WO2019101053A1 - 一种瑞舒伐他汀钙中间体新晶型 - Google Patents

一种瑞舒伐他汀钙中间体新晶型 Download PDF

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WO2019101053A1
WO2019101053A1 PCT/CN2018/116319 CN2018116319W WO2019101053A1 WO 2019101053 A1 WO2019101053 A1 WO 2019101053A1 CN 2018116319 W CN2018116319 W CN 2018116319W WO 2019101053 A1 WO2019101053 A1 WO 2019101053A1
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crystal form
compound
crystalline form
triphenylphosphine
form according
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French (fr)
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汪博宇
邱卓
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上虞京新药业有限公司
上海京新生物医药有限公司
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    • 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

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  • the invention belongs to the field of drug synthesis, and particularly relates to a rosuvastatin calcium intermediate [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonamide) Crystal form of -5-pyrimidinyl]triphenylphosphonium bromide and a process for the preparation thereof.
  • Rosuvastatin Calcium is a statin lipid regulating drug developed by Japan Yanyeyi Co., Ltd., which belongs to HMG-CoA reductase inhibitor and can reduce elevated low density cholesterol, total cholesterol and triglycerides. And apoprotein B concentration, while increasing the concentration of high density cholesterol. It can be used as a comprehensive treatment for primary hypercholesterolemia and mixed lipodystrophy and homozygous familial hypercholesterolemia. It is called super statin.
  • An important intermediate for the synthesis of rosuvastatin calcium is [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methyl) represented by the following formula I.
  • Sulfonamide)-5-pyrimidinyl]triphenylphosphonium bromide the alias of which is 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonamide -5-triphenylphosphine indole methyl-1-pyrimidine, 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidine- 5-methyltriphenyl bromide, CAS number is CAS No. 885477-83-8.
  • Compound I is a kind of cerium salt, which has certain hygroscopicity and is deliquescent, which is not conducive to long-term storage. Therefore, how to improve the stability of the compound I becomes a problem to be solved.
  • the inventors have intensively studied to develop a new crystal form, which improves the stability of the compound I and reduces the wettability thereof.
  • the present invention provides the following technical solutions.
  • a compound of formula I [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonamido)-5-pyrimidinyl]triphenyl bromide a crystalline form of phosphine using CuK ⁇ radiation, X-ray powder diffraction (ie, XRPD) spectrum expressed in 2 ⁇ angles of at least 7.475 ° ⁇ 0.2 °, 8.626 ° ⁇ 0.2 °, 9.414 ° ⁇ 0.2 °, 10.753 ° ⁇ 0.2 °, Diffraction peaks at 11.382° ⁇ 0.2° and 14.940° ⁇ 0.2°
  • the above crystal form has diffraction at least at 2 ⁇ values of 7.475° ⁇ 0.1°, 8.626° ⁇ 0.1°, 9.414° ⁇ 0.1°, 10.753° ⁇ 0.1°, 11.382° ⁇ 0.1°, and 14.940° ⁇ 0.1°. More preferably, the above crystal form exists at least at 2 ⁇ values of 7.745° ⁇ 0.02°, 8.626° ⁇ 0.02°, 9.414° ⁇ 0.02°, 10.753° ⁇ 0.02°, 11.382° ⁇ 0.02°, and 14.940° ⁇ 0.02°. Diffraction peaks; more preferably, the above crystal forms have diffraction peaks at least at 2 ⁇ values of 7.475°, 8.626°, 9.414°, 10.753°, 11.382°, and 14.940°.
  • the above crystal form further has a diffraction peak at least at a 2 ⁇ value of 16.062° ⁇ 0.2° and 24.745° ⁇ 0.2°; more preferably, the above crystal form is further at least at a 2 ⁇ value of 16.062° ⁇ 0.1° and 24.745 There is a diffraction peak at ° ⁇ 0.1°; more preferably, the above crystal form also has a diffraction peak at least at a 2 ⁇ value of 16.062° ⁇ 0.02° and 24.745° ⁇ 0.02°; more preferably, the above crystal form is at least at a 2 ⁇ value of 16.062° and There is a diffraction peak at 24.745°.
  • the above crystalline form has a DSC pattern as shown in FIG.
  • the above crystal form has a TGA pattern as shown in FIG.
  • the crystalline form has a water content of from 0.3% by weight to 10% by weight, preferably from 1% to 9%, preferably from 2% to 8%, more preferably from 3% to 7% by weight. %.
  • the present invention also provides a solid of the compound of the formula I, wherein the above crystalline form has a weight percentage of not less than 95%, preferably not less than 96%.
  • a process for the preparation of the above crystalline form and/or a solid of the compound of formula I above comprising the step of reacting triphenylphosphine hydrobromide with a compound of formula II 4- in the presence of triphenylphosphine 4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonyl)amino]pyrimidine-5-methanol is heated in a solvent, and after concentration, it is concentrated to dryness or filtered. Drying, that is, the crystal form of the compound represented by formula I,
  • the solvent is selected from the group consisting of water, tetrahydrofuran, acetonitrile, dichloromethane, toluene, isopropyl acetate, 1,2-dichloroethane, or a mixture of two or more thereof.
  • the molar ratio of triphenylphosphine hydrobromide to the compound of formula II in the above reaction system is about 1:1.
  • a small amount of triphenylphosphine is added to the above reaction system, wherein the molar ratio of triphenylphosphine hydrobromide to triphenylphosphine is from 1:0.01 to 0.10.
  • the above reaction step is basically carried out under heating in a solvent, the reaction conditions are mild, easy to control, and thus the operation is simple and safe.
  • the novel crystal form of the compound I of the invention has low wettability, good stability, and is convenient for long-term storage and transportation, thereby reducing the production cost of rosuvastatin calcium.
  • Figure 1 is an X-ray powder diffraction pattern (XPRD pattern) of a crystalline form of a compound of the present invention.
  • Figure 2 is a differential scanning calorimetry (DSC chart) of a crystalline form of Compound I of the present invention.
  • the abscissa is the temperature (°C); the ordinate is the heat flux (W/g).
  • FIG. 3 is a thermogravimetric analysis (TGA diagram) of a crystalline form of Compound I of the present invention.
  • Figure 4 is an X-ray powder diffraction pattern (XPRD pattern) of an anhydrous Compound I solid.
  • Figure 5 is a differential scanning calorimetry (DSC chart) of an anhydrous Compound I solid.
  • the abscissa is the temperature (°C); the ordinate is the heat flux (W/g).
  • crystal form can be characterized by X-ray powder diffraction (XPRD) spectrogram.
  • XPRD X-ray powder diffraction
  • the XPRD patterns of different crystal forms are different.
  • the position and / or relative intensity (I/I 0 ) of the diffraction peak or absorption peak expressed in 2 ⁇ angle will be no change.
  • relative intensity refers to the ratio of the intensity of the other peaks to the intensity of the peak having the highest intensity when the intensity of the highest intensity peak among all the diffraction peaks of the X-ray powder diffraction pattern is 100%.
  • the X-ray powder diffraction pattern will be slightly different.
  • the factors affecting the X-ray powder diffraction pattern are: the purity of the crystal, the degree of crystallization, the size of the powder sample itself, the sample volume of the sample holder, and the surface flatness of the powder loaded into the sample holder.
  • the crystalline form has substantially the same X-ray powder diffraction pattern as the X-ray powder diffraction pattern shown in FIG.
  • substantially identical means that at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% of the peaks in the X-ray powder diffraction pattern are present in the exemplary X-ray powder diffraction pattern given. 1 in.
  • the 2 ⁇ value of the X-ray powder diffraction pattern may vary slightly between machines, or between samples, and the values may differ by about 0.2 units (°), or by a difference of about 0.1 units (°), so The value cannot be interpreted as an absolute value.
  • the magnitude of the relative intensity of the diffraction peaks may also differ by about 5%, or by about 4%, or by about 3%, or by about 2%, or by about 1%, so that the XRPD traces included in the present invention are therefore included.
  • the intensity of the trace is illustrative and is not intended for absolute comparison.
  • the crystal form provided by the present invention uses CuK ⁇ radiation, and the X-ray powder diffraction spectrum expressed by 2 ⁇ angle is at least 7.745° ⁇ 0.05°, 8.626° ⁇ 0.05°, 9.414° ⁇ 0.05°, 10.753° ⁇ 0.05.
  • the above crystal forms are at least 2 ⁇ values of 7.745 ° ⁇ 0.02 °, 8.626 ° ⁇ 0.02 °, 9.414 ° ⁇ 0.02 °, 10.753 ° ⁇
  • Diffraction peaks are present at 0.02°, 11.382° ⁇ 0.02°, and 14.940° ⁇ 0.02°; more preferably, the above crystal forms are diffracted at least at 2 ⁇ values of 7.745°, 8.626°, 9.414°, 10.753°, 11.382°, and 14.940°. peak.
  • the above crystal form provided by the present invention uses CuK ⁇ radiation, and the X-ray powder diffraction spectrum expressed by 2 ⁇ angle is at least at 2 ⁇ values of 16.062° ⁇ 0.05° and 24.745° ⁇ 0.05°. There is a diffraction peak at present; more preferably, the crystal form further has a diffraction peak at least at a 2 ⁇ value of 16.062° ⁇ 0.02° and 24.745° ⁇ 0.02°; more preferably, the above crystal form is present at least at a 2 ⁇ value of 16.062° and 24.745°. Diffraction peaks.
  • diffrradiation peak when referring to data in a map and/or graph refers to a characteristic peak that would not be attributed to background noise by those skilled in the art.
  • Figure 4 is an XRPD spectrum of a compound I solid having a very small amount of water of crystallization prepared in accordance with Example 4 of the patent CN 103570762 A, which is significantly different from Figure 1 of the crystal form of the present invention.
  • the compound I solid prepared according to Example 4 of the patent CN103570762A is simply referred to as "anhydrous compound I solid".
  • anhydrous as used herein merely means that the water content is small relative to the crystal form of the present invention, and does not mean that it is absolutely anhydrous.
  • the solid water content of the compound I prepared according to Example 4 of the patent CN103570762A is 0.18. % is much lower than the water content of the new crystal form of the present invention.
  • the inventors have unexpectedly discovered in the study that when the compound I is prepared, if a small amount of triphenylphosphine is added to the reaction system, the obtained crystal form has a water content of 0.3% by weight to 10% by weight, and the stability of the crystal form is obtained. Compared with the anhydrous compound I, the solid content is greatly improved, and the wettability is greatly reduced. The reason for further study is to be further studied.
  • the water content of the crystalline form of the present invention is from 0.3% to 10% by weight, preferably from 0.5% to 9%, more preferably from 1% to 8%, still more preferably from 3% to 7%, still more preferably 4% by weight. From % to 7%, most preferably from 3.0% to 4.0%. If the water content is less than 0.3%, the hygroscopicity tends to increase; if the water content is more than 10%, the surface water is easily adsorbed.
  • the water of crystallization in the crystal form of the present invention is mainly derived from moisture generated in the reaction, and/or moisture in the aqueous solvent reaction system, because the solvent in the reaction system may be water or a mixture of water and an organic solvent such as tetrahydrofuran, acetonitrile or the like.
  • the existing compound I solid is referred to herein as "anhydrous compound I solid” or “no crystal type”;
  • the crystal form of the present invention is simply referred to as “crystal-containing type", “new crystal form”, or “crystal form A”.
  • the molar ratio of triphenylphosphine hydrobromide to triphenylphosphine is 1:0.01 to 0.10, for example, 1:0.01 to 0.08, 1:0.01 to 0.06, 1:0.02 to 0.05, 1 : 0.02 to 0.04 or 1:0.02 to 0.03.
  • triphenylphosphine when referring to a crystalline form, especially refers to triphenylphosphine in a non-salt form, and does not comprise any salt form of triphenylphosphine.
  • the present invention also analyzes the new crystal form by differential scanning calorimetry, and when analyzed by differential scanning calorimetry, it appears to exist in the DSC spectrum at a heating rate of 10 ° C per minute.
  • One endothermic peak is at 110-140 ° C, and its DSC spectrum is basically as shown in Figure 2. It should be understood that there may be similarities with the X-ray powder diffraction pattern values, and the values quoted by differential scanning calorimetry cannot be interpreted as absolute values.
  • the differential scanning calorimetry (DSC) spectrum of the crystalline form of the invention is substantially identical to that of FIG.
  • the DSC pattern of the crystalline form of the present invention is significantly different from the DSC pattern of the anhydrous Compound I solid.
  • Figure 5 is a DSC chart of the latter having an endothermic peak at about 240 to 247 °C.
  • FIG. 2 shows an endothermic peak caused by decrystallization of water, and the peak value of the endothermic peak is 130 °C.
  • the thermogravimetric analysis chart (TGA chart) shown in Fig. 3 shows a weight loss of 3.2% in the range of 100 ° C to 150 ° C, which is caused by the removal of water, and further proves that the crystal form is a hydrate crystal form.
  • the thermogravimetric analysis (TGA) pattern of the crystalline form of the invention is substantially identical to that of FIG.
  • the crystalline form of the present invention is substantially pure, and the term "substantially pure" means that the crystalline form is substantially free of other crystalline forms (such as the solid crystalline form of Compound I which does not contain water of crystallization), amorphous form (or Amorphous form), or an impurity such as a residual reactant.
  • the crystalline form of the invention has a purity of 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%, by weight percent, more It is preferably 100%.
  • Humidity i.e., hygroscopicity
  • hygroscopicity and “wetting property” and “wetting” have the same meaning. It can be used to determine the relatively stable region of a polymorphic drug, particularly a hydrate, by a wettability test, i.e., a water absorption isotherm assay.
  • the present invention performs a comparative study on the wettability of the crystalline form of the present invention (abbreviated as "Form A”) and the solid form of Compound I containing no water of crystallization (abbreviated as "no crystal type”) in a room temperature environment of 80% relative humidity.
  • Form A the crystalline form of the present invention
  • no crystal type the solid form of Compound I containing no water of crystallization
  • the results showed that the crystal-free type had hygroscopicity within 14 days; while the crystal form of the present invention was slightly hygroscopic. It can be seen that the crystal form of the invention has less wettability than the crystal-free type and is more stable.
  • the reactants and catalysts used in the examples of the present invention are all chemically pure, and can be used as they are or simply purified as needed; organic solvents and the like are all analytically pure and used directly.
  • the reagents were purchased from Shanghai Pharmaceutical Reagent Company of China Pharmaceutical (Group).
  • the amorphous form of Compound I is prepared according to the method reported in the prior art, such as Example 4 of CN103570762A, and is not limited thereto.
  • X-ray powder diffraction analysis was performed on a Rigaku D/Max-2550PC X-ray powder diffractometer using CuK ⁇ ray.
  • the test power was 40 kV ⁇ 250 mA
  • the scanning speed was 5°/min
  • the step width was 0.02°
  • the scanning range was 3 to 45°. ⁇ to 2 ⁇ continuous scanning of (2 ⁇ ).
  • the SDT Q600 thermogravimetric analyzer of TA Corporation was used under the conditions of a nitrogen gas velocity of 120 mL/min, a temperature increase rate of 10 ° C/min, and a temperature gradually rising from 20 ° C to 350 ° C.
  • the TA company DSC Q100 differential heat analyzer was used to measure at a nitrogen gas rate of 50 mL/min, a temperature increase rate of 10 ° C/min, and a temperature gradually rising from 30 ° C to 300 ° C.
  • triphenylphosphine hydrobromide 5 g
  • 5 g of 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonyl)amino]pyrimidine-5- Methanol Compound II
  • 0.1 g of triphenylphosphine, 100 ml of acetonitrile were added to a 250 ml three-necked flask, heated to reflux with stirring, and the reaction was followed by TLC. After completion of the reaction, it was concentrated to dryness to give a white solid. Yield: 98%; purity: 96.0%; moisture content: 3.2% by weight.
  • the crystal form of Compound I was prepared by adjusting the solvent type according to the method shown in Example 1 or Example 2. The results are shown in Table 1. Among them, for the mixed solvent, the ratio between the different solvents is expressed as a volume ratio.
  • the crystal form A of the present invention has a purity of 93% or more and a moisture content of usually 3.0 to 3.5% by weight.

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Abstract

本发明涉及一种瑞舒伐他汀钙中间体[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲磺酰胺基)-5-嘧啶基]三苯基溴化膦的新晶型及其制备方法，该晶型使用CuKα辐射、以2θ角度表示的XRPD光谱至少在7.475°±0.2°、8.626°±0.2°、9.414°±0.2°、10.753°±0.2°、11.382°±0.2°和14.940°±0.2°处存在衍射峰。该晶型引湿性低，稳定性好，便于长期存储和运输。

Description

一种瑞舒伐他汀钙中间体新晶型 技术领域
本发明属于药物合成领域，具体涉及一种瑞舒伐他汀钙中间体[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲磺酰胺基)-5-嘧啶基]三苯基溴化膦的晶型及其制备方法。
背景技术
瑞舒伐他汀钙(RosuvastatinCalcium)是由日本盐野义公司研制开发的一种他汀类血脂调节药，属于HMG-CoA还原酶抑制剂，可降低升高的低密度胆固醇、总胆固醇、甘油三酯和脱辅基蛋白B浓度，同时升高高密度胆固醇的浓度。可用于原发性高胆固醇血症和混合型脂肪代谢障碍症及纯合家族型高胆固醇血症的综合治疗，被称为超级他汀。用于合成瑞舒伐他汀钙的一种重要中间体是下述式I所示的[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲磺酰胺基)-5-嘧啶基]三苯基溴化膦，其别名是4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲磺酰胺基)-5-三苯基膦内鎓甲基-1-嘧啶、4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲磺酰氨基)嘧啶-5-甲基三苯基溴化物，CAS号码是CAS No.885477-83-8。
Figure PCTCN2018116319-appb-000001
化合物I是一种鏻盐，具有一定吸湿性，易潮解，不利于长期储放。因此，如何提高化合物I的稳定性成为一个需要解决的问题。
发明内容
针对现有化合物I存在的上述缺陷，发明人经过深入研究，开发出一种新的晶型，提高了化合物I的稳定性，降低其引湿性。具体而言，本发明提供了如下技术方案。
一种式I所示化合物[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲磺酰胺基)-5-嘧啶基]三苯 基溴化膦的晶型，其使用CuKα辐射、以2θ角度表示的X射线粉末衍射(即XRPD)光谱至少在7.475°±0.2°、8.626°±0.2°、9.414°±0.2°、10.753°±0.2°、11.382°±0.2°和14.940°±0.2°处存在衍射峰
Figure PCTCN2018116319-appb-000002
优选地，上述晶型至少在2θ值为在7.475°±0.1°、8.626°±0.1°、9.414°±0.1°、10.753°±0.1°、11.382°±0.1°和14.940°±0.1°处存在衍射峰；更优选上述晶型至少在2θ值为在7.475°±0.02°、8.626°±0.02°、9.414°±0.02°、10.753°±0.02°、11.382°±0.02°和14.940°±0.02°处存在衍射峰；更优选上述晶型至少在2θ值为在7.475°、8.626°、9.414°、10.753°、11.382°和14.940°处存在衍射峰。
在一种实施方式中，上述晶型还至少在2θ值为16.062°±0.2°和24.745°±0.2°处存在衍射峰；更优选上述晶型还至少在2θ值为16.062°±0.1°和24.745°±0.1°处存在衍射峰；更优选上述晶型还至少在2θ值为16.062°±0.02°和24.745°±0.02°处存在衍射峰；更优选上述晶型还至少在2θ值为16.062°和24.745°处存在衍射峰。
在一种实施方式中，上述晶型具有如图2所示的DSC图。
在一种实施方式中，上述晶型具有如图3所示的TGA图。
在一种实施方式中，上述晶型的含水量以重量百分含量计为0.3wt％～10wt％，优选为1％～9％，优选为2％～8％，更优选为3％～7％。
本发明还提供了一种式I所示化合物固体，其中上述晶型的重量百分含量不低于95％，优选不低于96％。
一种制备上述晶型和/或上述式I所示化合物固体的方法，包括如下步骤：在三苯基膦的存在下，使三苯基膦氢溴酸盐与式II所示化合物4-(4-氟苯基)-6-异丙基-2-[(N-甲基-N-甲磺酰)氨基]嘧啶-5-甲醇在溶剂中加热反应，反应完毕后浓缩至干、或者过滤烘干，即得式I所示化合物的晶型，
Figure PCTCN2018116319-appb-000003
在一种实施方式中，上述溶剂选自水、四氢呋喃、乙腈、二氯甲烷、甲苯、醋酸异丙酯、1,2-二氯乙烷、或者它们两种以上的混合物。
在一种优选的实施方式中，上述反应体系中三苯基膦氢溴酸盐与式II所示化合物的摩尔比大约为1:1。
在一种优选的实施方式中，上述反应体系中添加有少量三苯基膦，其中三苯基膦氢溴酸盐与三苯基膦的摩尔比为1：0.01～0.10。
上述反应步骤基本上是在溶剂中加热条件下进行的，反应条件温和，易于控制，因而操作简单、安全。
本发明的化合物I新晶型引湿性低，稳定性好，便于长期存储和运输，从而降低瑞舒伐他汀钙的生产成本。
附图说明
图1为本发明的一个化合物I晶型实施例的X射线粉末衍射图(XPRD图)。
图2为本发明的一个化合物I晶型实施例的差示扫描量热法图(DSC图)。横坐标是温度(℃)；纵坐标是热流量(W/g)。
图3为本发明的一个化合物I晶型实施例的热重分析图(TGA图)。
图4为无水化合物I固体的X射线粉末衍射图(XPRD图)。
图5为无水化合物I固体的差示扫描量热法图(DSC图)。横坐标是温度(℃)；纵坐标是热流量(W/g)。
具体实施方式
以下通过实施例进一步阐述本发明。应理解，这些实施例仅用于举例说明目的，而不是对本发明的限制。本领域技术人员根据本发明构思对其作出的各种改变或调整，均应落入本发明的保护范围内。
本文中涉及到多种物质的添加量、含量及浓度，其中所述的百分含量，除特别说明外，皆指质量百分含量。
某些化学物质在结晶时由于受各种因素影响，使分子内或分子间键合方式发生改变，致使分子或原子在晶格空间排列不同，形成不同的晶体结构。不同晶型往往具有不同的物理、化学性质，如熔点、硬度、稳定性、溶解速率等的差异。晶型可由X射线粉末衍射(XPRD)光谱图来表征，不同晶型的XPRD图是不同的，以2θ角度表示的衍射峰或称吸收峰的位置和/或相对强度(I/I 0)会有变化。
本发明的[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲磺酰胺基)-5-嘧啶基]三苯基溴化膦晶型的X射线粉末衍射图，表现为衍射峰位置即衍射角2θ(°)、晶面间距
Figure PCTCN2018116319-appb-000004
衍射峰相对强度(I/I 0)，概述于表1中。
表1化合物I的晶型的X射线粉末衍射结果
Figure PCTCN2018116319-appb-000005
Figure PCTCN2018116319-appb-000006
术语“相对强度”是指X-射线粉末衍射图的所有衍射峰中强度最高的峰的强度为100％时，其它峰的强度与强度最高的峰的强度的比值。
众所周知，有时同样一种晶型，在不同的测试条件下，X射线粉末衍射图会稍有不同。影响X射线粉末衍射图效果的因素有：晶体的纯度、晶化程度、粉末样品自身颗粒的大小、样品架装填粉末样品量、粉末装填到样品架中所处的表面平整度等。
在优选的实施方式中，晶型具有与图1中所示X射线粉末衍射光谱图实质相同的X射线粉末衍射图。
术语“实质相同”是指X射线粉末衍射图中至少70％、至少80％、至少90％、至少95％、或至少99％的峰出现在所给出的示例性X-射线粉末衍射光谱图1中。
应该理解，X射线粉末衍射图的2θ值可在机器之间、或样品之间稍有变化，其数值可能相差大约0.2个单位(°)，或者相差大约0.1个单位(°)，因此所引用的数值不能解释为绝对值。同样应该理解，衍射峰相对强度的大小同样可能相差大约5％，或者相差大约4％，或者相差大约3％，或者相差大约2％，或者相差大约1％，因此包括于本发明中的XRPD迹线(trace)强度是说明性的，并非意欲用于绝对比较。
应理解，本文中在表述数值特征时，术语“约”或者“大约”是指所表示的本数可以有±5％、±4％、±3％、±2％或±1％的误差范围或浮动范围。
作为优选的实施方式，本发明提供的晶型使用CuKα辐射、以2θ角度表示的X射线粉末衍射光谱至少在7.475°±0.05°、8.626°±0.05°、9.414°±0.05°、10.753°±0.05°、11.382°±0.05°和14.940°±0.05°处存在衍射峰；更优选上述晶型至少在2θ值为在7.475°±0.02°、8.626°±0.02°、9.414°±0.02°、10.753°±0.02°、11.382°±0.02°和14.940°±0.02°处存在衍射峰；更优选上述晶型至少在2θ值为在7.475°、8.626°、9.414°、10.753°、11.382°和14.940°处存在衍射峰。
进一步地，作为另一种优选的实施方式，本发明提供的上述晶型使用CuKα辐射、以2θ角度表示的X射线粉末衍射光谱还至少在2θ值为16.062°±0.05°和24.745°±0.05°处存在衍射峰；更优选上述晶型还至少在2θ值为16.062°±0.02°和24.745°±0.02°处存在衍射峰；更优选上述晶型还至少在2θ值为16.062°和24.745°处存在衍射峰。
当指图谱和/或图中数据时，术语“衍射峰”是指本领域的技术人员不会归属于背景噪音的特征峰。
研究发现，当化合物I是否包含结晶水、以及结晶水的多少将会影响到晶型的改变，这种变化反映在X射线粉末衍射(XRPD)光谱图中。比如，图4是按照专利CN103570762A的实施例4制备的结晶水含量极少的化合物I固体的XRPD光谱图，与本发明晶型的图1有明显区别。下文中，为描述方便起见，将按照专利CN103570762A的实施例4制备的化合物I固体简称为“无水化合物I固体”。应理解，此处所用的术语“无水”仅仅表示含水量相对于本发明晶型较小，并不是指绝对无水，比如按照专利CN103570762A实施例4制备的化合物I固体的结晶水含量为0.18％，大大低于本发明的新晶型的含水量。
发明人在研究中意外地发现，当制备化合物I时，如果在反应体系中添加少量的三苯基膦，所得到的晶型中含水量为0.3wt％～10wt％，该晶型的稳定性相比无水化合物I固体会大大提高，引湿性大大降低，其原因有待于进一步深入研究。
本发明晶型的含水量以重量百分含量计为0.3％～10％，优选为0.5％～9％，更优选为1％～8％，更优选为3％～7％，更优选为4％～7％，最优选为3.0％～4.0％。如果含水量低于0.3％，则吸湿性趋于增大；如果含水量高于10％，则极易吸附表面水。
本发明晶型中的结晶水主要来源于反应中产生的水分、以及/或者含水溶剂反应体系中的水分，因为反应体系中溶剂可以是水或者水与有机溶剂比如四氢呋喃、乙腈等的混合物。
为了显示本发明与现有的化合物I固体和现有的晶型之间的区别，本文中将现有的化合物I固体称作“无水化合物I固体”、或者“无水晶型”；相对应地，将本发明的晶型简称为“含水晶型”、“新晶型”、或者“晶型A”。
在反应体系中，其中三苯基膦氢溴酸盐与三苯基膦的摩尔比为1：0.01～0.10，比如为1：0.01～0.08、1：0.01～0.06、1：0.02～0.05、1：0.02～0.04或者1：0.02～0.03。
本文中，述及晶型时的术语“三苯基膦”，尤其是指非盐形式的三苯基膦，并不包含三苯基膦的任何盐形式。
此外，本发明还通过差示扫描量热技术对所述的新晶型进行了分析，在使用差示扫描量热技术进行分析时，表现为当升温速率为每分钟10℃的DSC图谱中存在1个吸热峰在110～140℃处，其DSC图谱基本如图2所示。应该理解，与X射线粉末衍射图数值可能有偏差具有相似情况，差示扫描量热技术所引用的数值也不能解释为绝对值。
在一种优选的实施方案中，本发明晶型的差示扫描量热法(DSC)谱图与图2实质相同。
本发明晶型的DSC图谱与无水化合物I固体的DSC图谱有明显区别，图5为后者的DSC图，其吸热峰在大约240～247℃处。
图2显示出有一个脱去结晶水引起的吸热峰，吸热峰的峰顶值为130℃。图3所示热重分析图(TGA图)显示了100℃至150℃范围内有3.2％的失重，由水的脱去引起，进一步证明该晶型为水合物晶型。在一种优选的实施方案中，本发明晶型的热重分析(TGA)图与图3实质相同。
本发明的晶型是基本上纯净的，术语“基本上纯净的”是指该晶型基本上不含有其他晶型(比如不包含结晶水的化合物I固体晶型)、无定形形式(或称非晶体形式)、或杂质比如残留的反应物。优选地，本发明晶型的纯度以重量百分比计为至少91％、至少92％、至少93％、至少94％、至少95％、至少96％、至少97％至少98％、至少99％，更优选为100％。
引湿性(即吸湿性)是影响晶型稳定性的一个重要因素。本发明中，术语“吸湿性”和“引湿性”、“引湿”意义相同。通过引湿性实验，即吸水等温线测定，可用于确定多晶型药物特别是水合物的相对稳定区域。
参照中国药典2010版附录对药物引湿性试验指导原则：潮解：吸收足量水分形成液体；极具引湿性：引湿增重不小于15％；具有引湿性：引湿增重2％-15％；略有引湿性：引湿增重0.2％-2％；无或者几乎无引湿性：引湿增重小于0.2％。
本发明在80％相对湿度的室温环境中进行了本发明晶型(简称“晶型A”)与不包含结晶水的化合物I固体晶型(简称“无水晶型”)的引湿性对比研究，结果显示：14天之内，无水晶型具有引湿性；而本发明晶型略有引湿性。可见本发明晶型比无水晶型引湿性小，更具有稳定性。
实施例
试剂：本发明实施例中使用的反应物和催化剂均为化学纯，可直接使用或根据需要经过简单纯化；有机溶剂等均为分析纯，直接使用。试剂均购自中国医药(集团)上海化学试剂公司。
化合物I的无水晶型按照现有文献比如CN103570762A中实施例4报道的方法制备，并且不局限于此。
检测方法及仪器：
X射线粉末衍射：
采用CuKα射线，在Rigaku D/Max-2550PC X-射线粉末衍射仪上进行X射线粉末衍射分析，测试功率为40kV×250mA，扫描速度5°/min、步宽0.02°，扫描范围3～45°(2θ)的θ～2θ连续扫描。
热重分析(TGA)：
采用TA公司的SDT Q600热重分析仪，在氮气速度为120mL/min、升温速度10℃/min、温度从20℃逐渐上升到350℃的条件下测定。
差示扫描量热法(DSC)表征：
采用TA公司DSC Q100差热量示分析仪，在氮气速度为50mL/min、升温速度为10℃/min、温度从30℃逐渐上升到300℃的条件下测定。
实施例1
将5g三苯基膦氢溴酸盐和5g的4-(4-氟苯基)-6-异丙基-2-[(N-甲基-N-甲磺酰)氨基]嘧啶-5-甲醇(化合物II)，0.1g三苯基膦，100ml乙腈加入250ml三口瓶中，加热至回流搅拌，TLC跟踪反应。反应完毕后浓缩至干，得到白色固体，即为化合物I。收率：98％；纯度：96.0％；水分含量：3.2wt％。
实施例2
将5g三苯基膦氢溴酸盐和5g的4-(4-氟苯基)-6-异丙基-2-[(N-甲基-N-甲磺酰)氨基]嘧啶-5-甲醇(化合物II)，0.1g三苯基膦，100ml甲苯加入250ml三口瓶中，加热至回流搅拌，TLC跟踪反应。反应完毕后降至室温，过滤，烘干得到白色固体，即为化合物I。收率：96％；纯度：99.0％；水分含量：3.3wt％。
实施例3-11
按照实施例1或实施例2所示的方法，通过调整溶剂种类来制备化合物I的含水晶型，结果如表1所示。其中，对于混合溶剂，不同溶剂之间的比例表示为体积比。
表1化合物I含水晶型的制备
Figure PCTCN2018116319-appb-000007
Figure PCTCN2018116319-appb-000008
实验表明，能够获得本发明的含水晶型A。本发明的晶型A的纯度都在93％以上，水分含量一般为3.0-3.5wt％。
实施例12引湿性实验
分别取晶型A和无水晶型各50mg，置于80％相对湿度的室温环境中，进行动态水分吸附(DVS)测试，测试结果如表2所示。
表2晶型A与无水晶型的引湿性对比结果
Figure PCTCN2018116319-appb-000009
上述结果表明：14天之内，无水晶型的引湿增重为6.5％，具有引湿性；而晶型A的引湿增重为0.26％，略有引湿性。可见晶型A比无水晶型引湿性小，更具有稳定性。

Claims (10)

  1. 一种式I所示化合物[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲磺酰胺基)-5-嘧啶基]三苯基溴化膦的晶型，其使用CuKα辐射、以2θ角度表示的X射线粉末衍射光谱至少在7.475°±0.2°、8.626°±0.2°、9.414°±0.2°、10.753°±0.2°、11.382°±0.2°和14.940°±0.2°处存在衍射峰
    Figure PCTCN2018116319-appb-100001
  2. 根据权利要求1所述的晶型，其特征在于，还至少在2θ值为16.062°±0.2°和24.745°±0.2°处存在衍射峰。
  3. 根据权利要求1所述的晶型，其特征在于，其至少在2θ值为在7.475°±0.02°、8.626°±0.02°、9.414°±0.02°、10.753°±0.02°、11.382°±0.02°和14.940°±0.02°处存在衍射峰。
  4. 根据权利要求3所述的晶型，其特征在于，还至少在2θ值为16.062°±0.02°和24.745°±0.02°处存在衍射峰。
  5. 根据权利要求1所述的晶型，其特征在于，其含水量为0.3wt％～10wt％。
  6. 根据权利要求1所述的晶型，其特征在于，其含水量为3wt％～7wt％。
  7. 一种式I所示化合物固体，其中根据权利要求1所述晶型的重量百分含量不低于95％。
  8. 制备根据权利要求1所述晶型的方法，包括如下步骤：在三苯基膦的存在下，使三苯基膦氢溴酸盐与式II所示化合物4-(4-氟苯基)-6-异丙基-2-[(N-甲基-N-甲磺酰)氨基]嘧啶-5-甲醇在溶剂中加热反应，反应完毕后浓缩至干、或者过滤烘干，即得式I所示化合物的晶型
    Figure PCTCN2018116319-appb-100002
  9. 根据权利要求8所述的方法，其特征在于，所述溶剂选自水、四氢呋喃、乙腈、二氯甲烷、甲苯、醋酸异丙酯、1,2-二氯乙烷、或者它们两种以上的混合物。
  10. 根据权利要求8所述的方法，其特征在于，反应体系中添加有三苯基膦，其中三苯基膦氢溴酸盐与三苯基膦的摩尔比为1：0.01～0.10。
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CN105175346A (zh) * 2015-05-19 2015-12-23 南京博优康远生物医药科技有限公司 一种合成瑞舒伐他汀钙中间体的方法

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