraction in the angle of diffraction 2 θ=3.7 ± 0.1,3.9 ± 0.1,7.7 ± 0.1,7.9 ± 0.1,11.5 ± 0.1,13.1 ± 0.1,13.5 ± 0.1,14.3 ± 0.1,15.5 ± 0.1,17.3 ± 0.1,18.8 ± 0.1,19.3 ± 0.1,20.3 ± 0.1,22.5 ± 0.1,22.7 there is characteristic peak at ± 0.1,23.2 ± 0.1 and 23.4 ± 0.1 degree of places, as shown in Figure 1；Called after A crystal formation canagliflozin.XRD figure spectrum is that it launches target is Cu/K α, and power supply is set to 40kV/100mA, and sweep speed is 2 degree min, and scanning step is 0.02 degree, and 2 θ sweep limitss are 2 degree to 40 degree in the upper collection of X-ray powder diffractometer (D/max-2500, Rigaku Rigaku).
Described A crystal formation canagliflozin crystal, its dsc analysis result shows, has a feature endothermic peak at 105 ± 2 DEG C, as shown in Figure 2.DSC data is analyzed by differential scanning calorimeter (DSC1/500, MettlerToledo company of Switzerland) and is obtained, and analysis condition is: be placed in aluminum crucible by sample 5～10mg, in high-purity N2Under protection, with the speed of 2 DEG C/min, sample temperature is risen to 125 DEG C by 25 DEG C.
The profile of described A crystal formation canagliflozin crystal is such as shown in Fig. 3 microphotograph.Habit microphotograph is observed by polarizing microscope (OLYMPUSBX51, MicroPublisher5.0RTU) and is recorded and obtains.
The preparation method of A crystal formation canagliflozin crystal of the present invention is as follows:
Being added in alcohols solvent by canagliflozin crude product, be configured to the suspension of 0.05～0.5g/mL, under stirring action, make solid be completely dissolved at 15～43 DEG C, drip dissolved agent in solution, dissolved agent consumption is 3～10 times of alcohols solvent volume；The suspension that sucking filtration is formed, obtains A crystal formation canagliflozin crystal product after drying.
The purity of described canagliflozin crude product is 92.0%～96.0%.
The described alcohols solvent mixed solvent of one or more in methanol, ethanol, n-butyl alcohol, isobutanol, sec-butyl alcohol, normal propyl alcohol, isopropanol, ethylene glycol, n-amyl alcohol or isoamyl alcohol.
The described dissolved agent mixed liquor of one or more in normal heptane, normal hexane, hexamethylene, normal octane, n-butyl ether, petroleum ether, ether or water.
In described method, the drop rate of dissolved agent is the 0.2%～5% of dropping dissolved agent volume per minute.
In described method drying condition be 30～65 DEG C, normal pressure when carry out 6～8h.
The inventive method has the advantages that
The dilution crystallization method operating procedure adopted is simple to operation, consuming time short, power consumption is few.The product stability prepared is good, purity higher than 99%, yield about 90%, after product stores 100 days under room temperature, drying condition, product purity, color, form do not change.Product is prone to pulverize and be prone to add the dosage form of pharmaceutical composition, and cost is low, it is easier to commercial industries scale is implemented.
A crystal formation canagliflozin provides a new crystal formation as the selection of canagliflozin, and the application of Ka Gelie is provided more choices.
Described A crystal formation canagliflozin is applied to the raw material of the effective ingredient of 1 type and type 2 diabetes mellitus, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, post prandial hyperglycemia, hyperinsulinemia.
Accompanying drawing explanation
The X-ray powder diffraction pattern of Fig. 1: A crystal formation canagliflozin crystal；
The dsc analysis figure of Fig. 2: A crystal formation canagliflozin crystal；
The microphotograph of Fig. 3: A crystal formation canagliflozin crystal.
Detailed description of the invention
Embodiment 1:
Canagliflozin solid 5.1g dry, purity 92.0% is added in 100mL normal propyl alcohol and form suspension, under agitation this suspension is heated to 15 DEG C, makes solid all dissolve；With the speed of 0.6mL/min to the hexamethylene dripping 300mL in solution, obtain suspension, vacuum filtration magma, by product 30 DEG C, under normal pressure dry 8 hours to constant weight, obtain A crystal formation canagliflozin product.The X-ray powder diffraction of product as it is shown in figure 1, it is in the angle of diffraction 2 θ=3.71,3.94,7.77,7.92,11.53,13.16,13.58,14.30,15.56,17.32,18.81,19.36,20.31,22.50,22.79,23.24,23.48 there is characteristic peak at degree place, dsc analysis figure such as Fig. 2, it has feature endothermic peak at 105.4 DEG C.Habit microphotograph is as shown in Figure 3.
The A crystal formation canagliflozin product stability prepared is good, and purity 99.3%, yield 88.3%, after product stores 100 days under room temperature, drying condition, product purity, color, form do not change.Product is prone to pulverize and be prone to add the dosage form of pharmaceutical composition.
Embodiment 2:
Canagliflozin solid 14.3g dry, purity 96.0% is added in 100mL isopropanol and form suspension, under agitation this suspension is heated to 25 DEG C, makes solid all dissolve；With the speed of 5mL/min to the mixing dissolved agent dripping the normal hexane of 400mL and the water of 100mL in solution, obtain suspension, vacuum filtration magma, by product 45 DEG C, under normal pressure dry 7 hours to constant weight, obtain A crystal formation canagliflozin.The X-ray powder diffraction of product in the angle of diffraction 2 θ=3.73,3.96,7.78,7.94,11.53,13.15,13.57,14.31,15.58,17.34,18.82,19.35,20.32,22.52,22.79,23.25, there is characteristic peak at 23.48 degree of places, and dsc analysis figure has feature endothermic peak at 105.56 DEG C of places.
The A crystal formation canagliflozin product stability prepared is good, and purity 99.1%, yield 89.6%, after product stores 100 days under room temperature, drying condition, product purity, color, form do not change.Product is prone to pulverize and be prone to add the dosage form of pharmaceutical composition.
Embodiment 3:
Canagliflozin solid 28.5g dry, purity 94.0% is added 40mL ethanol and 60mL n-amyl alcohol are formed suspension, under agitation this suspension is heated to 38 DEG C, makes solid all dissolve；Obtain suspension with the speed of 26mL/min to the petroleum ether dripping 650mL in solution, vacuum filtration magma, by product 45 DEG C, within 6 hours, be dried to constant weight under normal pressure, obtain A crystal formation canagliflozin.The X-ray powder diffraction of product in the angle of diffraction 2 θ=3.74,3.96,7.77,7.95,11.55,13.17,13.58,14.32,15.59,17.36,18.82,19.36,20.33,22.53,22.78,23.25, there is characteristic peak at 23.48 degree of places, and dsc analysis figure has feature endothermic peak at 106.72 DEG C of places.
The A crystal formation canagliflozin product stability prepared is good, and purity 99.2%, yield 90.5%, after product stores 100 days under room temperature, drying condition, product purity, color, form do not change.Product is prone to pulverize and be prone to add the dosage form of pharmaceutical composition.
Embodiment 4:
Canagliflozin solid 50.0g dry, purity 95.0% is added 30mL normal propyl alcohol and 70mL methanol are formed suspension, under agitation this suspension is heated to 43 DEG C, makes solid all dissolve；With the normal heptane mixing dissolved agent to the normal octane and 500mL that drip 500mL in solution of the speed of 50mL/min, obtain suspension, vacuum filtration magma, by product 65 DEG C, under normal pressure dry 6 hours to constant weight, obtain A crystal formation canagliflozin.The X-ray powder diffraction of product in the angle of diffraction 2 θ=3.72,3.94,7.76,7.95,11.54,13.16,13.57,14.32,15.58,17.35,18.81,19.35,20.33,22.53,22.77,23.24, there is characteristic peak at 23.47 degree of places, and dsc analysis figure has feature endothermic peak at 105.82 DEG C of places.
The A crystal formation canagliflozin product stability prepared is good, and purity 99.1%, yield 91.2%, after product stores 100 days under room temperature, drying condition, product purity, color, form do not change.Product is prone to pulverize and be prone to add the dosage form of pharmaceutical composition.
A crystal formation canagliflozin crystal of disclosure and proposition and preparation method thereof, those skilled in the art can by link realizations such as reference present disclosure, suitable feed change, technological parameters.The method of the present invention and product have passed through preferred embodiment and are described, method described herein and product substantially can be modified or suitably change and combination by person skilled in without departing from present invention, spirit and scope, realize the technology of the present invention.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the art, they are considered as including in present invention spirit, scope and content.
Claims (5)
1. the crystal formation of a canagliflozin, it is characterised in that X-ray powder diffraction in the angle of diffraction 2 θ=3.7 ± 0.1,3.9 ± 0.1,7.7 ± 0.1,7.9 ± 0.1,11.5 ± 0.1,13.1 ± 0.1,13.5 ± 0.1,14.3 ± 0.1,15.5 ± 0.1,17.3 ± 0.1,18.8 ± 0.1,19.3 ± 0.1,20.3 ± 0.1,22.5 ± 0.1,22.7 there is characteristic peak at ± 0.1,23.2 ± 0.1 and 23.4 ± 0.1 degree of places.
2. crystal as claimed in claim 1, is characterized in that dsc analysis result shows, has a feature endothermic peak at 105 ± 2 DEG C.
3. the preparation method of canagliflozin crystal formation as claimed in claim 1, is characterized in that:
Canagliflozin crude product is added in alcohols solvent, it is configured to the suspension of 0.05～0.5g/mL, under stirring action, solid is made to be completely dissolved at 15～43 DEG C, dissolved agent is dripped in solution, dissolved agent consumption is 3～10 times of alcohols solvent volume, and the drop rate of dissolved agent is the 0.2%～5% of dropping dissolved agent volume per minute；The suspension that sucking filtration is formed, obtains canagliflozin novel crystal forms after drying；
The described alcohols solvent mixed solvent of one or more in methanol, ethanol, n-butyl alcohol, isobutanol, sec-butyl alcohol, normal propyl alcohol, isopropanol, ethylene glycol, n-amyl alcohol or isoamyl alcohol；The described dissolved agent mixed liquor of one or more in normal heptane, normal hexane, hexamethylene, normal octane, n-butyl ether, petroleum ether or ether.
4. method as claimed in claim 3, it is characterized in that described drying condition to be temperature be 30～65 DEG C, normal pressure when carry out 6～8h.
5. the crystal formation of canagliflozin as claimed in claim 1 is for preparing the purposes in the medicine for the treatment of 1 type and type 2 diabetes mellitus, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, hyperglycemia, hyperinsulinemia.
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| CN104974146B (en) * | 2014-09-15 | 2018-02-02 | 苏州晶云药物科技有限公司 | Crystal formation E, crystal formation F of canagliflozin and preparation method thereof |
| CN104530023A (en) * | 2014-12-25 | 2015-04-22 | 重庆医药工业研究院有限责任公司 | Crystal form I of Canagliflozin and preparation method thereof |
| CN104530024B (en) | 2015-02-04 | 2017-08-08 | 上海迪赛诺药业有限公司 | Crystal formation of 1 (β D glycopyranosyls) 4 methyl 3 [5 (4 fluorophenyl) 2 thienyl methyls] benzene and preparation method thereof |
| EP3256482B1 (en) * | 2015-02-09 | 2019-11-27 | Indoco Remedies Limited | Process for the preparation of sglt inhibitor compounds |
| CZ2015824A3 (en) * | 2015-11-20 | 2017-05-31 | Zentiva, K.S. | A crystalline form of Canagliflozin and the method of its preparation |
| CN105541818A (en) * | 2016-03-04 | 2016-05-04 | 浙江华海药业股份有限公司 | Novel crystal form of canagliflozin hydrate and preparation method of novel crystal form |
| CN108017626A (en) * | 2016-11-04 | 2018-05-11 | 上海奥博生物医药技术有限公司 | A kind of canagliflozin semihydrate novel crystal forms |
| CN106588898A (en) | 2017-02-20 | 2017-04-26 | 浙江华海药业股份有限公司 | Preparation method for amorphous form of canagliflozin |
| CN107311993A (en) * | 2017-08-09 | 2017-11-03 | 江苏德源药业股份有限公司 | A kind of crystal formation II of canagliflozin and preparation method thereof |
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| UY30730A1 (en) * | 2006-12-04 | 2008-07-03 | Mitsubishi Tanabe Pharma Corp | CRYSTAL FORM OF HEMIHYDRATE 1- (B (BETA) -D-GLUCOPYRANOSIL) -4-METHYL-3- [5- (4-FLUOROPHENYL) -2-TIENYLMETHYL] BENZENE |
| JP5596545B2 (en) * | 2007-09-10 | 2014-09-24 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | Method for producing a compound useful as an inhibitor of SGLT |
| US9174971B2 (en) * | 2009-10-14 | 2015-11-03 | Janssen Pharmaceutica Nv | Process for the preparation of compounds useful as inhibitors of SGLT2 |
| WO2011142478A1 (en) * | 2010-05-11 | 2011-11-17 | Mitsubishi Tanabe Pharma Corporation | Canagliflozin containing tablets |
| AU2012241897C1 (en) * | 2011-04-13 | 2017-05-11 | Janssen Pharmaceutica Nv | Process for the preparation of compounds useful as inhibitors of SGLT2 |
| TWI542596B (en) * | 2011-05-09 | 2016-07-21 | 健生藥品公司 | L-proline and citric acid co-crystals of (2s,3r,4r,5s,6r)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2h-pyran-3,4,5-triol |
| BR112014010574A2 (en) * | 2011-10-31 | 2017-05-02 | Scinopharm Taiwan Ltd | crystalline and non-crystalline forms of sglt2 inhibitors |
| CN103641822B (en) * | 2013-10-21 | 2016-06-08 | 江苏奥赛康药业股份有限公司 | A kind of Ka Gelie purifies compound and pharmaceutical composition thereof |
| CN103554092A (en) * | 2013-11-11 | 2014-02-05 | 苏州晶云药物科技有限公司 | New crystal form B of 1-(beta-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl] benzene and preparation method of new crystal form B |
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