CN104610208A - (1S)-1,6-dideoxy-1-[4-methoxy-3-(trans-4-n-propylcyclohexyl)methylphenyl]-D-glucopyranose crystal form A, preparation method and applications thereof - Google Patents
(1S)-1,6-dideoxy-1-[4-methoxy-3-(trans-4-n-propylcyclohexyl)methylphenyl]-D-glucopyranose crystal form A, preparation method and applications thereof Download PDFInfo
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- CN104610208A CN104610208A CN201310541681.8A CN201310541681A CN104610208A CN 104610208 A CN104610208 A CN 104610208A CN 201310541681 A CN201310541681 A CN 201310541681A CN 104610208 A CN104610208 A CN 104610208A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/10—Oxygen atoms
Abstract
The present invention belongs to the technical field of medicines, and specifically discloses the crystal form A of a deoxy C-glucoside SGLT2 inhibitor (1S)-1,6-dideoxy-1-[4-methoxy-3-(trans-4-n-propylcyclohexyl)methylphenyl]-D-glucopyranose (DO), a preparation method and applications thereof. According to the present invention, the X-ray powder diffraction characteristic absorption peak (2[theta]) values of the crystal form are 3.80, 6.54, 8.34, 9.88, 11.34, 14.52, 15.08, 18.06, 18.96, 19.38, 19.94, 20.92, 21.72 and 22.28, the 2[theta] measurement error is +/-0.2, and the crystal form has characteristics of stable appearance state, further compound purity increase, stable storage and the like, and be directly supplied for the raw material drug. The DO is defined in the instruction.
Description
Technical field
The invention belongs to medical art, relate to a kind of crystal formation of the phenyl C-glucoside derivative containing deoxyglucose structure, be specifically related to one (1S)-1, the crystal form A of 6-dideoxy-1-[4-methoxyl group-3-(trans-4-n-propyl cyclohexyl) aminomethyl phenyl]-D-Glucopyranose, and the preparation method and application of this crystal formation.
Background technology
The present inventor (1S)-1,6-dideoxy-1-[4-methoxyl group-3-(trans-4-n-propyl cyclohexyl) aminomethyl phenyl]-D-Glucopyranose (for convenience of description, hereinafter referred to as DO) as Na
+-glucose cotransporter 2(or be called 2 type sodium glucose cotransporter, sodium-dependent glucose cotransporter2, is abbreviated as SGLT2) inhibitor have submitted application for a patent for invention (CN201310016846.X).This compound can be used for the pharmaceutical composition preparing treatment diabetes, and its chemical structural formula is as follows:
In research process, the present inventor finds, the later stage of preparing the final step of above-claimed cpd DO is separated by solvent evaporated to obtain product from solution, its form is a kind of solid matter between white foam and white solid, and this state fluctuate between each batch indefinite, be difficult to keep constant apparent condition, be not suitable for directly using as bulk drug.Meanwhile, because this compound often presents certain foam characteristic, thus increase the difficulty of purifying further, bring certain difficulty to the highly purified bulk drug of preparation.
Summary of the invention
Therefore, the object of the invention is to overcome above-mentioned defect, provide a kind of crystal form A of DO, this crystal formation has stable apparent condition, contribute to the purity improving DO further, and improve storage stability, stably the supply system for bulk drug, and the preparation method and application of this crystal formation can be provided.
The invention provides one (1S)-1, the crystal form A of 6-dideoxy-1-[4-methoxyl group-3-(trans-4-n-propyl cyclohexyl) aminomethyl phenyl]-D-Glucopyranose (DO), the X-ray powder diffraction (PXRD, Powder X-ray Diffraction) represented with 2 θ angles has diffraction peak 3.80,6.54,8.34,9.88,11.34,14.52,15.08,18.06,18.96,19.38,19.94,20.92,21.72,22.28 ° of vicinity.
According to crystal form A of the present invention, wherein, its X-ray powder diffraction is 23.23,13.50,10.59,8.95,7.80,6.10,5.87,4.91,4.68,4.58,4.45,4.24,4.09,3.99 in spacing d value
vicinity, position there is diffraction peak.Preferably, between described spacing d value and 2 θ angles, corresponding relation is as shown in table 1.
Corresponding relation between table 1 spacing d value and 2 θ
According to crystal form A of the present invention, wherein, its differential thermal analysis (DTA, Differential Thermal Analysis) collection of illustrative plates can have endotherm(ic)peak at 146 DEG C of places.
According to crystal form A of the present invention, wherein, its X-ray powder diffraction as shown in Figure 2.
Present invention also offers the method preparing above-mentioned crystal form A, the method comprises: by (1S)-1,6-dideoxy-1-[4-methoxyl group-3-(trans-4-n-propyl cyclohexyl) aminomethyl phenyl]-D-Glucopyranose is dissolved in a kind of good solvent, this solution can be heated subsequently, slowly add a kind of poor solvent, then under agitation slowly cooling crystallization, collected by suction crystallization, then dry, obtain crystal form A.
According to method of the present invention, wherein, good solvent is selected from acetic acid, acetone, methyl alcohol, ethanol, Virahol, and poor solvent is water; Or good solvent is selected from ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isopropyl acetate, poor solvent is selected from normal hexane, hexanaphthene, isopropyl ether, ether, sherwood oil.
According to method of the present invention, wherein, described (1S)-1, mass/volume/the volume ratio (g/mL/mL) of 6-dideoxy-1-[4-methoxyl group-3-(trans-4-n-propyl cyclohexyl) aminomethyl phenyl]-D-Glucopyranose/good solvent/poor solvent is 1:5 ~ 10:3 ~ 30, is preferably 1:7:7.
Preferably, use vacuum oil pump to carry out drying operation, time of drying is 4 ~ 8 hours, is preferably 5 hours.
Present invention also offers a kind of pharmaceutical composition, described pharmaceutical composition includes crystal form A of the present invention and one or more pharmaceutically acceptable auxiliary materials of effective amount.Described pharmaceutically acceptable auxiliary material can be the matrix or the auxiliary material that keep pharmaceutical dosage form, by selecting according to different medicaments or composition use, optionally comprise carrier, vehicle, thinner, weighting agent, tackiness agent, disintegrating agent, lubricant, glidant, effervescent, correctives, sanitas, coating material etc.Vehicle comprises the composition of one or more in such as Microcrystalline Cellulose, lactose, pregelatinized Starch, starch, dextrin, calcium phosphate, sucrose, dextran, N.F,USP MANNITOL, sorbyl alcohol, glucose, fructose, water, polyoxyethylene glycol, propylene glycol, glycerine, cyclodextrin, cyclodextrin derivative.Weighting agent comprises the composition of one or more of such as lactose, sucrose, dextrin, starch, pregelatinized Starch, N.F,USP MANNITOL, sorbyl alcohol, secondary calcium phosphate, calcium sulfate, calcium carbonate, Microcrystalline Cellulose.Tackiness agent comprises the composition of one or more of such as sucrose, starch, polyvidone, Xylo-Mucine, hypromellose, hydroxypropylcellulose, methylcellulose gum, polyoxyethylene glycol, medicinal alcohol, water.Disintegrating agent comprises the composition of one or more of such as starch, crosslinked polyvidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carmethose, gas-producing disintegrant.
According to pharmaceutical composition of the present invention, wherein, described pharmaceutical composition can be solid orally ingestible, liquid oral medicine or injection.Preferably, described solid orally ingestible comprises dispersible tablet, enteric coated tablet, chewable tablet, orally disintegrating tablet, capsule or granule; Described liquid oral medicine comprises oral solution; Described injection comprises injection liquid drugs injection, injection freeze-dried powder, infusion solutions or primary infusion.
The purposes of crystal form A in the pharmaceutical composition for the preparation for the treatment of diabetes that present invention also offers crystal form A or prepare according to method of the present invention.The present inventor has found that DO has the restraining effect of SGLT2, can be used as the medicine of effective constituent for the preparation of diabetes aspect.And by the external suppression to humanization SGLT2 and rat glucose in urine excretion model validation, crystal form A of the present invention has higher SGLT2 inhibit activities.
The crystal form A of DO of the present invention is effective in quite wide dosage range.The dosage taken such as every day, within the scope of 1mg ~ 500mg/ people, is divided into once or administration for several times.The actual dosage taking the crystal form A of DO of the present invention can be decided according to relevant situation by doctor.These situations comprise: the physical state of patient, route of administration, age, body weight, individual reaction to medicine, the severity etc. of symptom.
Compared with the DO sample between spumescence and normal solid obtained by modes such as direct evaporate to dryness solution, DO crystal form A prepared by the present invention batch between to have good appearance stability (be white solid, but not the spumescence feature had to a certain degree) and circulation ratio, and purity improves further.Such as, the present inventor is found by test, this crystal form A continuous production 10 batches batch within the scope of, its outward appearance is stable, is all normal white solids, and analyzes through PXRD and DTA that often to criticize are all stable crystal form As.In addition, analyze through HPLC for each batch, the purity of crystal form A is 99.40% ~ 99.60%, is all significantly higher than the purity 98.04% of DO raw material.
In addition, crystal form A of the present invention also has good storage stability.Such as, the present inventor verifies by experiment, and this crystal form A is in the stability experiment to light, heat, water vapour of two weeks by a definite date, and its impurity is not significantly increased, and thus has good storage stability.
Based on above-mentioned characteristic, crystal form A of the present invention as the stable supplying source of DO bulk drug, can be more suitable for suitability for industrialized production.
Accompanying drawing explanation
Below, describe embodiment of the present invention in detail by reference to the accompanying drawings, wherein:
Fig. 1 shows differential thermal analysis (DTA) collection of illustrative plates of crystal form A obtained in embodiment 1;
Fig. 2 shows the PXRD collection of illustrative plates of crystal form A obtained in embodiment 1.
Embodiment
Further illustrate the present invention below by specific embodiment, but should be understood to, these embodiments are only used for the use specifically described more in detail, and should not be construed as limiting the present invention in any form.
General description is carried out to the material used in the present invention's test and test method in this part.Although for realizing many materials that the object of the invention uses and working method is well known in the art, the present invention still describes in detail as far as possible at this.It will be apparent to those skilled in the art that within a context, if not specified, material therefor of the present invention and working method are well known in the art.
With the following Examples, the condition determination of the present invention to crystal form A is as follows:
X-ray powder diffraction (PXRD) condition:
Instrument: Rigaku D/Max-2500 type 18kW
Diffractometer: polycrystal powder diffractometer
Target: Cu-K α radiation,
2 θ=3 ~ 50 °
Pipe pressure: 40KV
Guan Liu: 100mA
Sweep velocity: 8 DEG C/min
Crystalline graphite monochromator
DS/SS=1°
RS：0.3mm
Differential thermal analysis (DTA) condition:
Instrument: Rigaku PTC-10A TG-DTA analyser
Temperature rise rate: 10 DEG C/min
Scanning temperature range: 0 ~ 300 DEG C
Reference substance: Al
2o
3
The crystal form A to be measured of sample size: 5.8mg
High performance liquid chromatography (HPLC) condition:
Chromatographic column: C
18, 150mm × 4.6mm, 5 μm
Moving phase: methanol/water/acetic acid=70/30/0.25
Wavelength: 230nm
Flow velocity: 0.8ml/min
Sample size: 10 μ L
Column temperature: 35 DEG C
Instrument: generally analyse general L6 liquid chromatograph
Hitachi L-7250 automatic sampler
Generally analyse general LC Win chromatographic working station
embodiment 1
The present embodiment is for illustration of the crystal form A of DO of the present invention and preparation process thereof.
DO is as raw material in preparation.Can with reference to following reaction process:
Concrete preparation process can be:
Add the THF of 32.5g (0.1mol) Compound I and 300mL drying in the dry round-bottomed flask of a 1L, add magneton, with the sealing of rubber cork after nitrogen purging.Flask is placed in liquid nitrogen-ethanol system and is cooled to-78 DEG C, starts induction stirring.The n-Butyl Lithium of 62.5mL (0.1mol) 1.6M is slowly dripped with syringe, continue at such a temperature after dropwising to stir half an hour, then slowly drip by syringe the solution that THF that 43.3g (0.1mol) II is dissolved in 200mL drying makes.Reaction mixture continues stirring 1 hour at such a temperature, is then slowly warming up to room temperature reaction 1 hour.Reaction mixture is poured in 400mL frozen water, stirs, uses saturated NaHCO
3solution regulates the dichloromethane extraction of pH=4-6,100mL × 3.Merge organic phase, weak brine washs, and anhydrous sodium sulfate drying, on a rotary evaporator evaporate to dryness, resistates is the crude product of III-M.This crude product, without purifying, is directly used in next step reaction.
The crude product of the compound III-M of above-mentioned preparation is dissolved in the methylene dichloride of 500mL drying in the round-bottomed flask of 1L, adds 23.3g (0.2mol) Et
3siH, stirs under-30 DEG C of coolings.The solution that methylene dichloride that 14.2g (0.1mmol) boron trifluoride diethyl etherate is dissolved in 50mL drying makes slowly is dripped by dropping funnel.After dropwising, reaction mixture continues stirring and is then warming up to room temperature gradually in 1 hour at-30 DEG C, and at room temperature continues stirring 5 hours, and TLC shows reaction to be completed.In compound of reaction, carefully add 200mL saturated sodium bicarbonate solution, be poured in 2000mL frozen water after continuing to stir half an hour, stir, the dichloromethane extraction of 500mL × 3.Merge organic phase, weak brine washs, and anhydrous sodium sulfate drying, on a rotary evaporator evaporate to dryness, resistates column chromatography purification, obtains the sterling of IV, white solid, fusing point 105-106.5 DEG C.
33.1g (50mmol) compound IV is dissolved in 200mL THF, and add 5.0g10%Pd/C, under room temperature, catalytic hydrogenation is spent the night.Reaction mixture suction filtration, filtrate is evaporate to dryness on a rotary evaporator, and resistates obtains a white foam solid after short column column chromatography purification, is DO.White has the solid of foam property.
Get the round-bottomed flask that product DO that 1.00g aforesaid method obtains is placed in 100mL, add ethyl acetate 7mL, stir, with the hot water heating of 50 DEG C, obtain a clear soln.Then in round-bottomed flask, slowly drip 7mL normal hexane, after dropwising, remove heating source (hot water), stir under Temperature fall and spend the night, obtain a white magma shape system.Collected by suction crystallization, and in vacuum oil pump at 30 DEG C dry 5 hours, obtain the white solid 0.71g of DO of the present invention, the rate of recovery is 71%.
Differential thermal analysis (DTA) collection of illustrative plates of this DO crystal form A and X-ray diffraction (PXRD) collection of illustrative plates respectively as depicted in figs. 1 and 2, can determine that the DO crystal formation that the present embodiment obtains is crystal form A.
embodiment 2-10
With reference to the working method of embodiment 1, use 1.00g DO as raw material, conversion related experiment parameter, still can prepare the crystal form A (table 2) of DO.
The crystal form A of DO is prepared under table 2. different experiments parameter
| Embodiment | Good solvent and volume thereof | Poor solvent and volume thereof | Temperature (DEG C) during solvent | Yield (%) |
| 2 | Ethyl acetate 5mL | Hexanaphthene 20mL | 45 | 71 |
| 3 | N-propyl acetate 10mL | Ether 10mL | 35 | 68 |
| 4 | Isopropyl acetate 7mL | Isopropyl ether 10mL | 50 | 66 |
| 5 | N-butyl acetate 8mL | Sherwood oil 10mL | 50 | 64 |
| 6 | Isobutyl acetate 10mL | Normal hexane 6mL | 50 | 76 |
| 7 | Ethanol 7mL | Water 10mL | 50 | 78 |
| 8 | Acetone 7mL | Water 10mL | 50 | 74 |
| 9 | Acetic acid 7mL | Water 10mL | 50 | 74 |
| 10 | Methyl alcohol 10mL | Water 15mL | 50 | 63 |
The white solid determined in above-described embodiment by DTA and PXRD is the crystal form A of DO.
embodiment 11
The present embodiment is for illustration of the preparation of the tablet containing DO crystal form A of the present invention.
Obtained for embodiment 1 sample crystal form A, pregelatinized Starch and Microcrystalline Cellulose are sieved, fully mix, add the solution containing recipe quantity polyvinylpyrrolidone with recipe quantity, mixing, softwood processed, sieves, wet granular processed, in 50 ~ 60 DEG C of dryings; Then Sodium carboxymethyl starch, Magnesium Stearate and talcum powder are sieved in advance, join in above-mentioned dried particle with recipe quantity, compressing tablet, obtains the tablet containing DO crystal form A.
embodiment 12
The IC that the crystal form A that the method recorded according to document (Meng, W.et al, J.Med.Chem., 2008,51,1145-1149) measures the obtained DO of embodiment 1 suppresses SGLT2 and SGLT1
50value.Measurement result is as shown in table 3 below:
The IC that the crystal form A showing 3.DO suppresses SGLT2 and SGLT1
50value
According to IC in upper table
50the measurement result of value is known, and the crystal form A of DO is strong optionally SGLT2 inhibitor.
embodiment 13
Adopt HPLC to measure the purity of the obtained crystal form A of embodiment 1, its purity is 99.54%.And to record purity for the preparation of the DO raw material of crystal form A be 98.04%.It can thus be appreciated that the purity of crystal form A significantly improves, be more suitable for the batch production for medicine.
embodiment 14
DO crystal form A obtained for embodiment 1 is carried out influence factor test with DO raw material as a comparison, respectively at illumination (natural sunlight, on average be about 80000Lx), place two weeks (14 days) under the condition of high temperature (60 DEG C) and high humidity (80% relative humidity at 40 DEG C), compared outward appearance, impurity number and impurity level (measuring with HPLC) with the 0th day.Test-results is respectively in table 4 ~ 6.
Table 4. light durability testing data
Table 5. thimble test data
Table 6. high humidity stability test data
From table 3 ~ 5, in stability test under the illumination of two weeks by a definite date, high temperature, super-humid conditions, there is not visible change in the outward appearance of crystal form A of the present invention, crystal formation keeps stable, measured by HPLC, its impurity number and total impurities also obviously do not increase, thus compared with DO raw material simultaneously, crystal form A has better package stability, can as the stable source of DO bulk drug.
embodiment 15
By rat glucose in urine excretion model determination DO crystal form A to the rejection ability of SGLT2.
The high sugar of normal SD rats height fat is fed after one month, with the repeatedly abdominal injection modeling of streptozocin low dose (diabetes B model), measures blood-sugar content before and after modeling.After modeling success, modeling rat is measured and body weight random packet (8/group) according to twenty-four-hour urine sugar, be respectively one group of blank group (giving equal-volume 0.5%CMC sodium solution) and testing compound group (10mg/kg).Fasting 16 hours before each group of rat experiment.After gavage gives the obtained DO crystal form A 0.5h of experimental rat embodiment 1, then gavage gives glucose (2g/kg).The urine of 0 ~ 12h time period after collection administration, with the urine sugar value of determination of glucose oxidase each time period.Experiment records crystal form A can induce generation 743mg glucose in urine/200g body weight in this experiment, illustrates that crystal form A has stronger glucose in urine and discharges ability.
Although present invention has been description to a certain degree, significantly, under the condition not departing from the spirit and scope of the present invention, can carry out the suitable change of each condition.Be appreciated that and the invention is not restricted to described embodiment, and be attributed to the scope of claim, it comprises the equivalent replacement of described each factor.
Claims (11)
1. (1S)-1, the crystal form A of 6-dideoxy-1-[4-methoxyl group-3-(trans-4-n-propyl cyclohexyl) aminomethyl phenyl]-D-Glucopyranose (DO), it is characterized in that, this crystal form X-ray powder diffraction charateristic avsorption band (2 θ) value is: 3.80,6.54,8.34,9.88,11.34,14.52,15.08,18.06,18.96,19.38,19.94,20.92,21.72,22.28; 2 θ measuring error are ± 0.2;
2. crystal form A according to claim 1, is characterized in that, described X-ray powder diffraction charateristic avsorption band (2 θ) and spacing d have following corresponding relation:
3. crystal form A according to claim 1 and 2, is characterized in that, described X-ray powder diffraction is as shown in Figure of description 2.
4. crystal form A according to claim 1 and 2, is characterized in that, described poor crystal form thermal analyses collection of illustrative plates has endotherm(ic)peak at 146 DEG C of places.
5. (1S)-1 as claimed in claim 1 or 2, the preparation method of the crystal form A of 6-dideoxy-1-[4-methoxyl group-3-(trans-4-n-propyl cyclohexyl) aminomethyl phenyl]-D-Glucopyranose, it is characterized in that, by (1S)-1,6-dideoxy-1-[4-methoxyl group-3-(trans-4-n-propyl cyclohexyl) aminomethyl phenyl]-D-Glucopyranose is dissolved in a kind of good solvent, slowly add a kind of poor solvent, stir lower crystallization, suction filtration, drying, obtain crystal form A.
6. preparation method according to claim 5, is characterized in that, described good solvent is acetic acid, acetone, methyl alcohol, ethanol, Virahol; Described poor solvent is water.
7. preparation method according to claim 5, is characterized in that, described good solvent is ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isopropyl acetate; Described poor solvent is normal hexane, hexanaphthene, isopropyl ether, ether, sherwood oil.
8. according to the arbitrary described preparation method of claim 5-7, it is characterized in that, described (1S)-1,6-the usage ratio of dideoxy-1-[4-methoxyl group-3-(trans-4-n-propyl cyclohexyl) aminomethyl phenyl]-D-Glucopyranose and good solvent and poor solvent be 1:5 ~ 10:3 ~ 30; Described ratio is quality-volume-volume ratio; Unit is g/mL/mL, is preferably 1:7:7.
9. a pharmaceutical composition, is characterized in that, described pharmaceutical composition includes the crystal form A as described in any one of claim 1 ~ 2 and one or more pharmaceutically acceptable auxiliary materials of effective amount.
10. pharmaceutical composition according to claim 9, is characterized in that, described pharmaceutical composition is solid orally ingestible, liquid oral medicine or injection; Preferably, described solid orally ingestible comprises dispersible tablet, enteric coated tablet, chewable tablet, orally disintegrating tablet, capsule or granule; Described liquid oral medicine comprises oral solution; Described injection comprises injection liquid drugs injection, injection freeze-dried powder, infusion solutions or primary infusion.
The purposes of crystal form A described in 11. claims 1 or 2 in the medicine for the preparation for the treatment of diabetes.
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| WO2021004388A1 (en) * | 2019-07-05 | 2021-01-14 | 山东丹红制药有限公司 | Crystal form of sglt inhibitor and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2021004388A1 (en) * | 2019-07-05 | 2021-01-14 | 山东丹红制药有限公司 | Crystal form of sglt inhibitor and application thereof |
| AU2020310274B2 (en) * | 2019-07-05 | 2022-09-29 | Shandong Danhong Pharmaceutical Co., Ltd. | Crystal form of SGLT inhibitor and application thereof |
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