CN105523994A - Crystal form III of lomitapide mesylate - Google Patents
Crystal form III of lomitapide mesylate Download PDFInfo
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- CN105523994A CN105523994A CN201610075881.2A CN201610075881A CN105523994A CN 105523994 A CN105523994 A CN 105523994A CN 201610075881 A CN201610075881 A CN 201610075881A CN 105523994 A CN105523994 A CN 105523994A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The invention provides a crystal form III of lomitapide mesylate. An X-ray diffraction pattern of the crystal form comprises diffraction peaks obtained when a diffraction angle 2theta is equal to 9.912 degrees, 11.584 degrees, 14.651 degrees, 15.444 degrees, 17.416 degrees, 21.154 degrees and 21.984 degrees, and an error of 2theta is plus or minus 0.2 degrees. A preparation technology is stable and controllable and can be applied to industrial production, and the prepared crystal form III has good stability and can meet medicinal requirements of production, transportation and storage; the crystal form III has higher purity and lower impurity content, does not contain a residual solvent or contains fewer residual solvents and meets the requirement of related pharmaceutical product residual solvent limitation specified by national pharmacopoeia, so that the crystal can be better taken as a medicinal active ingredient for use.
Description
Technical field
The present invention relates to medicine new crystal, relate in particular to hypercholesterolemia medicine N-(2,2,2-trifluoroethyl)-9-[4-[4-[4,-(trifluoromethyl) [1,1 ,-biphenyl-2-base] formamido-] piperidin-1-yl] butyl] new crystal and preparation method thereof of-9-H-fluorenyl-9-carboxamide mesylate salt (methylsulfonic acid Lome he group).
Background technology
Methylsulfonic acid Lome he send (Lomitapidemesylate) to be oral small molecules MTP (MTP) inhibitor developed by Aegerion company, in December, 2012 ratifies listing by U.S. FDA, commodity are called Lojuxda, be used for the treatment of hypercholesterolia, comprise primary hypercholesterolemia and familial form hypercholesterolemia.Its chemistry N-(2 by name, 2,2-trifluoroethyl)-9-[4-[4-[4,-(trifluoromethyl) [1,1,-biphenyl-2-base] formamido-] piperidin-1-yl] butyl]-9-H-fluorenyl-9-carboxamide mesylate salt, shown in structural formula following (I).
Patent of invention WO2015121877 describes methylsulfonic acid Lome, and he sends the preparation of unformed powder.Due to the problem of unformed powder in pharmaceutical preparation in possibility existence and stability, can colour-change be there is in preservation process, and easily occur that content declines, the situation that impurity increases, cause the problem that permanent stability are not good.
Document " Du Xinming, the synthesis " J " of his group of methylsulfonic acid Lome. Chinese Journal of Pharmaceuticals, 2014,45 (9) " his group of Lome is added in alcohol solvent, be warming up to 60 DEG C, slowly drip methylsulfonic acid heating reflux reaction, be cooled to room temperature, leave standstill, separate out white solid methylsulfonic acid Lome he group.We repeatedly repeat above method and obtain white solid, and test the collection of illustrative plates that obtains without characteristic feature peak through XRD, this white solid structure is undefined structure.
Document " Zhang Xuyang, the improvement in synthesis " J " of his group of methylsulfonic acid Lome. synthetic chemistry, 2015,23 (5) 445 ~ 448. " a kind of method is disclosed, in three-necked bottle, add his group of Lome, methylsulfonic acid and methyl alcohol successively, in room temperature reaction under stirring, decompression steams solvent and obtains white solid, m.p.129 DEG C-138 DEG C, purity 99.2% (HPLC).We are repeatedly repeated this experimental technique, cannot crystallize out, adopt and are cooled to 25 DEG C ~-15 DEG C, leave standstill or stir the Crystallization method of 1 ~ 15h, all can not separate out solid.After adopting into mesylate, the method for direct vacuum rotary steam obtains thick solid, not easily washs.Vacuum-drying obtains white powder, and it is that about 99%, XRD detection collection of illustrative plates and accompanying drawing 3 peak shape are similar that HPLC detects purity, and this white solid structure is undefined structure.
Unformed is metastable structure on a kind of thermodynamics, the present inventor adopts the trimethyl carbinol to be that he sends raw material to carry out dissolving cooling precipitation solid to solvent to methylsulfonic acid Lome, filtration washing drying obtains unformed powder, after it is preserved 1h and 60h at 0 DEG C, test sample XRD figure spectrum respectively, see Figure of description 3 and Figure of description 4.
In general, solid pharmaceutical molecule has the multiple crystal habit such as polycrystalline, eutectic; The different crystal forms of same drug molecule may there were significant differences in crystalline structure, stability, producibility and bioavailability etc., thus directly affect curative effect and the exploitability of medicine.Therefore, drug crystal forms research is extremely important in drug research and development industry, and this area is needed badly and found purity is high, stability good, solubility property is excellent, suitability for industrialized is produced his Cefpirome Culfate crystal formation of methylsulfonic acid Lome and develop its preparation technology.
Summary of the invention
The object of this invention is to provide new crystal III of his group of methylsulfonic acid Lome and preparation method thereof.
Content of the present invention is described in detail as follows:
The crystal form II I of his group of a kind of methylsulfonic acid Lome, the x-ray diffraction pattern of this crystallized form has the diffraction peak being included in diffraction angle 2 θ: 9.912 degree, 11.584 degree, 14.651 degree, 15.444 degree, 17.416 degree, 21.154 degree, 21.984 degree, and 2 θ errors are ± 0.2 degree.
In a kind of scheme, methylsulfonic acid Lome he send crystal form II I to have the peak form characteristics shown in Figure of description 1, diffraction angle (2 θ), spacing (d) and relative intensity (%) are as following table:
Table 1
Methylsulfonic acid Lome he send in the DSC thermogram of crystal form II I, start at 123.24 DEG C of places melt, have the endotherm(ic)peak that is sharp-pointed near 129.45 DEG C, fusing point is about 123 DEG C, described DSC temperature rise rate 10 DEG C/min.
He sends the preparation method of crystal form II I to present invention also offers methylsulfonic acid Lome, comprises following steps:
(1) his group of raw material methylsulfonic acid Lome is added heating for dissolving in acetonitrile solvent;
(2) cooling or concentrated solvent separate out methylsulfonic acid Lome he send crystal III.
Further, his group of methylsulfonic acid Lome is 1:7 ~ 15 with the mass ratio of acetonitrile, preferred 1:10 ~ 12.
The method of recrystallization is not particularly limited, and can be undertaken by common recrystallization operation method.Such as, can with his group of raw material methylsulfonic acid Lome after acetonitrile heating for dissolving slowly cooling leave standstill crystallization, or direct solvent evaporated after heating for dissolving, also can take stirring and crystallizing, after crystallization completes, after filtration, washing, drying, required crystallization can be obtained.The xln of institute's leaching usually under reduced pressure, at about 30 ~ 100 DEG C, preferably carries out vacuum-drying under the heating condition of 40 ~ 60 DEG C, just can reach the effect of removal recrystallization solvent.
In a kind of scheme, by raw material methylsulfonic acid Lome he group join in acetonitrile, heat more than 50 DEG C clearly molten.Then be cooled to 0-5 DEG C of cooling crystallization 2-3h, he sends crystal form II I to obtain methylsulfonic acid Lome.
Measured by differential scanning calorimeter (DSC), X ray diffracting spectrum, to the methylsulfonic acid Lome obtained, he sends crystal III to carry out crystal formation research, detects the dissolvent residual of gained crystallization simultaneously.
The methylsulfonic acid Lome of preparing according to method of the present invention he send crystal form II I not containing or only containing the acetonitrile residual solvent of lower aq, meet the limitation requirement of the relevant pharmaceutical prod residual solvent of state-promulgated pharmacopoeia regulation.
The purity measuring he crystal form II I of methylsulfonic acid Lome through efficient liquid-phase chromatography method (HPLC) is more than 99.7%, maximum single contaminant is less than 0.1%, the method methylsulfonic acid Lome of preparing he send crystal form purity high, be conducive to the preparation of high purity chemicals.
The methylsulfonic acid Lome adopting accelerated test to prepare the present invention he send crystal III to carry out stability study, find that this crystal formation has excellent chemical stability, crystal formation is remaining unchanged through hot and humid environment accelerated test, has and stores preferably and processing stability.
Lome he group crude product prepare reference US5712279A method obtain.
He sends crystal formation I powder solid embodiment 2 to be prepared methylsulfonic acid Lome, carry out XRD detection, XRD figure spectrum is as shown in Figure of description 2, and characteristic of correspondence diffraction angle (2 θ), spacing (d) are as shown in the table with relative intensity (%):
Table 2
Method with reference to embodiment 4 prepares methylsulfonic acid Lome, and he sends unformed powder, by itself and methylsulfonic acid Lome, he sends crystal form II I powder respectively with 1:3 simultaneously, the mass ratio of 1:1 and 3:1 mixes, carry out XRD detection, its peak form characteristics and methylsulfonic acid Lome he send the XRD figure of crystal form II I to be composed all to have bigger difference, wherein methylsulfonic acid Lome he send his XRD figure of sending the sample test of crystal form II I powder 1:1 physical mixed to obtain of unformed powder and methylsulfonic acid Lome to compose as shown in Figure of description 5, characteristic of correspondence diffraction angle (2 θ), spacing (d) is as shown in the table with relative intensity (%):
Table 3
For the crystal formation of the same race of same compound, its X-ray diffractogram has similarity on the whole, characterizes the d value error of peak position generally within ± 2%, and most of error can not exceed ± 2%, and relative intensity error may comparatively greatly, but variation tendency is consistent.In addition, in the qualification of mixture, because degradation factor under content can cause portion diffracts line to lack, now, without the need to relying in high-purity sample the whole bands of a spectrum observed, even bands of a spectrum may be also distinctive to given crystallization.When determining diffraction angle 2 θ of the powder x-ray diffraction collection of illustrative plates in specification sheets of the present invention and claims, the value of gained be interpreted as this value ± scope of 1.0 degree in, better in the scope of this value ± 0.2 degree, described powder x-ray diffraction figure is the collection of illustrative plates obtained with CuK alpha-ray.Fusing point in DSC thermogram, the value of gained be interpreted as this value ± scopes of 3.0 DEG C of degree in, better in the scope of this value ± 1 DEG C.
Term " multi-crystalline compounds " refers to the different crystal forms of same compound and includes but not limited to comprise the hydrate (such as: there is the Bound moisture in crystalline texture) of same compound and other solid state molecular forms of solvate (such as: than water other is in conjunction with solvent).The phenomenon that same drug molecule forms multiple crystal formation is called polymorph in pharmaceuticals, and polymorph in pharmaceuticals is ubiquitous phenomenon in solid pharmaceutical.
Term " powder x-ray diffraction collection of illustrative plates " (be called for short XRD) refer to experimental observation to diffractogram or be derived from its parameter.Powder x-ray diffraction collection of illustrative plates is characterized by peak position and peak intensity.
In XRD figure spectrum, " intensity, CPS " is writing a Chinese character in simplified form of " intensityintegrationcountspersecond ", represents diffraction peak intensity.
Accompanying drawing explanation
He sends the powder x-ray diffraction figure of crystal form II I to Figure 1 shows that methylsulfonic acid Lome of the present invention.The longitudinal axis represents peak intensity, and transverse axis represents diffraction angle (2 θ).
He sends the powder x-ray diffraction figure of crystal formation I to Figure 2 shows that methylsulfonic acid Lome of the present invention.The longitudinal axis represents peak intensity, and transverse axis represents diffraction angle (2 θ).
He sends the powder x-ray diffraction figure of 1h test after unformed powder preparation to Figure 3 shows that methylsulfonic acid Lome of the present invention.The longitudinal axis represents peak intensity, and transverse axis represents diffraction angle (2 θ).
Figure 4 shows that methylsulfonic acid Lome of the present invention he send unformed powder preparation after place 60h test powder x-ray diffraction figure.The longitudinal axis represents peak intensity, and transverse axis represents diffraction angle (2 θ).
He sends his XRD figure of sending the sample test of crystal form II I powder 1:1 physical mixed to obtain of unformed powder and methylsulfonic acid Lome to be composed to Figure 5 shows that methylsulfonic acid Lome.
He sends the DSC thermogram of crystal form II I to Figure 6 shows that methylsulfonic acid Lome.The longitudinal axis represents mW/mg, and transverse axis represents temperature DEG C.
The invention provides new crystal III of his group of methylsulfonic acid Lome and preparation method thereof.Stable preparation process of the present invention is controlled, can be adapted to suitability for industrialized production, the crystal form II I obtained is good at the condition stability inferior of illumination, high temperature, high humidity, and under grinding, pressure and the condition such as to be heated, stability of crystal form is good, can meet the medicinal requirements that production and transport stores; The crystal form II I purity that the present invention obtains is higher, foreign matter content is less, do not contain or only contain the residual solvent of lower aq, meet the limitation requirement of the relevant pharmaceutical prod residual solvent of state-promulgated pharmacopoeia regulation, thus crystallization of the present invention can use as medicating active ingredients preferably.
Embodiment
Following examples further describe the present invention, but these embodiments are only for illustration of the present invention, instead of limitation of the scope of the invention.
Embodiment 1 Lome he send the preparation of (compound VI II)
Weigh Compound IV51g (1.1eq), VII57g (1.0eq), in single port bottle, add the DMF of salt of wormwood 36g (2.0eq) and 1000ml, stirring reaction 24h at 50 DEG C.Reaction terminates, and process obtains white crude.74g product VIII is obtained after vacuum-drying.
Embodiment 2 methylsulfonic acid Lome he send the preparation of crystal formation I
By Lome, he sends 10g to join in the isopropyl acetate of 120ml, heat more than 50 DEG C clearly molten.Add 1.49g methylsulfonic acid stirring reaction and be about 1h, be cooled to 0-5 DEG C of cooling crystallization 2-3h.Suction filtration, collect crystal in 50 DEG C of vacuum-drying 24h, he sends powder solid I crystal 10.3g to obtain methylsulfonic acid Lome, (yield 90%).HPLC detects purity 99.93%.
1H-NMR(400MHz，CDCl3)δ0.811(2H，m)，1.69(2H，m)，1.78(2H，d)，2.43(2H，m)，2.56(2H，m)，2.69(2H，s)，3.42(2H，d)，3.70(2H，m)，3.95(2H，m)，5.38(2H，t)，6.19(2H，d)，7.38(2H，m)，7.65(2H，d)，7.79(2H，d)，10.34(2H，s)。
Embodiment 3 methylsulfonic acid Lome he send the preparation of crystal form II I
By methylsulfonic acid Lome of embodiment 2 gained, he sends (1g) to add in 10ml acetonitrile solvent and is heated to about 50 DEG C stirring and dissolving; Be cooled to 0 ~ 5 DEG C; Stir 3h, separate out solid.Suction filtration, consider cake acetonitrile wash, 50 DEG C of vacuum-drying 24h obtain white solid (0.96g), and XRD is detected as crystal form II I.HPLC detects purity 99.95%.
Embodiment 4 methylsulfonic acid Lome he send unformed powder
By gained methylsulfonic acid Lome in embodiment 2, he sends the trimethyl carbinol of powder 0.1g and 1mL to mix, heat more than 50 DEG C molten clear after be cooled to 0 DEG C; Stir 3h, separate out solid, suction filtration, consider the cake trimethyl carbinol and wash, 50 DEG C of vacuum-drying 24h gained solid 0.09g, detect without sharp-pointed charateristic avsorption band through XRD, powder is unformed solid.
Embodiment 5 methylsulfonic acid Lome he send crystal form II I stability study
Crystal form II I pressed powder embodiment 3 prepared is uncovered divides placement, investigates at illumination (4500Lx), heating (40 DEG C, 60 DEG C), the stability of sample under high humidity (RH75%, RH90%) condition.Investigating sample time is 5 days and 10 days, and HPLC detects purity and sees the following form.
Table 4
Study on the stability result shows methylsulfonic acid Lome, and he sends crystal form II I crystallized sample under the condition of uncovered placement, study on the stability result display under illumination, high temperature and super-humid conditions, under high humidity and illumination condition, having good stability of product, under the high temperature conditions, product has degraded trend, and prompting should shady and cool or cryopreservation.
Embodiment 6 methylsulfonic acid Lome he send crystal form II I stability study
Crystal form II I pressed powder embodiment 3 prepared carries out grinding and compressing tablet process, and result of study shows stable crystal form, and detailed experimental data sees table.
Table 5
Test-results: through stability test process, finding that the main 2 θ angles of crystal form II I all noticeable change do not occur, there is not considerable change in crystal formation kind and fusing point, illustrates that this product stability of crystal form is better, and not easily occur to turn brilliant, the processing stability of crystal formation is better.
Claims (2)
1. the crystal form II I of his group of methylsulfonic acid Lome, it is characterized in that the x-ray diffraction pattern of this crystallized form has the diffraction peak being included in diffraction angle 2 θ: 9.912 degree, 11.584 degree, 14.651 degree, 15.444 degree, 17.416 degree, 21.154 degree, 21.984 degree, 2 θ errors are ± 0.2 degree, and described powder x-ray diffraction figure is the collection of illustrative plates obtained with CuK alpha-ray.
2. a preparation method of the crystal form II I of his group of methylsulfonic acid Lome, is characterized in that comprising following steps:
(1) his group of raw material methylsulfonic acid Lome is added heating for dissolving in acetonitrile solvent;
(2) cooling or concentrated solvent separate out methylsulfonic acid Lome he send crystal III.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111187200A (en) * | 2020-04-09 | 2020-05-22 | 南京昊绿生物科技有限公司 | Synthesis method of lomitapide-D8 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998003069A1 (en) * | 1996-07-24 | 1998-01-29 | Bristol-Myers Squibb Company | Method for lowering serum lipid levels employing an mtp inhibitor in combination with another cholesterol lowering drug |
| CN103690960A (en) * | 2013-12-18 | 2014-04-02 | 北京科源创欣科技有限公司 | Lomitapide mesylate medicinal composition and preparation method thereof |
| WO2015121877A2 (en) * | 2014-02-17 | 2015-08-20 | Hetero Research Foundation | Polymorphs of lomitapide and its salts |
| WO2016012934A1 (en) * | 2014-07-21 | 2016-01-28 | Mylan Laboratories Ltd | Process for making lomitapide mesylate |
-
2016
- 2016-02-03 CN CN201610075881.2A patent/CN105523994B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998003069A1 (en) * | 1996-07-24 | 1998-01-29 | Bristol-Myers Squibb Company | Method for lowering serum lipid levels employing an mtp inhibitor in combination with another cholesterol lowering drug |
| CN103690960A (en) * | 2013-12-18 | 2014-04-02 | 北京科源创欣科技有限公司 | Lomitapide mesylate medicinal composition and preparation method thereof |
| WO2015121877A2 (en) * | 2014-02-17 | 2015-08-20 | Hetero Research Foundation | Polymorphs of lomitapide and its salts |
| WO2016012934A1 (en) * | 2014-07-21 | 2016-01-28 | Mylan Laboratories Ltd | Process for making lomitapide mesylate |
Non-Patent Citations (5)
| Title |
|---|
| SVETOSLAV H. SLAVOV,等: "Computational identification of a phospholipidosis toxicophore using 13C and 15N NMR-distance based fingerprints", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
| 张旭阳,等: "家族性高胆固醇血症治疗新药甲磺酸洛美他派", 《中国新药杂志》 * |
| 张旭阳,等: "甲磺酸洛美他派的合成工艺改进", 《合成化学》 * |
| 杜鑫明,等: "甲磺酸洛美他派的合成", 《中国医药工业杂志》 * |
| 潘卫三: "《工业药剂学(第3版)》", 31 August 2015, 中国医药科技出版社 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111187200A (en) * | 2020-04-09 | 2020-05-22 | 南京昊绿生物科技有限公司 | Synthesis method of lomitapide-D8 |
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