CN109824723A - A kind of rosuvastain calcium intermediate novel crystal forms - Google Patents
A kind of rosuvastain calcium intermediate novel crystal forms Download PDFInfo
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- 239000013078 crystal Substances 0.000 title claims abstract description 94
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 title abstract description 7
- 229910052791 calcium Inorganic materials 0.000 title abstract description 7
- 239000011575 calcium Substances 0.000 title abstract description 7
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 28
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims abstract description 12
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims abstract description 9
- 230000005855 radiation Effects 0.000 claims abstract description 5
- 238000001228 spectrum Methods 0.000 claims abstract description 5
- CMSYDJVRTHCWFP-UHFFFAOYSA-N triphenylphosphane;hydrobromide Chemical compound Br.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 CMSYDJVRTHCWFP-UHFFFAOYSA-N 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 39
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 18
- 239000007787 solid Substances 0.000 claims description 17
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 3
- 125000001207 fluorophenyl group Chemical group 0.000 claims description 3
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 claims 1
- MVQVNTPHUGQQHK-UHFFFAOYSA-N 3-pyridinemethanol Chemical compound OCC1=CC=CN=C1 MVQVNTPHUGQQHK-UHFFFAOYSA-N 0.000 claims 1
- -1 dichloromethane Alkane Chemical class 0.000 claims 1
- 229940011051 isopropyl acetate Drugs 0.000 claims 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 3
- 230000007774 longterm Effects 0.000 abstract description 2
- 238000003860 storage Methods 0.000 abstract description 2
- 238000000113 differential scanning calorimetry Methods 0.000 description 13
- 238000002425 crystallisation Methods 0.000 description 8
- 230000008025 crystallization Effects 0.000 description 8
- 238000002411 thermogravimetry Methods 0.000 description 8
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 230000004584 weight gain Effects 0.000 description 6
- 235000019786 weight gain Nutrition 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 235000012000 cholesterol Nutrition 0.000 description 3
- TYRDEZUMAVRTEO-UHFFFAOYSA-N pyrimidin-5-ylmethanol Chemical compound OCC1=CN=CN=C1 TYRDEZUMAVRTEO-UHFFFAOYSA-N 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 2
- 208000035150 Hypercholesterolemia Diseases 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 238000007707 calorimetry Methods 0.000 description 2
- 238000009924 canning Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 101150102415 Apob gene Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 208000032928 Dyslipidaemia Diseases 0.000 description 1
- 208000017170 Lipid metabolism disease Diseases 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- GGEHQGAHLWFTET-UHFFFAOYSA-M [4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-propan-2-ylpyrimidin-5-yl]methyl-triphenylphosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)CC=1C(C(C)C)=NC(N(C)S(C)(=O)=O)=NC=1C1=CC=C(F)C=C1 GGEHQGAHLWFTET-UHFFFAOYSA-M 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000005260 alpha ray Effects 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 230000019771 cognition Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- RPGWZZNNEUHDAQ-UHFFFAOYSA-N phenylphosphine Chemical compound PC1=CC=CC=C1 RPGWZZNNEUHDAQ-UHFFFAOYSA-N 0.000 description 1
- PMOIAJVKYNVHQE-UHFFFAOYSA-N phosphanium;bromide Chemical compound [PH4+].[Br-] PMOIAJVKYNVHQE-UHFFFAOYSA-N 0.000 description 1
- 150000004714 phosphonium salts Chemical class 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- LALFOYNTGMUKGG-BGRFNVSISA-L rosuvastatin calcium Chemical compound [Ca+2].CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O.CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O LALFOYNTGMUKGG-BGRFNVSISA-L 0.000 description 1
- 229960004796 rosuvastatin calcium Drugs 0.000 description 1
- 239000002352 surface water Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6509—Six-membered rings
- C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of novel crystal forms and preparation method thereof of rosuvastain calcium intermediate [4- (4- fluorophenyl) -6- isopropyl -2- (N- methyl-N-methanesulfonamide base) -5- pyrimidine radicals] triphenylphosphinebromide, the crystal form using CuK α radiation, there are diffraction maximums at least at 7.475 ° ± 0.2 °, 8.626 ° ± 0.2 °, 9.414 ° ± 0.2 °, 10.753 ° ± 0.2 °, 11.382 ° ± 0.2 ° and 14.940 ° ± 0.2 ° for the XRPD spectrum that is indicated with 2 θ angles.The crystal form low in hygroscopicity, stability is good, convenient for long-term storage and transport.
Description
Technical field
The invention belongs to pharmaceutical synthesis fields, and in particular to a kind of rosuvastain calcium intermediate [4- (4- fluorophenyl) -6-
Isopropyl -2- (N- methyl-N-methanesulfonamide base) -5- pyrimidine radicals] triphenylphosphinebromide crystal form and preparation method thereof.
Background technique
Rosuvastain calcium (RosuvastatinCalcium) is a kind of statin developed by Yan Yeyi company of Japan
Class regulating plasma lipid medicine, belongs to HMG-CoA reductase inhibitor, can reduce raised low density cholesterol, total cholesterol, glycerol three
Ester and apoB concentration, raise simultaneously the concentration of high density cholesterol.It can be used for primary hypercholesterolemia and mixing
The complex treatment of type dyslipidemia and homozygous familial form hypercholesterolemia, referred to as superstatin.It is auspicious for synthesizing
Relaxing, to cut down a kind of important intermediate of statin calcium be [4- (4- fluorophenyl) -6- isopropyl -2- (N- methyl-N- shown in following formula I
Methylsulfonyl amido) -5- pyrimidine radicals] triphenylphosphinebromide, alias is 4- (4- fluorophenyl) -6- isopropyl -2- (N- methyl-N-
Methylsulfonyl amido) methyl-1-pyrimidine, 4- (4- fluorophenyl) -6- isopropyl -2- (N- methyl-N- methylsulphur in -5- triphenylphosphine
Acylamino-) pyrimidine -5- methyltriphenylphospbromide bromide object, cas number is CAS No.885477-83-8.
Compound I is a phosphonium salt, has certain hygroscopicity, easily deliquesces, be unfavorable for storing for a long time.Therefore, how to improve
The stability of compound I becomes a problem to be solved.
Summary of the invention
For drawbacks described above existing for existing compound I, inventor develops a kind of new crystal form by further investigation,
The stability for improving compound I, reduce its draw it is moist.Specifically, the present invention provides following technical solutions.
[4- (4- fluorophenyl) -6- isopropyl -2- (N- methyl-N-methanesulfonamide base) -5- is phonetic for compound shown in a kind of Formulas I
Piperidinyl] triphenylphosphinebromide crystal form, use CuK α radiation, X-ray powder diffraction (i.e. XRPD) light for indicating with 2 θ angles
Spectrum at least 7.475 ° ± 0.2 °, 8.626 ° ± 0.2 °, 9.414 ° ± 0.2 °, 10.753 ° ± 0.2 °, 11.382 ° ± 0.2 ° and
There are diffraction maximums at 14.940 ° ± 0.2 °
Preferably, above-mentioned crystal form at least 2 θ values be 7.475 ° ± 0.1 °, 8.626 ° ± 0.1 °, 9.414 ° ± 0.1 °,
There are diffraction maximums at 10.753 ° ± 0.1 °, 11.382 ° ± 0.1 ° and 14.940 ° ± 0.1 °；More preferable above-mentioned crystal form is at least in 2 θ
Value is at 7.475 ° ± 0.02 °, 8.626 ° ± 0.02 °, 9.414 ° ± 0.02 °, 10.753 ° ± 0.02 °, 11.382 ° ± 0.02 °
With 14.940 ° ± 0.02 ° at there are diffraction maximums；More preferable above-mentioned crystal form at least 2 θ values be 7.475 °, 8.626 °,
There are diffraction maximums at 9.414 °, 10.753 °, 11.382 ° and 14.940 °.
In one embodiment, above-mentioned crystal form also at least 2 θ values be 16.062 ° ± 0.2 ° and 24.745 ° ± 0.2 ° at
There are diffraction maximums；Also at least there are diffraction at 2 θ values is 16.062 ° ± 0.1 ° and 24.745 ° ± 0.1 ° for more preferable above-mentioned crystal form
Peak；Also at least there are diffraction maximums at 2 θ values is 16.062 ° ± 0.02 ° and 24.745 ° ± 0.02 ° for more preferable above-mentioned crystal form；More
It is preferred that also at least there are diffraction maximums at 2 θ values is 16.062 ° and 24.745 ° for above-mentioned crystal form.
In one embodiment, there is above-mentioned crystal form DSC as shown in Figure 2 to scheme.
In one embodiment, there is above-mentioned crystal form TGA as shown in Figure 3 to scheme.
In one embodiment, the water content of above-mentioned crystal form is 0.3wt%~10wt% with weight, excellent
It is selected as 1%~9%, preferably 2%~8%, more preferably 3%~7%.
The present invention also provides compound solids shown in a kind of Formulas I, wherein the weight percentage of above-mentioned crystal form is not less than
95%, preferably not less than 96%.
A method of compound solid shown in above-mentioned crystal form and/or above-mentioned Formulas I is prepared, is included the following steps: in triphen
In the presence of base phosphine, make compound 4- (4- fluorophenyl) -6- isopropyl -2- [(N- first shown in triphenylphosphine hydrobromate and Formula II
Base-N- methylsulfonyl) amino] pyrimidine -5- methanol heats reaction in a solvent, it is concentrated to dryness after completion of the reaction or filtering drying,
Up to the crystal form of compound shown in Formulas I,
In one embodiment, above-mentioned solvent is selected from water, tetrahydrofuran, acetonitrile, methylene chloride, toluene, acetic acid isopropyl
Ester, 1,2- dichloroethanes or their two or more mixtures.
In a preferred embodiment, triphenylphosphine hydrobromate and compound shown in Formula II in above-mentioned reaction system
Molar ratio be about 1:1.
In a preferred embodiment, a small amount of triphenylphosphine is added in above-mentioned reaction system, wherein triphenylphosphine
The molar ratio of hydrobromate and triphenylphosphine is 1:0.01~0.10.
Above-mentioned reaction step is substantially to carry out under heating condition in a solvent, and reaction condition is mild, easily controllable, because
And easy to operate, safety.
The compound of the present invention I novel crystal forms low in hygroscopicity, stability is good, convenient for long-term storage and transport, to reduce auspicious
It relaxes and cuts down the production cost of statin calcium.
Detailed description of the invention
Fig. 1 is the X-ray powder diffraction figure (XPRD figure) of a compound I crystal embodiment of the invention.
Fig. 2 is the differential scanning calorimetry figure (DSC figure) of a compound I crystal embodiment of the invention.Abscissa is
Temperature (DEG C)；Ordinate is heat flow (W/g).
Fig. 3 is the thermogravimetric analysis figure (TGA figure) of a compound I crystal embodiment of the invention.
Fig. 4 is the X-ray powder diffraction figure (XPRD figure) of anhydrous compound I solid.
Fig. 5 is the differential scanning calorimetry figure (DSC figure) of anhydrous compound I solid.Abscissa is temperature (DEG C)；Ordinate
It is heat flow (W/g).
Specific embodiment
The present invention is further explained by the following examples.It should be understood that these embodiments are only used for illustrating purpose, and
It is not limitation of the present invention.Those skilled in the art conceive the various changes or adjustment made to it according to the present invention, should all
It falls within the scope of protection of the present invention.
Additive amount, content and the concentration of many kinds of substance is referred to herein, wherein the percentage composition, except special instruction
Outside, all refer to mass percentage.
Certain chemical substances due to affected by various factors, change intramolecular or intermolecular bonding mode in crystallization
Become, causes molecule or atom to arrange in lattice vacancy different, form different crystal structures.Different crystal forms often have different
Physics, chemical property, such as the difference of fusing point, hardness, stability, rate of dissolution.Crystal form can be by X-ray powder diffraction (XPRD)
Spectrogram characterizes, and the XPRD figure of different crystal forms is different, the position of the diffraction maximum or absorption peak that are indicated with 2 θ angles and/
Or relative intensity (I/I0) can change.
[4- (4- fluorophenyl) -6- isopropyl -2- (N- methyl-N-methanesulfonamide base) -5- pyrimidine radicals] triphen of the invention
The X-ray powder diffraction figure of base bromide phosphine crystal form shows as diffraction maximum position i.e. 2 θ (°) of the angle of diffraction, interplanar distance dDiffraction
Peak relative intensity (I/I0), it is summarized in table 1.
The X-ray powder diffraction result of the crystal form of 1 compound I of table
Term " relative intensity " refers to that the intensity at the highest peak of intensity in all diffraction maximums of X-ray powder diffraction figure is
When 100%, the ratio of the intensity of the intensity and highest peak of intensity at other peaks.
It is well known that same a kind of crystal form sometimes, under different test conditions, X-ray powder diffraction figure can slightly not
Together.Influence X-ray powder diffraction figure effect because being known as: the purity of crystal, crystallization degree, powder sample itself particle it is big
Small, specimen holder filling powder sample amount, the powder packing surface smoothness etc. locating into specimen holder.
In a preferred embodiment, crystal form has the X substantially identical with X-ray powder diffraction spectrogram shown in Fig. 1
Ray powder diffraction pattern.
Term " substantially identical " refers at least 70% in X-ray powder diffraction figure, at least 80%, at least 90%, at least
95% or at least 99% peak appears in given exemplary X-ray powder diffraction spectrogram 1.
It should be understood that 2 θ values of X-ray powder diffraction figure can vary slightly between machine or between sample, numerical value
It may differ by about 0.2 unit (°), or about 0.1 unit (°) of difference, therefore cited numerical value cannot be construed to
Absolute value.It shall again be understood that the equally possible difference about 5% of the size of diffraction maximum relative intensity, or difference about 4%,
Perhaps difference about 3% perhaps difference about 2% or difference about 1%, therefore the XRPD trace being included in the present invention
(trace) intensity is illustrative, is not meant for absolutely relatively.
It should be understood that herein when state numerical characteristics, term " about " or this number represented by " about " referring to can be with
There are ± 5%, ± 4%, ± 3%, ± 2% or ± 1% error range or floating range.
As preferred embodiment, crystal form provided by the invention uses CuK α radiation, the X-ray powder that indicates with 2 θ angles
Last difraction spectrum at least 7.475 ° ± 0.05 °, 8.626 ° ± 0.05 °, 9.414 ° ± 0.05 °, 10.753 ° ± 0.05 °,
There are diffraction maximums at 11.382 ° ± 0.05 ° and 14.940 ° ± 0.05 °；More preferable above-mentioned crystal form is at least at 7.475 ° in 2 θ values
± 0.02 °, 8.626 ° ± 0.02 °, 9.414 ° ± 0.02 °, 10.753 ° ± 0.02 °, 11.382 ° ± 0.02 ° and 14.940 ° ±
There are diffraction maximums at 0.02 °；More preferable above-mentioned crystal form at least 2 θ values be 7.475 °, 8.626 °, 9.414 °, 10.753 °,
There are diffraction maximums at 11.382 ° and 14.940 °.
Further, as another preferred embodiment, above-mentioned crystal form provided by the invention using CuK α radiation, with
The X-ray powder diffraction spectrum that 2 θ angles indicate also at least is deposited at 2 θ values is 16.062 ° ± 0.05 ° and 24.745 ° ± 0.05 °
In diffraction maximum；Also at least there are diffraction at 2 θ values is 16.062 ° ± 0.02 ° and 24.745 ° ± 0.02 ° for more preferable above-mentioned crystal form
Peak；Also at least there are diffraction maximums at 2 θ values is 16.062 ° and 24.745 ° for more preferable above-mentioned crystal form.
When referring to data in map and/or figure, term " diffraction maximum " refers to that those skilled in the art will not belong to back
The characteristic peak of scape noise.
The study found that when compound I whether include the crystallization water and the crystallization water number will influence whether changing for crystal form
Become, this variation is reflected in X-ray powder diffraction (XRPD) spectrogram.For example, Fig. 4 is according to patent CN103570762A
The XRPD spectrogram of the few compound I solid of crystal water content prepared by embodiment 4, has obviously with Fig. 1 of crystal form of the present invention
Difference.Hereinafter, for the sake of for convenience of description, the compound I solid that will be prepared according to the embodiment 4 of patent CN103570762A is simple
Referred to as " anhydrous compound I solid ".It should be understood that terminology used herein " anhydrous " is merely representative of water content relative to of the invention brilliant
Type is smaller, does not imply that absolute, such as the knot of the compound I solid prepared according to patent CN103570762A embodiment 4
Brilliant water content is 0.18%, is significantly less than the water content of novel crystal forms of the invention.
Inventor is under study for action it was unexpectedly observed that as prepare compound I, if adding a small amount of three in the reaction system
Phenylphosphine, water content is 0.3wt%~10wt% in obtained crystal form, and the stability of the crystal form is consolidated compared to anhydrous compound I
Cognition greatly improves, draw it is moist substantially reduce, reason is up for further furtheing investigate.
The water content of crystal form of the present invention with weight be 0.3%~10%, preferably 0.5%~9%, it is more excellent
It is selected as 1%~8%, more preferably 3%~7%, more preferably 4%~7%, most preferably 3.0%~4.0%.If aqueous
Amount is lower than 0.3%, then hygroscopicity tends to increase；If water content is higher than 10%, easily absorption surface water.
The crystallization water in crystal form of the present invention is mainly derived from the moisture generated in reaction and/or aqueous solvent reaction
Moisture in system, because solvent can be water or water and organic solvent such as tetrahydrofuran, acetonitrile etc. in reaction system
Mixture.
It, herein will be existing in order to show the present invention and the difference between existing compound I solid and existing crystal form
Compound I solid be referred to as " anhydrous compound I solid " or " anhydrous crystal forms "；Correspondingly, referred to as by crystal form of the invention
For " aqueous crystal form ", " novel crystal forms " or " crystal form A ".
In the reaction system, wherein the molar ratio of triphenylphosphine hydrobromate and triphenylphosphine is 1:0.01~0.10, than
For example 1:0.01~0.08,1:0.01~0.06,1:0.02~0.05,1:0.02~0.04 or 1:0.02~0.03.
Herein, the term " triphenylphosphine " when crystal form is addressed, refers in particular to the triphenylphosphine of salt-independent shape, and do not include
Any salt form of triphenylphosphine.
The novel crystal forms are analyzed in addition, the present invention also passes through differential canning calorimetry, are using differential
When scanning Calorimetric Techniques are analyzed, show as when there are 1 endothermic peaks to exist in the DSC map that heating rate is 10 DEG C per minute
At 110~140 DEG C, DSC map is substantially as shown in Figure 2.It should be understood that and X-ray powder diffraction figure numerical value may have deviation
With similar situation, numerical value cited in differential canning calorimetry can not be construed to absolute value.
In a preferred embodiment, differential scanning calorimetry (DSC) spectrogram of crystal form of the present invention and Fig. 2 essence phase
Together.
The DSC map of crystal form of the present invention and the DSC map of anhydrous compound I solid have significant difference, and Fig. 5 is the latter's
DSC figure, endothermic peak is at about 240~247 DEG C.
Fig. 2 has shown that is sloughed an endothermic peak caused by the crystallization water, and the summit value of endothermic peak is 130 DEG C.Heat shown in Fig. 3
Weight analysis figure (TGA figure) shows there is 3.2% weightlessness within the scope of 100 DEG C to 150 DEG C, is caused by sloughing for water, further demonstrate,proves
The bright crystal form is hydrate crystal forms.In a preferred embodiment, thermogravimetric analysis (TGA) figure and Fig. 3 of crystal form of the present invention
It is substantially identical.
Crystal form of the invention be it is essentially pure, term " essentially pure " refers to the crystal form essentially free of it
His crystal form (such as the compound I crystalline solid form for not including the crystallization water), amorphous form (or amorphous form) or impurity ratio
Such as remaining reactant.Preferably, the purity of crystal form of the present invention be by weight percentage at least 91%, at least 92%, at least
93%, at least 94%, at least 95%, at least 96%, at least 97% at least 98%, at least 99%, more preferably 100%.
Drawing moist (i.e. hygroscopicity) is to influence a key factor of stability of crystal form.In the present invention, term " hygroscopicity "
" drawing moist ", " drawing wet " meaning are identical.By hygroscopicity test, i.e. water sucting isotherm measures, and can be used for determining polymorphic medicine
The opposite stability region of object especially hydrate.
Referring to 2010 editions annex of Chinese Pharmacopoeia to drug draws moist test guideline: deliquescing: absorbing enough moisture and formed
Liquid；It is great draw it is moist: draw wet weight gain not less than 15%；It is moist with drawing: to draw wet weight gain 2%-15%；Slightly draw moist: drawing
Wet weight gain 0.2%-2%；Nothing is moist almost without drawing: drawing wet weight gain less than 0.2%.
The present invention has carried out crystal form of the present invention (referred to as " crystal form A ") and has not been included in the room temperature environment of 80% relative humidity
The compound I crystalline solid form (referred to as " anhydrous crystal forms ") of the crystallization water draws moist comparative study, as the result is shown: within 14 days, nothing
Crystal type is moist with drawing；And crystal form of the present invention slightly draw it is moist.It can be seen that crystal form of the present invention draw than anhydrous crystal forms it is moist small, more
There is stability.
Embodiment
Reagent: reactant and catalyst used in the embodiment of the present invention are that chemistry is pure, be can be used directly or according to need
To pass through simple purification；Organic solvent etc. is that analysis is pure, is directly used.Reagent is purchased from Chinese Medicine (group) Shanghai chemistry
Reagent Company.
The anhydrous crystal forms of compound I are prepared according to the method that embodiment 4 in existing literature such as CN103570762A is reported,
And it is not limited to this.
Detection method and instrument:
X-ray powder diffraction:
Using CuK alpha ray, x-ray powder is carried out on Rigaku D/Max-2550PC X-ray powder diffraction instrument and is spread out
Penetrate analysis, measured power is 40kV × 250mA, 0.02 ° of 5 °/min of scanning speed, step width, the θ of 3~45 ° of scanning range (2 θ)~
2 θ continuous scannings.
Thermogravimetric analysis (TGA):
Using the SDT Q600 thermogravimetric analyzer of TA company, nitrogen speed be 120mL/min, 10 DEG C of heating rate/
Min, temperature from 20 DEG C gradually rise to 350 DEG C under conditions of measure.
Differential scanning calorimetry (DSC) characterization:
Analyzer is shown using TA company DSC Q100 differential thermal amount, nitrogen speed be 50mL/min, heating rate be 10 DEG C/
Min, temperature from 30 DEG C gradually rise to 300 DEG C under conditions of measure.
Embodiment 1
By 4- (4- the fluorophenyl) -6- isopropyl -2- [(N- methyl-N- methylsulfonyl) of 5g triphenylphosphine hydrobromate and 5g
Amino] pyrimidine -5- methanol (compound II), 0.1g triphenylphosphine, 100ml acetonitrile be added 250ml there-necked flask in, be heated to flowing back
Stirring, TLC tracking reaction.It is concentrated to dryness after completion of the reaction, obtains white solid, as compound I.Yield: 98%；Purity:
96.0%；Moisture content: 3.2wt%.
Embodiment 2
By 4- (4- the fluorophenyl) -6- isopropyl -2- [(N- methyl-N- methylsulfonyl) of 5g triphenylphosphine hydrobromate and 5g
Amino] pyrimidine -5- methanol (compound II), 0.1g triphenylphosphine, 100ml toluene be added 250ml there-necked flask in, be heated to flowing back
Stirring, TLC tracking reaction.It is down to room temperature after completion of the reaction, filters, drying obtains white solid, as compound I.Yield:
96%；Purity: 99.0%；Moisture content: 3.3wt%.
Embodiment 3-11
According to method shown in embodiment 1 or embodiment 2, by adjusting solvent type come prepare compound I containing crystal
Type, the results are shown in Table 1.Wherein, for mixed solvent, the ratio between different solvents is expressed as volume ratio.
The preparation of the 1 aqueous crystal form of compound I of table
Experiment shows that aqueous crystal form A of the invention can be obtained.The purity of crystal form A of the invention is all 93% or more, water
Point content is generally 3.0-3.5wt%.
12 hygroscopicity test of embodiment
Crystal form A and each 50mg of anhydrous crystal forms are taken respectively, is placed in the room temperature environment of 80% relative humidity, and dynamic water is carried out
(DVS) test is adsorbed, test result is as shown in table 2.
2 crystal form A of table and anhydrous crystal forms draw moist comparing result
The above results show: within 14 days, the wet weight gain of drawing of anhydrous crystal forms is 6.5%, moist with drawing；And crystal form A
Drawing wet weight gain is 0.26%, is slightly drawn moist.It can be seen that crystal form A draw than anhydrous crystal forms it is moist small, have more stability.
Claims (10)
1. a kind of [4- (4- fluorophenyl) -6- isopropyl -2- (N- methyl-N-methanesulfonamide the base) -5- pyrimidine of compound shown in Formulas I
Base] triphenylphosphinebromide crystal form, using CuK α radiation, at least existed with the X-ray powder diffraction spectrum that 2 θ angles indicate
7.475 ° ± 0.2 °, 8.626 ° ± 0.2 °, 9.414 ° ± 0.2 °, 10.753 ° ± 0.2 °, 11.382 ° ± 0.2 ° and 14.940 ° ±
There are diffraction maximums at 0.2 °
2. crystal form according to claim 1, which is characterized in that also at least 2 θ values be 16.062 ° ± 0.2 ° and 24.745 °
There are diffraction maximums at ± 0.2 °.
3. crystal form according to claim 1, which is characterized in that it is at least at 7.475 ° ± 0.02 °, 8.626 ° in 2 θ values
There are diffraction at ± 0.02 °, 9.414 ° ± 0.02 °, 10.753 ° ± 0.02 °, 11.382 ° ± 0.02 ° and 14.940 ° ± 0.02 °
Peak.
4. crystal form according to claim 3, which is characterized in that also at least 2 θ values be 16.062 ° ± 0.02 ° and
There are diffraction maximums at 24.745 ° ± 0.02 °.
5. crystal form according to claim 1, which is characterized in that its water content is 0.3wt%~10wt%.
6. crystal form according to claim 1, which is characterized in that its water content is 3wt%~7wt%.
7. compound solid shown in a kind of Formulas I, wherein the weight percentage of crystal form is not less than according to claim 1
95%.
8. the method for preparing crystal form according to claim 1, includes the following steps: to make triphen in the presence of triphenylphosphine
Base phosphine hydrobromate and (4- the fluorophenyl) -6- isopropyl of compound 4- shown in Formula II -2- [(N- methyl-N- methylsulfonyl) amino] are phonetic
Pyridine -5- methanol heats reaction in a solvent, is concentrated to dryness after completion of the reaction or filtering drying is to get compound shown in Formulas I
Crystal form
9. according to the method described in claim 8, it is characterized in that, the solvent is selected from water, tetrahydrofuran, acetonitrile, dichloromethane
Alkane, toluene, isopropyl acetate, 1,2- dichloroethanes or their two or more mixtures.
10. according to the method described in claim 8, it is characterized in that, being added with triphenylphosphine, wherein triphenyl in reaction system
The molar ratio of phosphine hydrobromate and triphenylphosphine is 1:0.01~0.10.
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| CN201711179414.5A CN109824723A (en) | 2017-11-23 | 2017-11-23 | A kind of rosuvastain calcium intermediate novel crystal forms |
| PCT/CN2018/116319 WO2019101053A1 (en) | 2017-11-23 | 2018-11-20 | New crystal form of rosuvastatin calcium intermediate |
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|---|---|---|---|---|
| CN1687087A (en) * | 2005-05-16 | 2005-10-26 | 浙江海正药业股份有限公司 | Method for preparing Rosuvastain and its intermediate |
| CN101376647A (en) * | 2007-08-31 | 2009-03-04 | 中山奕安泰医药科技有限公司 | Method for synthesizing rosuvastatin intermediate and rosuvastatin |
| CN102311457A (en) * | 2011-09-16 | 2012-01-11 | 苏州莱克施德药业有限公司 | Preparation method of rosuvastatin |
| CN103570762A (en) * | 2013-11-25 | 2014-02-12 | 复旦大学 | Preparation method of ((4-p-fluorophenyl-6-isopropyl-2-(N-methylmethanesulfonamide)-5-pyridyl) methyl)triphenyl phosphonium salt |
| CN104817505A (en) * | 2015-04-23 | 2015-08-05 | 南京博优康远生物医药科技有限公司 | Method of preparing N-[4-(4-fluorophenyl)-5-hydroxymethyl-6-isopropyl-pyrimidine-2-yl]-N-methylmethanesulfonamide |
| CN105175346A (en) * | 2015-05-19 | 2015-12-23 | 南京博优康远生物医药科技有限公司 | Method for synthesis of rosuvastatin calcium intermediate |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104529908B (en) * | 2014-12-12 | 2017-11-03 | 浙江京新药业股份有限公司 | A kind of preparation method of rosuvastain calcium |
-
2017
- 2017-11-23 CN CN201711179414.5A patent/CN109824723A/en active Pending
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- 2018-11-20 WO PCT/CN2018/116319 patent/WO2019101053A1/en active Application Filing
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1687087A (en) * | 2005-05-16 | 2005-10-26 | 浙江海正药业股份有限公司 | Method for preparing Rosuvastain and its intermediate |
| CN101376647A (en) * | 2007-08-31 | 2009-03-04 | 中山奕安泰医药科技有限公司 | Method for synthesizing rosuvastatin intermediate and rosuvastatin |
| CN102311457A (en) * | 2011-09-16 | 2012-01-11 | 苏州莱克施德药业有限公司 | Preparation method of rosuvastatin |
| CN103570762A (en) * | 2013-11-25 | 2014-02-12 | 复旦大学 | Preparation method of ((4-p-fluorophenyl-6-isopropyl-2-(N-methylmethanesulfonamide)-5-pyridyl) methyl)triphenyl phosphonium salt |
| CN104817505A (en) * | 2015-04-23 | 2015-08-05 | 南京博优康远生物医药科技有限公司 | Method of preparing N-[4-(4-fluorophenyl)-5-hydroxymethyl-6-isopropyl-pyrimidine-2-yl]-N-methylmethanesulfonamide |
| CN105175346A (en) * | 2015-05-19 | 2015-12-23 | 南京博优康远生物医药科技有限公司 | Method for synthesis of rosuvastatin calcium intermediate |
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