CN104736521B - Rui Gefeini salt crystal formation and its production and use - Google Patents

Rui Gefeini salt crystal formation and its production and use Download PDF

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CN104736521B
CN104736521B CN201380052962.5A CN201380052962A CN104736521B CN 104736521 B CN104736521 B CN 104736521B CN 201380052962 A CN201380052962 A CN 201380052962A CN 104736521 B CN104736521 B CN 104736521B
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rui gefeini
crystal formation
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rui
gefeini
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CN104736521A (en
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宋小叶
劳海萍
盛晓霞
盛晓红
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HANGZHOU PUSHA PHARMACEUTICAL TECHNOLOGY Co Ltd
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • C07—ORGANIC CHEMISTRY
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract

The application relates to novel Rui Gefeini salt and crystal formation thereof, and compared with known Rui Gefeini monohydrate and crystal formation thereof, the Rui Gefeini salt of the application and crystal formation thereof have one or more characteristics improved.The application further relates to described Rui Gefeini salt and the preparation method of crystal formation, its pharmaceutical composition and the purposes in the medicine preparing treatment metastatic colorectal cancer thereof.

Description

Rui Gefeini salt crystal formation and its production and use
Technical field
The application relates to pharmaceutical chemistry crystallization technique field.In particular it relates to Rui Gefeini salt and crystal formation thereof, further relate to institute State Rui Gefeini salt and the preparation method of crystal formation, its pharmaceutical composition and purposes.
Background technology
Rui Gefeini is the PTS of JIUYUE in 2012 FDA approval on the 27th.Rui Gefeini is the tyrosine of a Mutiple Targets Inhibitors of kinases, is used for treating metastatic colorectal cancer (metastatic colorectal cancer).Developer is to visit Ear medicines and health protection drugmaker (Bayer Healthcare Pharmaceuticals).Trade name Stivarga, lists shape Formula is the monohydrate of Rui Gefeini free alkali.
The English name of Rui Gefeini is Regorafenib, is also called BAY73-4506；Chemical name is 4-{4-[3- (4-chloro-3-trifluoromethyl)-urea groups]-3-fluorophenoxy }-pyridine-2-carboxylic acids Methanamide, molecular formula is C21H15ClF4N4O3；Molecular weight is 482.8；Chemical structural formula is as follows:
Patent documentation WO2005/009961 discloses Rui Gefeini and salt, Preparation Method And The Use.Specifically, real Execute example 1 and disclose Rui Gefeini and preparation method thereof, and disclose it1HNMR and MS (HPLC/ES) data.Embodiment 2～4 is public Open the hydrochlorate of Rui Gefeini, mesylate and benzene sulfonate and preparation method thereof, and disclose the fusing point of three kinds of salt.
Patent documentation WO2008/043446 discloses Rui Gefeini monohydrate and preparation method thereof, and discloses its X and penetrate Ray diffraction diagram (XRD), thermogravimetric analysis/Differential scanning calorimetry figure (TGA/DSC), Raman spectrum, infrared spectrum (IR), near infrared light Spectrum (NIR), far-infrared spectrum (FIR) and 13C-solid state nmr wave spectrum (13C-NMR) sign data, containing of this compound The water yield is 3.6% (weight).Rui Gefeini monohydrate shows high stability in preparing Pharmaceutical composition.
Patent documentation WO2008/058644 crystal formation II disclosing Rui Gefeini and preparation method thereof, its fusing point is 181 DEG C, the weightless ＜ 0.4% of TGA display, the advantage of crystal formation II is and to have highly dissoluble in organic solvent in water.WO2008/ 058644 also discloses that obtain according to patent documentation WO2005/009961 is Rui Gefeini crystal formation I, its fusing point 186～206 DEG C, the weightless ＜ 0.4% of TGA display.The document also discloses that Rui Gefeini crystal formation II and the XRD of crystal formation I, TGA/DSC, Raman light Spectrum, IR, NIR, FIR and13The sign data of C-NMR.
Patent documentation WO2008/055629 crystal formation III disclosing Rui Gefeini and preparation method thereof, its fusing point is 141 DEG C, the weightless ＜ 0.4% of TGA display, and disclose the XRD of crystal formation III, TGA/DSC, Raman spectrum, IR, NIR, FIR and13C- The sign data of NMR, the advantage of crystal formation III is and to have highly dissoluble in organic solvent in water.Additionally, this patent documentation is also Disclose Rui Gefeini monohydrate and be converted into the mode of crystal formation III.
Patent documentation WO2013/000917 discloses Rui Gefeini and hydrate, solvate and pharmaceutically can connect The salt being subject to or crystal formation, preparation for treating the application of ophthalmic diseases medicine, but do not disclose its pharmaceutically acceptable salt or The preparation of crystal formation or its sign data.
The present inventor studies discovery: the crystal formation I of Rui Gefeini free alkali, crystal formation II, crystal formation III and Rui Gefeini mono-are hydrated The crystal formation of thing is hydrophobic, dissolubility extreme difference in water；Rui Gefeini benzene sulfonate solubilizing effect in water is poor；Rui Gefei Buddhist nun's mesylate is weight change about 7.2% in 20%～80% RH range, hygroscopic；Rui Gefeini hydrochlorate is at height The lower instability of temperature, after 140 DEG C of desolventizings, can be changed into Rui Gefeini free alkali.
Therefore, this area remains a need for developing new Rui Gefeini salt and crystal formation thereof.
Summary of the invention
The application provides Rui Gefeini salt and crystal formation thereof, including Rui Gefeini toluenesulfonate, Rui Gefeini to chlorine Benzene sulfonate, Rui Gefeini 1,5-napadisilate, Rui Gefeini ethanedisulphonate, Rui Gefeini hydrobromate, Rui Gefeini Esilate, Rui Gefeini 2-naphthalene sulfonate and the crystal formation of these salt.
Compared with known Rui Gefeini salt and crystal formation thereof, novel Rui Gefeini salt and crystal formation thereof that the application provides have There is the performance that one or more are more superior.Concrete improvement characteristic such as, has higher degree of crystallinity, dissolubility, dissolution velocity, Relatively low hygroscopicity, preferable bin stability；The particularly Rui Gefeini salt of the crystal form of the application has favourable non- Hygroscopicity, dissolubility, preferable heat stability and preferable bin stability.
Therefore, one of present context is to provide Rui Gefeini toluenesulfonate and crystal formation thereof and it is prepared Method.
The Rui Gefeini toluenesulfonate that the application provides, is that Rui Gefeini and p-methyl benzenesulfonic acid are with 1: 1 mole Than the compound formed, its structural formula is as follows:
The application provides the preparation method of Rui Gefeini toluenesulfonate, described method to include: form auspicious lattice respectively Non-Buddhist nun and the p-methyl benzenesulfonic acid solution system in soluble solvent, the mol ratio of Rui Gefeini and p-methyl benzenesulfonic acid is 1: 1 ～1: 2, mix two individual system and form suspension, remove solvent, obtain described Rui Gefeini toluenesulfonate；Preferably described Soluble solvent is alcohols, esters, ketone, ethers and alkane；Preferably employ Filtration and remove soluble solvent.
The application provides Rui Gefeini toluenesulfonate crystal formation T, its X-ray powder diffraction figure 2 θ be 4.5 ± At 0.2 °, 13.4 ± 0.2 °, 18.1 ± 0.2 °, 20.8 ± 0.2 °, 21.9 ± 0.2 ° and 23.0 ± 0.2 °, there is characteristic peak；Enter one Step ground, its X-ray powder diffraction figure 2 θ be 4.5 ± 0.2 °, 11.0 ± 0.2 °, 11.5 ± 0.2 °, 13.4 ± 0.2 °, 14.8 ± 0.2 °, 16.6 ± 0.2 °, 18.1 ± 0.2 °, 20.4 ± 0.2 °, 20.8 ± 0.2 °, 21.9 ± 0.2 °, 23.0 ± 0.2 ° and 25.0 At ± 0.2 °, there is characteristic peak；Further, 2 θ characteristic peaks and the relative intensity thereof of its X-ray powder diffraction figure is:
The application also provides for the preparation method of Rui Gefeini toluenesulfonate crystal formation T, and described method includes: shape respectively Become Rui Gefeini and p-methyl benzenesulfonic acid solution system in soluble solvent, Rui Gefeini and the mol ratio of p-methyl benzenesulfonic acid It is 1: 1～1: 2, mixes two individual system and form suspension, crystallize at a temperature of-10 DEG C～50 DEG C, obtain described crystal formation T.Institute State soluble solvent and be preferably C1～C4Alcohol, C4～C5Ester, C3～C4Ketone, methyl tertiary butyl ether(MTBE) or normal heptane；Rui Gefeini's is solvable In solvent, the concentration of solution is preferably its under recrystallization temperature in soluble solvent 0.1～1 times of dissolubility, and more preferably 0.5 ～1 times；The concentration of the soluble solvent solution of p-methyl benzenesulfonic acid be preferably its under recrystallization temperature in soluble solvent dissolubility 0.5～1 times；The mol ratio of Rui Gefeini and p-methyl benzenesulfonic acid is preferably 1: 1～1: 1.5；The most described recrystallization temperature is Room temperature, the crystallize time is 1～48 hour, more preferably 1～10 hour.
Compared with the prior art, especially comparing with known Rui Gefeini monohydrate and crystal formation thereof, the application's is auspicious Ge Feini toluenesulfonate and crystal formation T thereof have one or more characteristics improved, such as: preferably dissolubility, dissolving Speed, relatively low hygroscopicity, higher decomposition temperature and preferable bin stability.
Described Rui Gefeini toluenesulfonate crystal formation T has the advantages that
The most described crystal formation T weight change in 20%～80% RH range is only about 0.04%, relative to auspicious lattice Non-Buddhist nun's monohydrate and crystal formation (its weight change in 20%～80% RH range is about 0.11%) thereof are less susceptible to inhale Wet；
2. relative to Rui Gefeini monohydrate and crystal formation thereof, it has higher decomposition temperature；
3., in the presence of sodium lauryl sulphate (SDS), relative to Rui Gefeini monohydrate and crystal formation thereof, it has relatively Good solubilizing effect.
The most described crystal formation T is sheet-like particle, big relative to Rui Gefeini monohydrate and crystal particle thereof, good fluidity；
5. room-temperature stable, ambient temperatare puts 6 months, and crystal formation and fusing point are constant.
The two of present context be to provide Rui Gefeini to chloro benzene sulfonate and crystal formation thereof, with and preparation method thereof.
The application provide Rui Gefeini to chloro benzene sulfonate, be Rui Gefeini and to chloro benzenesulfonic acid with 1: 1 mole Than the compound formed, its structural formula is as follows:
The application provides the preparation method of Rui Gefeini closilate, described method to include: form Rui Gefei respectively Buddhist nun and the p-chlorobenzenesulfonic acid solution system in soluble solvent, the mol ratio of Rui Gefeini and p-chlorobenzenesulfonic acid is 1: 1～1: 2, Mix two individual system and form suspension, remove solvent, obtain described Rui Gefeini closilate；The most described soluble solvent For alcohols, esters, ketone, ethers and alkane；Preferably employ Filtration and remove soluble solvent.
The application provides Rui Gefeini closilate crystal formation C, its X-ray powder diffraction figure 2 θ be 9.0 ± 0.2 °, At 9.9 ± 0.2 °, 18.2 ± 0.2 °, 19.9 ± 0.2 °, 23.1 ± 0.2 ° and 27.4 ± 0.2 °, there is characteristic peak；Further, Its X-ray powder diffraction figure 2 θ be 9.0 ± 0.2 °, 9.9 ± 0.2 °, 12.4 ± 0.2 °, 15.7 ± 0.2 °, 18.2 ° ± 0.2, 19.9 ± 0.2 °, 21.9 ± 0.2 °, 23.1 ± 0.2 °, 24.1 ± 0.2 °, 25.2 ± 0.2 °, 25.5 ± 0.2 ° and 27.4 ± 0.2 ° Place has characteristic peak；Further, 2 θ characteristic peaks and the relative intensity thereof of its X-ray powder diffraction figure is:
The application also provides for the preparation method of described Rui Gefeini closilate crystal formation C, and described method includes: respectively Form Rui Gefeini and p-chlorobenzenesulfonic acid solution system in soluble solvent, the mol ratio 1 of Rui Gefeini and p-chlorobenzenesulfonic acid: 1～1: 2, mix two individual system and form suspension, crystallize at a temperature of-10 DEG C～50 DEG C, obtain described crystal formation C.Described can Solvent is preferably C1～C4Alcohol, C4～C5Ester, C3～C4Ketone, methyl tertiary butyl ether(MTBE) or normal heptane；The soluble solvent of Rui Gefeini The concentration of solution is preferably its under recrystallization temperature in soluble solvent 0.1～1 times of dissolubility, more preferably 0.5～1 times； The concentration of the soluble solvent solution of p-chlorobenzenesulfonic acid is preferably it under recrystallization temperature in soluble solvent the 0.5～1 of dissolubility Times；The mol ratio of Rui Gefeini and p-chlorobenzenesulfonic acid is preferably 1: 1～1: 1.5；The most described recrystallization temperature is room temperature, during crystallize Between be 1-48 hour, more preferably 1～10 hour.
Compared with the prior art, especially comparing with known Rui Gefeini monohydrate and crystal formation thereof, the application's is auspicious Ge Feini closilate and crystal formation C thereof have one or more characteristics improved, and the highest dissolubility, dissolving are fast Degree, higher decomposition temperature and preferable bin stability.
Described Rui Gefeini closilate crystal formation C has the advantages that
1. room-temperature stable, ambient temperatare puts 6 months, and crystal formation and fusing point are constant；
2. relative to Rui Gefeini monohydrate and crystal formation thereof, it has higher decomposition temperature；
3., in the presence of sodium lauryl sulphate (SDS), relative to Rui Gefeini monohydrate and crystal formation thereof, it has relatively Good solubilizing effect.
The three of present context are to provide Rui Gefeini 1,5-napadisilate and crystal formation thereof, with and preparation method thereof.
The Rui Gefeini 1 that the application provides, 5-napadisilate, is Rui Gefeini and 1, and 5-napadisilate rubs with 2: 1 The compound that your ratio is formed, its structural formula is as follows:
The application provides described Rui Gefeini 1, the preparation method of 5-napadisilate, comprises the following steps: formed respectively Rui Gefeini and 1,5-naphthalenedisulfonic acid solution system in soluble solvent, the mol ratio of Rui Gefeini and 1,5-naphthalenedisulfonic acid is 1: 1～2: 1 mixing two individual system form suspension, remove solvent, obtain described Rui Gefeini 1,5-napadisilate；Preferably institute Stating soluble solvent is alcohols, esters, ketone, ethers or alkane；Preferably employ Filtration and remove soluble solvent.
The application provides Rui Gefeini 1,5-napadisilate crystal formation N, its X-ray powder diffraction figure 2 θ be 7.3 ± At 0.2 °, 10.3 ± 0.2 °, 12.8 ± 0.2 °, 15.1 ± 0.2 °, 18.8 ± 0.2 ° and 26.1 ± 0.2 °, there is characteristic peak；Enter one Step ground, its X-ray powder diffraction figure 2 θ be 7.3 ± 0.2 °, 8.3 ± 0.2 °, 9.6 ± 0.2 °, 10.3 ± 0.2 °, 11.6 ± 0.2°、12.8±0.2°、13.7±0.2°、15.1±0.2°、16.5±0.2°、18.8±0.2°、19.8±0.2°、21.1± At 0.2 ° and 26.1 ± 0.2 °, there is characteristic peak；Further, its X-ray powder diffraction figure substantially 2 θ characteristic peak and relatively Intensity is as follows:
The application also provides for the preparation method of described Rui Gefeini 1,5-napadisilate crystal formation N, and described method includes: point Not Xing Cheng Rui Gefeini and 1,5-naphthalenedisulfonic acid solution system in soluble solvent, rubbing of Rui Gefeini and 1,5-naphthalenedisulfonic acid Your ratio is 1: 1～2: 1, mixes two individual system and forms suspension, crystallize at a temperature of-10 DEG C～50 DEG C, obtains described crystal formation N.Described soluble solvent is preferably C1～C4Alcohol, C4～C5Ester, C3～C4Ketone, methyl tertiary butyl ether(MTBE) or normal heptane；Rui Gefeini's The concentration of soluble solvent solution is preferably its under recrystallization temperature in soluble solvent 0.1～1 times of dissolubility, more preferably 0.5～1 times；1,5～the concentration of soluble solvent solution of naphthalenedisulfonic acid to be preferably it molten in soluble solvent under recrystallization temperature 0.5～1 times of Xie Du；The mol ratio of Rui Gefeini and 1,5-naphthalenedisulfonic acid is preferably 2: 1.5～2: 1；The most described crystallize temperature Degree is room temperature, and the crystallize time is 1～48 hour, more preferably 1～10 hour.
Compared with the prior art, especially comparing with known Rui Gefeini monohydrate and crystal formation thereof, the application's is auspicious Ge Feini 1,5-napadisilate and crystal formation N thereof have one or more characteristics improved, such as: higher dissolubility, dissolving Speed, higher decomposition temperature and preferable bin stability.
Described Rui Gefeini 1,5-napadisilate crystal formation N has the advantages that
1. room-temperature stable, ambient temperatare puts 6 months, and crystal formation and fusing point are constant；
2. relative to Rui Gefeini monohydrate and crystal formation thereof, it has higher decomposition temperature；
3., in the presence of sodium lauryl sulphate (SDS), relative to Rui Gefeini monohydrate and crystal formation thereof, it has relatively Good solubilizing effect.
The four of present context be to provide Rui Gefeini ethanedisulphonate and crystal formation thereof, with and preparation method thereof.
The auspicious lattice ethanedisulphonate that the application provides, is Rui Gefeini and change that ethanedisulphonate is formed with 2: 1 mol ratios Compound, its structural formula is as follows:
The application provides the preparation method of described Rui Gefeini ethanedisulphonate, comprises the following steps: form auspicious lattice respectively Non-Buddhist nun and the ethionic acid solution system in soluble solvent, the mol ratio of Rui Gefeini and ethionic acid is 1: 1～2: 1, mixed Close two individual system and form suspension, remove solvent, obtain described Rui Gefeini ethanedisulphonate；The most described soluble solvent is alcohol Class, esters, ketone, ethers or alkane；Preferably employ Filtration and remove soluble solvent.
The application provides Rui Gefeini ethanedisulphonate crystal formation E, its X-ray powder diffraction figure 2 θ be 10.6 ± 0.2 °, At 12.1 ± 0.2 °, 17.0 ± 0.2 °, 18.1 ± 0.2 °, 22.7 ± 0.2 ° and 23.6 ° ± 0.2 °, there is characteristic peak；Further Ground, its X-ray powder diffraction figure 2 θ be 10.6 ± 0.2 °, 12.1 ± 0.2 °, 14.1 ± 0.2 °, 15.8 ± 0.2 °, 17.0 ± 0.2 °, 18.1 ± 0.2 °, 20.1 ± 0.2 °, 21.3 ± 0.2 °, 22.7 ± 0.2 °, 23.6 ± 0.2 °, 24.5 ± 0.2 ° and 27.8 At ± 0.2 °, there is characteristic peak；Further, its X-ray powder diffraction figure substantially 2 θ characteristic peak and relative intensity thereof are as follows:
The application also provides for the preparation method of described Rui Gefeini ethanedisulphonate crystal formation E, and described method includes: shape respectively Becoming Rui Gefeini and ethionic acid solution system in soluble solvent, the mol ratio of Rui Gefeini and ethionic acid is 1: 1～2 : 1, mix two individual system and form suspension, crystallize at a temperature of-10 DEG C～50 DEG C, obtain described crystal formation E.Described solvable molten Agent is preferably C1～C4Alcohol, C4～C5Ester, C3～C4Ketone, methyl tertiary butyl ether(MTBE) or normal heptane；The soluble solvent solution of Rui Gefeini Concentration be preferably its under recrystallization temperature in soluble solvent 0.1～1 times of dissolubility, more preferably 0.5～1 times；Second two The concentration of the soluble solvent solution of sulfonic acid is preferably its under recrystallization temperature in soluble solvent 0.5～1 times of dissolubility；Rui Ge The mol ratio of non-Buddhist nun and ethionic acid is preferably 2: 1.5～2: 1；The most described recrystallization temperature is room temperature, and the crystallize time is 1～48 Hour, more preferably 1～10 hour.
Compared with the prior art, especially comparing with known Rui Gefeini monohydrate and crystal formation thereof, the application's is auspicious Ge Feini ethanedisulphonate and crystal formation E thereof have one or more characteristics improved, such as: higher dissolubility, dissolution velocity, Higher decomposition temperature and preferable bin stability.
Described Rui Gefeini ethanedisulphonate crystal formation N has the advantages that
1. room-temperature stable, ambient temperatare puts 6 months, and crystal formation and fusing point are constant；
2. relative to Rui Gefeini monohydrate and crystal formation thereof, it has higher decomposition temperature；
3., in the presence of sodium lauryl sulphate (SDS), relative to Rui Gefeini monohydrate and crystal formation thereof, it has relatively Good solubilizing effect.
The five of present context be to provide Rui Gefeini hydrobromate and crystal formation thereof, with and preparation method thereof.
The Rui Gefeini hydrobromate that the application provides, is Rui Gefeini and change that hydrobromate is formed with 1: 1 mol ratio Compound, its structural formula is as follows:
The application provides the preparation method of described Rui Gefeini hydrobromate, comprises the following steps: form Rui Gefei respectively Buddhist nun and the hydrobromic acid solution system in soluble solvent, Rui Gefeini and hydrobromic mol ratio are 1: 1～1: 2, mix two System forming suspension, removes solvent, obtains described Rui Gefeini hydrobromate；The most described soluble solvent is alcohols, ketone Or alkane；Preferably employ Filtration and remove soluble solvent.
The application provides Rui Gefeini hydrobromate crystal formation H1, its X-ray powder diffraction figure 2 θ be 5.1 ± 0.2 °, At 10.1 ± 0.2 °, 15.1 ± 0.2 °, 18.2 ± 0.2 °, 19.5 ± 0.2 ° and 24.8 ± 0.2 °, there is characteristic peak；Further, Its X-ray powder diffraction figure 2 θ be 5.1 ± 0.2 °, 10.1 ° ± 0.2,15.1 ± 0.2 °, 18.2 ± 0.2 °, 19.5 ± 0.2 °, At 20.3 ± 0.2 °, 23.2 ± 0.2 °, 24.8 ± 0.2 °, 25.2 ± 0.2 ° and 30.0 ± 0.2 °, there is characteristic peak；Further Ground, its X-ray powder diffraction figure substantially 2 θ characteristic peak and relative intensity thereof are as follows:
The application also provides for the preparation method of described Rui Gefeini hydrobromate crystal formation H1, and described method includes: shape respectively Becoming Rui Gefeini and hydrobromic acid solution system in soluble solvent, Rui Gefeini and hydrobromic mol ratio is 1: 1～1: 2, Mix two individual system and form suspension, crystallize at a temperature of-10 DEG C～50 DEG C, obtain described crystal formation H1.Described soluble solvent It is preferably C1～C4Alcohol, C3～C4Ketone or normal heptane；Rui Gefeini concentration of solution in soluble solvent is preferably it in crystallize temperature Under degree in soluble solvent 0.1～1 times of dissolubility, more preferably 0.5～1 times；The concentration of hydrobromic soluble solvent solution It is preferably its under recrystallization temperature in soluble solvent 0.5～1 times of dissolubility；Rui Gefeini and hydrobromic mol ratio are preferred It is 1: 1～1: 1.5；The most described recrystallization temperature is room temperature, and the crystallize time is 1～48 hour, more preferably 1～10 hour.
Compared with the prior art, especially comparing with known Rui Gefeini monohydrate and crystal formation thereof, the application's is auspicious Ge Feini hydrobromate and crystal formation H1 thereof have one or more characteristics improved, such as: higher dissolubility, dissolution velocity and Preferably bin stability.
Described Rui Gefeini hydrobromate crystal formation H1 has the advantages that
1. room-temperature stable, ambient temperatare puts 6 months, and crystal formation and fusing point are constant；
2. relative to Rui Gefeini monohydrate and crystal formation thereof, it has higher decomposition temperature；
3., in the presence of sodium lauryl sulphate (SDS), relative to Rui Gefeini monohydrate and crystal formation thereof, it has relatively Good solubilizing effect.
The application provides Rui Gefeini hydrobromate crystal formation H2, its X-ray powder diffraction figure 2 θ be 10.6 ± 0.2 °, At 12.0 ± 0.2 °, 16.8 ± 0.2 °, 19.2 ± 0.2 °, 21.3 ± 0.2 ° and 24.4 ± 0.2 °, there is characteristic peak；Further, Its X-ray powder diffraction figure 2 θ be 10.6 ± 0.2 °, 12.0 ± 0.2 °, 16.8 ± 0.2 °, 17.0 ± 0.2 °, 18.9 ± 0.2°、19.2±0.2°、20.2±0.2°、20.5±0.2°、21.3±0.2°、24.1±0.2°、24.4±0.2°、25.7± At 0.2 ° and 26.5 ± 0.2 °, there is characteristic peak；Further, its X-ray powder diffraction figure substantially 2 θ characteristic peak and relatively Intensity is as follows:
The application provides the preparation method of described Rui Gefeini hydrobromate crystal formation H2, and described method includes: by Rui Gefei Buddhist nun hydrobromate crystal formation H1 forms suspension in a solvent, and described suspension is crystallize at a temperature of-10 DEG C～50 DEG C, obtains institute State crystal formation H2.Wherein said solvent is selected from ethyl acetate, methyl tertiary butyl ether(MTBE) or its mixture；Rui Gefeini hydrobromate crystal formation The consumption of H1 is preferably its under recrystallization temperature in described dicyandiamide solution 1.1～20 times of dissolubility, more preferably 1.5～10 Times；The most described recrystallization temperature is room temperature, and the crystallize time is 1～72 hour, more preferably 1～10 hour.
Compared with the prior art, especially comparing with known Rui Gefeini monohydrate and crystal formation thereof, the application's is auspicious Ge Feini hydrobromate and crystal formation H2 thereof have one or more characteristics improved, such as: higher dissolubility, dissolution velocity and Preferably bin stability.
Described Rui Gefeini esilate crystal formation H2 has the advantages that
Described Rui Gefeini hydrobromate crystal formation H2 is the allomorphism of Rui Gefeini hydrobromate crystal formation H1, both property Matter is basically identical, has higher decomposition temperature, in the presence of sodium lauryl sulphate (SDS), is hydrated relative to Rui Gefeini mono- Thing and crystal formation thereof, it has preferable solubilizing effect.
The six of present context be to provide Rui Gefeini esilate and crystal formation thereof, with and preparation method thereof.
The Rui Gefeini esilate that the application provides, is Rui Gefeini and change that esilate is formed with 1: 1 mol ratio Compound, its structural formula is as follows:
The application provides the preparation method of described Rui Gefeini esilate, comprises the following steps: form Rui Gefei respectively Buddhist nun and the ethyl sulfonic acid solution system in soluble solvent, the mol ratio of Rui Gefeini and ethyl sulfonic acid is 1: 1～1: 2, mixes two System forming suspension, removes solvent, obtains described Rui Gefeini esilate；The most described soluble solvent is esters, alcohols Or ketone；Preferably employ Filtration and remove soluble solvent.
The application provides Rui Gefeini esilate crystal formation Et1, its X-ray powder diffraction figure 2 θ be 8.2 ± 0.2 °, At 8.9 ± 0.2 °, 13.0 ± 0.2 °, 18.8 ± 0.2 °, 23.6 ± 0.2 ° and 24.6 ± 0.2 °, there is characteristic peak；Further, Its X-ray powder diffraction figure 2 θ be 8.2 ± 0.2 °, 8.9 ± 0.2 °, 12.2 ± 0.2 °, 13.0 ± 0.2 °, 14.4 ± 0.2 °, 16.2 ± 0.2 °, 17.9 ± 0.2 °, 18.8 ± 0.2 °, 20.1 ± 0.2 °, 22.0 ± 0.2 °, 23.6 ± 0.2 ° and 24.6 ± 0.2 ° Place has characteristic peak；Further, 2 θ characteristic peaks and the relative intensity thereof of its X-ray powder diffraction figure are as follows:
The application also provides for the preparation method of described Rui Gefeini esilate crystal formation Et1, and described method includes: shape respectively Becoming Rui Gefeini and ethyl sulfonic acid solution system in soluble solvent, the mol ratio of Rui Gefeini and ethyl sulfonic acid is 1: 1～1: 2, Mix two individual system and form suspension, crystallize at a temperature of-10 DEG C～50 DEG C, obtain described crystal formation Et1.Described soluble solvent It is preferably C1～C4Alcohol, C3～C4Ketone or C4～C5Ester；The concentration of the soluble solvent solution of Rui Gefeini is preferably it in crystallize temperature Under degree in soluble solvent 0.1～1 times of dissolubility, more preferably 0.5～1 times；The concentration of the soluble solvent solution of ethyl sulfonic acid It is preferably its under recrystallization temperature in soluble solvent 0.5～1 times of dissolubility；The mol ratio of Rui Gefeini and ethyl sulfonic acid is preferred It is 1: 1～1: 1.5；The most described recrystallization temperature is room temperature, and the crystallize time is 1～48 hour, more preferably 1-10 hour.
Compared with the prior art, especially comparing with known Rui Gefeini monohydrate and crystal formation thereof, the application's is auspicious Ge Feini esilate and crystal formation Et1 thereof have one or more characteristics improved, the highest dissolubility, dissolution velocity, Higher decomposition temperature and preferable bin stability.
Described Rui Gefeini esilate crystal formation Et1 has the advantages that
1. room-temperature stable, ambient temperatare puts 6 months, and crystal formation and fusing point are constant；
2. relative to Rui Gefeini monohydrate and crystal formation thereof, it has higher decomposition temperature；
3., in the presence of sodium lauryl sulphate (SDS), relative to Rui Gefeini monohydrate and crystal formation thereof, it has relatively Good solubilizing effect.
The application also provides for Rui Gefeini esilate crystal formation Et2, its X-ray powder diffraction figure 2 θ be 12.3 ± At 0.2 °, 13.6 ± 0.2 °, 16.0 ± 0.2 °, 20.5 ± 0.2 °, 24.3 ± 0.2 ° and 24.5 ± 0.2 °, there is characteristic peak；Enter one Step ground, its X-ray powder diffraction figure 2 θ be 7.4 ± 0.2 °, 8.2 ± 0.2 °, 12.3 ± 0.2 °, 13.6 ± 0.2 °, 16.0 ± 0.2 °, 16.9 ± 0.2 °, 18.5 ± 0.2 °, 20.5 ± 0.2 °, 20.9 ± 0.2 °, 22.1 ± 0.2 °, 24.3 ± 0.2 ° and 24.5 At ± 0.2 °, there is characteristic peak；Further, characteristic peak and the relative intensity thereof of its X-ray powder diffraction figure are as follows:
The application provides the preparation method of described Rui Gefeini esilate crystal formation Et2, and described method includes: by Rui Gefei Buddhist nun esilate crystal formation Et1 forms suspension in a solvent, and described suspension is crystallize at-10 DEG C～50 DEG C, obtains described crystalline substance Type Et2.Wherein said solvent is selected from methyl tertiary butyl ether(MTBE), normal heptane or its mixture；Rui Gefeini esilate crystal formation Et1's Consumption is preferably 1.1～20 times of the dissolubility under its recrystallization temperature in described dicyandiamide solution, more preferably 1.5～10 times； The most described recrystallization temperature is room temperature, and the crystallize time is 1～72 hour, more preferably 1～10 hour.
Compared with the prior art, especially comparing with known Rui Gefeini monohydrate and crystal formation thereof, the application's is auspicious Ge Feini hydrobromate and brilliant Et2 thereof have one or more characteristics improved, such as: higher dissolubility, dissolution velocity and Preferably bin stability.
Described Rui Gefeini esilate crystal formation Et2 has the advantages that
Described Rui Gefeini hydrobromate crystal formation Et2 is the allomorphism of Rui Gefeini hydrobromate crystal formation Et1, both Character is basically identical, has higher decomposition temperature, in the presence of sodium lauryl sulphate (SDS), relative to Rui Gefeini mono-water Compound and crystal formation thereof, it has preferable solubilizing effect.
The seven of present context be to provide Rui Gefeini 2-naphthalene sulfonate and crystal formation thereof, with and preparation method thereof.
The application provides Rui Gefeini 2-naphthalene sulfonate, and it is that Rui Gefeini and 2-LOMAR PWA EINECS 246-676-2 is formed with 1: 1 mol ratio Compound, its structural formula is as follows:
Described Rui Gefeini 2-naphthalene sulfonate crystal formation Na, its X-ray powder diffraction figure 2 θ be 4.7 ± 0.2 °, 13.7 ± At 0.2 °, 16.4 ± 0.2 °, 18.0 ± 0.2 °, 20.2 ± 0.2 ° and 21.9 ± 0.2 °, there is characteristic peak；Further, its X penetrates Line powder diagram 2 θ be 4.7 ± 0.2 °, 10.5 ± 0.2 °, 11.1 ± 0.2 °, 13.7 ± 0.2 °, 14.3 ± 0.2 °, 16.4 Have at ± 0.2 °, 18.0 ± 0.2 °, 20.2 ± 0.2 °, 21.5 ± 0.2 °, 21.9 ± 0.2 °, 22.5 ± 0.2 ° and 24.0 ± 0.2 ° There is characteristic peak；Further, characteristic peak and the relative intensity thereof of its X-ray powder diffraction figure are as follows:
The application provides the preparation method of described Rui Gefeini 2-naphthalene sulfonate crystal formation Na, and described method includes: shape respectively Becoming Rui Gefeini and 2-LOMAR PWA EINECS 246-676-2 solution system in soluble solvent, the mol ratio of Rui Gefeini and 2-LOMAR PWA EINECS 246-676-2 is 1: 1～1 : 2, by two individual system mixing, described mixed liquor stirs at-10 DEG C～50 DEG C, removes soluble solvent, adds normal heptane and is formed outstanding Turbid liquid, described suspension is crystallize at-10 DEG C～50 DEG C, obtains described crystal formation Na.Described soluble solvent is preferably C1～C4Alcohol, C4～C5Ester, C3～C4Ketone or methyl tertiary butyl ether(MTBE)；The consumption of Rui Gefeini is preferably it under recrystallization temperature in soluble solvent 0.1～1 times of dissolubility, more preferably 0.5～1 times；The consumption of normal heptane be preferably Rui Gefeini soluble solvent 0.1～ 0.5 times；The consumption of 2-LOMAR PWA EINECS 246-676-2 is preferably its under recrystallization temperature in soluble solvent 0.5～1 times of dissolubility；Rui Gefeini It is preferably 1: 1～1: 1.5 with the mol ratio of 2-LOMAR PWA EINECS 246-676-2；Described mixed liquor is preferably stirred at room temperature 1 minute to 48 hours, more Preferably 1～10 hour；Described suspension is preferably stirred at room temperature 1～48 hour, more preferably 1～10 hour.
Compared with the prior art, especially comparing with known Rui Gefeini monohydrate and crystal formation thereof, the application's is auspicious Ge Feini 2-naphthalene sulfonate crystal formation Na has one or more characteristics improved, such as: higher dissolubility, dissolution velocity, relatively High decomposition temperature and and preferable bin stability.
Described Rui Gefeini 2-naphthalene sulfonate crystal formation Na has the advantages that
1. room-temperature stable, ambient temperatare puts 6 months, and crystal formation and fusing point are constant；
2. relative to Rui Gefeini monohydrate and crystal formation thereof, it has higher decomposition temperature；
3., in the presence of sodium lauryl sulphate (SDS), relative to Rui Gefeini monohydrate and crystal formation thereof, it has relatively Good solubilizing effect.
In any of the above described preparation method of the application:
Indicating unless special, " room temperature " refers to the temperature of about 10～30 DEG C.
Described stirring, can use the conventional method of this area to complete, alr mode such as magnetic agitation, mechanical agitation Deng, mixing speed is 50～1800 revs/min, preferably 300～900 revs/min.
Described removal solvent, can use the ordinary skill in the art to complete, such as, filter, be centrifuged or evaporation.Described mistake Filter is usually and carries out sucking filtration, preferably pressure less than 0.09MPa with the pressure less than atmospheric pressure at ambient temperature.Described centrifugal Concrete operations are: the sample being intended to separate is placed in centrifuge tube, is centrifuged with the speed of 6000 revs/min, until solid is whole It is sink to bottom centrifuge tube.Described evaporation can under atmospheric pressure or under vacuo in about 20～40 DEG C be carried out, or utilizes inertia Air-flow evaporates.When removing solvent step and being to carry out for suspension stirring, remove solvent preferably by filtering.
Various crystal formations obtained by said method can be further dried.Described dry, the routine of this area can be used Technology completes, such as normal temperature drying, forced air drying or drying under reduced pressure, carries out in fume hood, convection oven or vacuum drying oven；Can To carry out under reducing pressure or not reducing pressure, preferably pressure is less than 0.09Mpa；Baking temperature about 30～50 DEG C；Drying time is 10 ～72 hours, preferably 10～48 hours, more preferably 10～24 hours.
Described volatilization is a kind of crystallization mode that the application uses, and obtains solid by removing solvent.The evaporation used sets Standby e.g. Rotary Evaporators, evacuation type vapo(u)rization system, nitrogen blows type vapo(u)rization system or vortex vacuum vapo(u)rization system.
Described ultrasonic, can promote that sample dissolves, concrete operations are: the container that will be equipped with sample suspension is placed in ultrasound wave In washer, with the power ultrasonic 1 of 20Khz～40Khz～30 minutes, preferably with 40Khz power ultrasonic 5 minutes.
Initiation material Rui Gefeini free alkali in the application can refer to patent documentation WO2005/009961 embodiment 1 and retouches The method stated prepares, during the document is incorporated herein by way of reference.
The application provides a kind of pharmaceutical composition, and described pharmaceutical composition comprises treatment and/or the one of prevention effective dose Or multiple Rui Gefeini salt described herein and crystal formation thereof, and at least one pharmaceutically acceptable carrier.Wherein, described Rui Gefeini salt and crystal formation thereof are selected from Rui Gefeini toluenesulfonate, Rui Gefeini toluenesulfonate crystal formation T, Rui Ge Non-Buddhist nun's closilate, Rui Gefeini closilate crystal formation C, Rui Gefeini 1,5-napadisilate, Rui Gefeini 1, 5-napadisilate crystal formation N, Rui Gefeini ethanedisulphonate, Rui Gefeini ethanedisulphonate crystal formation E, Rui Gefeini hydrobromic acid Salt, Rui Gefeini hydrobromate crystal formation H1, Rui Gefeini hydrobromate crystal formation H2, Rui Gefeini esilate, Rui Gefeini second Sulfonate crystal formation Et1, Rui Gefeini esilate crystal formation Et2, Rui Gefeini 2-naphthalene sulfonate or Rui Gefeini 2-naphthalene sulfonate Crystal formation Na.Additionally, described pharmaceutical composition can also comprise other pharmaceutically useful Rui Gefeini or the crystal formation of its salt or amorphous； Optionally, described pharmaceutical composition can also comprise one or more other pharmaceutically useful medicine activity components.
Carrier in described pharmaceutical composition includes saccharide, cellulose and its derivates, starch or modified starch, solid without Machine thing such as calcium phosphate, dicalcium phosphate, hydroxyapatite, calcium sulfate, calcium carbonate, semisolid such as lipid or paraffin, binding agent is such as Microcrystalline Cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, fluidizer such as colloidal state Silicon dioxide, light anhydrous silicic acid, crystalline cellulose, Pulvis Talci or magnesium stearate, disintegrating agent such as Sodium Carboxymethyl Starch, the poly-dimension of friendship Ketone, cross-linked carboxymethyl cellulose, sodium carboxymethyl cellulose, dried corn starch, lubricant such as stearic acid, magnesium stearate, stearoyl Fumaric acid sodium, Polyethylene Glycol.
On described pharmaceutical composition Chinese materia medica, acceptable carrier includes but not limited to: diluent, such as starch, modified shallow lake Powder, lactose, Powderd cellulose, microcrystalline Cellulose, calcium phosphate dibasic anhydrous, tricalcium phosphate, mannitol, sorbitol, sugar etc.；Bonding Agent, such as arabic gum, guar gum, gelatin, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, poly-second Glycol, copolyvidone etc.；Disintegrating agent, such as starch, carboxymethyl starch sodium, sodium starch glycollate, pregelatinized Starch, crosslinking gather Dimension ketone, cross-linking sodium carboxymethyl cellulose, silica sol etc.；Lubricant, such as stearic acid, magnesium stearate, zinc stearate, benzene Sodium formate, sodium acetate etc.；Fluidizer, such as silica sol etc.；Complex forming agents, the cyclodextrin of the most various ranks and Resin；Rate of release controlling agent, such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose Element, methylcellulose, methyl methacrylate, wax etc..Other available pharmaceutically acceptable carriers include but not limited to into Membrane, plasticizer, coloring agent, flavoring agent, viscosity modifier, preservative, antioxidant etc..
Described pharmaceutical composition can be solid-state or liquid, such as solid oral dosage form, including tablet, granule, powder, ball Agent and capsule；Liquid oral dosage form, including solution, syrup, suspensoid, dispersant and Emulsion；Injectable formulation, including Solution, dispersant and lyophilized preparation.Formula may be adapted to the quickly release of active component, postpones release or regulation release.Can be Conventional, dispersible, masticable, Orally dissolving or the preparation of rapid melting.Route of administration includes being administered orally, vein note Penetrate, subcutaneous injection, transdermal administration, rectally, intranasal administration, sublingual administration etc..
Described pharmaceutical composition can use in prior art and well known to a person skilled in the art prepared by method.In preparation During pharmaceutical composition, Rui Gefeini salt or its crystal formation of one or more of the application are pharmaceutically acceptable with one or more Carrier mixes mutually, optionally, mixes mutually with the other drug active component of one or more.Solid preparation can be by directly mixed Prepared by the techniques such as conjunction, granulation.
The application provide the Rui Gefeini salt of the application or its crystal formation or aforesaid comprise the application Rui Gefeini salt or The pharmaceutical composition of its crystal formation is used for the purposes treated and/or prevent in the medicine of higher proliferation disease in preparation, wherein said Higher proliferation disease is selected from solid tumor, lymphoma, sarcoma, leukemia, breast carcinoma, respiratory cancer, the brain cancer, genital cancer, disappears Change road cancer, carcinoma of urethra, cancer eye, hepatocarcinoma, skin carcinoma, head and neck cancer, thyroid carcinoma and/or parathyroid carcinoma, particularly transitivity knot Intestinal rectal cancer.Wherein said Rui Gefeini salt and crystal formation thereof are that Rui Gefeini toluenesulfonate, Rui Gefeini are to methylbenzene Sulfonate crystal formation T, Rui Gefeini closilate, Rui Gefeini closilate crystal formation C, Rui Gefeini 1,5-naphthalene two sulphur Hydrochlorate, Rui Gefeini 1,5-napadisilate N, Rui Gefeini ethanedisulphonate, Rui Gefeini ethanedisulphonate E, Rui Gefeini Hydrobromate, Rui Gefeini hydrobromate H1, Rui Gefeini hydrobromate H2, Rui Gefeini hydrobromate, Rui Gefeini second sulphur Hydrochlorate, Rui Gefeini esilate crystal formation Et1, Rui Gefeini esilate crystal formation Et2, Rui Gefeini 2-naphthalene sulfonate or auspicious lattice Non-Buddhist nun 2-naphthalene sulfonate crystal formation Na.
Further, the application provides the method for the treatment of higher proliferation disease, including giving patient treatment and/or prevention has The Rui Gefeini salt of the application of one or more of effect amount or its crystal formation or aforesaid comprise the application Rui Gefeini salt or The pharmaceutical composition of its crystal formation, wherein said Rui Gefeini salt and crystal formation thereof include but not limited to Rui Gefeini p-methyl benzenesulfonic acid Salt, Rui Gefeini toluenesulfonate crystal formation T, Rui Gefeini closilate, Rui Gefeini closilate crystal formation C, Rui Gefeini 1,5-napadisilate, Rui Gefeini 1,5-napadisilate N, Rui Gefeini ethanedisulphonate, Rui Gefeini Ethanedisulphonate E, Rui Gefeini hydrobromate, Rui Gefeini hydrobromate H1, Rui Gefeini hydrobromate H2, Rui Gefeini hydrogen Bromate, Rui Gefeini esilate, Rui Gefeini esilate crystal formation Et1, Rui Gefeini esilate crystal formation Et2, Rui Ge Non-Buddhist nun's 2-naphthalene sulfonate, Rui Gefeini 2-naphthalene sulfonate crystal formation Na, wherein said higher proliferation disease includes but not limited to reality Body tumor, lymphoma, sarcoma, leukemia, breast carcinoma, respiratory cancer, the brain cancer, genital cancer, digestive tract cancer, carcinoma of urethra, cancer eye, Hepatocarcinoma, skin carcinoma, head and neck cancer, thyroid carcinoma and/or parathyroid carcinoma, particularly metastatic colorectal cancer, wherein said trouble Person is mammal including people.
Accompanying drawing explanation
Fig. 1 is the XRPD figure of the Rui Gefeini by WO2005/009961 embodiment 1 preparation.
Fig. 2 is the XRPD figure of Rui Gefeini monohydrate crystalline form.
Fig. 3 is the PLM figure of Rui Gefeini monohydrate crystalline form.
Fig. 4 is the TGA figure of Rui Gefeini monohydrate crystalline form.
Fig. 5 is the DSC figure of Rui Gefeini monohydrate crystalline form.
Fig. 6 is the adsorption isothermal curve of Rui Gefeini monohydrate crystalline form.
Fig. 7 is the XRPD figure of Rui Gefeini toluenesulfonate crystal formation T.
Fig. 8 is the PLM figure of Rui Gefeini toluenesulfonate crystal formation T.
Fig. 9 is the TGA figure of Rui Gefeini toluenesulfonate crystal formation T.
Figure 10 is the DSC figure of Rui Gefeini toluenesulfonate crystal formation T.
Figure 11 is the adsorption isothermal curve of Rui Gefeini toluenesulfonate crystal formation T.
Figure 12 is the XRPD figure of Rui Gefeini closilate crystal formation C.
Figure 13 is the PLM figure of Rui Gefeini closilate crystal formation C.
Figure 14 is the TGA figure of Rui Gefeini closilate crystal formation C.
Figure 15 is the DSC figure of Rui Gefeini closilate crystal formation C.
Figure 16 is the adsorption isothermal curve of Rui Gefeini closilate crystal formation C.
Figure 17 is the 1 of Rui Gefeini, the XRPD figure of 5-napadisilate crystal formation N.
Figure 18 is the 1 of Rui Gefeini, the PLM figure of 5-napadisilate crystal formation N.
Figure 19 is the 1 of Rui Gefeini, the TGA figure of 5-napadisilate crystal formation N.
Figure 20 is the 1 of Rui Gefeini, the DSC figure of 5-napadisilate crystal formation N.
Figure 21 is the 1 of Rui Gefeini, the adsorption isothermal curve of 5-napadisilate crystal formation N.
Figure 22 is the XRPD figure of Rui Gefeini ethanedisulphonate crystal formation E.
Figure 23 is the PLM figure of Rui Gefeini ethanedisulphonate crystal formation E.
Figure 24 is the TGA figure of Rui Gefeini ethanedisulphonate crystal formation E.
Figure 25 is the DSC figure of Rui Gefeini ethanedisulphonate crystal formation E.
Figure 26 is the adsorption isothermal curve of Rui Gefeini ethanedisulphonate crystal formation E.
Figure 27 is the XRPD figure of Rui Gefeini hydrobromate crystal formation H1.
Figure 28 is the PLM figure of Rui Gefeini hydrobromate crystal formation H1.
Figure 29 is the TGA figure of Rui Gefeini hydrobromate crystal formation H1.
Figure 30 is the DSC figure of Rui Gefeini hydrobromate crystal formation H1.
Figure 31 is the adsorption isothermal curve of Rui Gefeini hydrobromate crystal formation H1.
Figure 32 is the XRPD figure of Rui Gefeini hydrobromate crystal formation H2.
Figure 33 is the XRPD figure of Rui Gefeini esilate crystal formation Et1.
Figure 34 is the PLM figure of Rui Gefeini esilate crystal formation Et1.
Figure 35 is the TGA figure of Rui Gefeini esilate crystal formation Et1.
Figure 36 is the DSC figure of Rui Gefeini esilate crystal formation Et1.
Figure 37 is the adsorption isothermal curve of Rui Gefeini esilate crystal formation Et1.
Figure 38 is the XRPD figure of Rui Gefeini esilate crystal formation Et2.
Figure 39 is the XRPD figure of the 2-naphthalene sulfonate crystal formation Na of Rui Gefeini.
Figure 40 is the PLM figure of the 2-naphthalene sulfonate crystal formation Na of Rui Gefeini.
Figure 41 is the TGA figure of the 2-naphthalene sulfonate crystal formation Na of Rui Gefeini.
Figure 42 is the DSC figure of the 2-naphthalene sulfonate crystal formation Na of Rui Gefeini.
Figure 43 is the adsorption isothermal curve of the 2-naphthalene sulfonate crystal formation Na of Rui Gefeini.
Detailed description of the invention
The application describes the crystal formation of the application, its preparation method in detail with further reference to following example, described embodiment And application.It will be apparent for a person skilled in the art that many change for material and method can be without departing from this Implement in the case of inventive concept.
Gather instrument used by data and method:
The instrument that X-ray powder diffraction (XPRD) is used is Bruker D8 Advance diffractometer, adopts By the Ka X-ray that copper target wavelength is 1.54nm, under the operating condition of 40kV and 40mA, θ-2 θ clinometer, Mo monochromator, Lynxeye detector.Instrument detected with corundum before use.Acquisition software is Diffrac Plus XRD Commander.Sample is tested at ambient temperature, and the sample needing detection is placed on areflexia plate.Testing conditions in detail As follows, angular range: 3-40 ° of 2 θ, step-length: 0.02 ° of 2 θ, speed: 0.2 second/step.Unless stated otherwise, sample is the most not Ground.
Polarization light microscope (PLM) collection of illustrative plates picks up from XP-500E micropolariscope (the Shanghai limited public affairs of rectangular optical instrument Department).Take a small amount of powder sample to be placed on microscope slide, drip a small amount of mineral oil with preferably dispersed powders sample, covered, Then sample is placed on the object stage of XP-500E micropolariscope (Shanghai rectangular optical instrument company limited), selects The suitably pattern of amplification observing samples taking pictures.
Differential thermal analysis (DSC) data are picked up from TA Instruments Q200 MDSC, and instrument control software is Thermal Advantage, analyzing software is Universal Analysis.Generally take the sample of 1-10 milligram to be positioned over and add a cover punching and (remove Non-specifically illustrate) aluminum crucible in, be dried N with the programming rate of 10 DEG C/min at 50ml/min2Protection under by sample from room Temperature rise to 200 DEG C or 300 DEG C, TA software records sample thermal change in temperature-rise period simultaneously.In the present invention, fusing point is Report by initial temperature.
Thermogravimetric analysis (TGA) data are picked up from TA Instruments Q500 TGA, and instrument control software is Thermal Advantage, analyzing software is Universal Analysis.The sample generally taking 5-15mg is positioned in platinum crucible, adopts By the mode of segmentation high resolution detection, it is dried N with the programming rate of 10 DEG C/min at 50ml/min2Protection under by sample from room Temperature rise is to 300 DEG C, and TA software records sample weight in temperature-rise period changes simultaneously.
Dynamically moisture content adsorption analysis (DVS) data are picked up from TA Instruments Q5000 TGA, instrument control software Being Thermal Advantage, analyzing software is Universal Analysis.The sample generally taking 1-10mg is positioned over platinum In crucible, usual TA software records sample, in relative humidity change of the weight change procedure from 0% to 80% to 0%, is drawn Adsorption isothermal curve.According to the concrete condition of sample, also sample can be used different absorption and De contamination step.
Nmr analysis (1HNMR) data are picked up from Bruker Ascend Tm 500.Full range is generally used to excite, spectrum width 30PPM, pulse, 30 ° of angles excite, and scan 16 times, and digitized quadrature detects, temperature control 298K.
High-efficient liquid phase analysis (HPLC) data are picked up from Agilent 1260, and instrument control software is Agilent chemistry work Standing B.04 version online, analyzing software is Agilent chem workstation B.04 version offline.Use C18 chromatographic column, 150mm*4.6mm, column temperature 25 DEG C, wavelength 220nm, flow velocity 1.3ml/min, sample size 5ul, run time 15min.Mobile phase A For the water containing 0.05%TFA, Mobile phase B is acetonitrile, gradient such as following table:
Various reagent used in embodiment are commercially available purchase if no special instructions.
Temperature in embodiment is room temperature if no special instructions.
Ultrasound procedure in embodiment is carried out 5 minutes under 40kHz power.
Embodiment 1
The preparation of Rui Gefeini free alkali, with reference to the method described by WO2005/009961 embodiment 1.
Particularly as follows:
To toluene (3 millis of 4-(4-ammonia-3-fluorophenoxy) pyridine-2-carboxylic acids Methanamide (1.42 grams, 5.46 mMs) Rise) solution adds 4-chloro-3-(trifluoromethyl) phenyl isocyanate (1.2 grams, 5.46 mMs).Described mixture room temperature is stirred Mix 48 hours.Obtained solid filtration under diminished pressure, room temperature in vacuo be dried 4 hours obtain described compound (1.14 grams, 2.35 mMs； Yield 43%).
X-ray powder diffraction figure is as shown in Figure 1.Display: disclosed in the sample of embodiment 1 preparation and WO2008/058644 The X-ray powder diffraction figure of Rui Gefeini crystal formation I is essentially identical.
1H-NMR (DMSO-d6) 2.80 (d, J=4.5,3H), 7.07-7.10 (m, 1H), 7.19 (dd, J=3.0,6.0, 1H), 7.35 (dd, J=2.5,11.5,1H), 7.43 (d, J=2.5,1H), 7.64 (s, 2H), 8.13-8.19 (m, 2H), 8.50 (d, J=5.5,1H), 8.75 (s, 1H), 8.79-8.81 (m, 1H), 9.54 (s, 1H)；MS (HPLC/ES) 483.06m/z=(M+ 1).Display: the sample of embodiment 1 preparation is consistent with Rui Gefeini free alkali prepared by WO2005/009961 embodiment 1.
Embodiment 2
Weigh the Rui Gefeini of 1.01g embodiment 1 preparation in the round-bottomed flask of 250ml, add after 24ml acetone ultrasonic Make molten clearly；Under stirring condition, 120ml water droplet is added to, in the acetone soln of Rui Gefeini, has white solid to analyse during dropping Go out, filtration under diminished pressure, 40 DEG C of dried in vacuum overnight, obtain 0.92g Rui Gefeini monohydrate white solid, productivity 87.8%.
X-ray powder diffraction figure is as shown in Figure 2.Penetrate with the X of the Rui Gefeini monohydrate disclosed in WO2008/043446 Line powder diagram is essentially identical.
PLM collection of illustrative plates is as shown in Figure 3.Display: less rhabdolith.
TGA collection of illustrative plates is as shown in Figure 4.Display: weightlessness 4.3% before 150 DEG C, decomposition temperature is 211 DEG C.
DSC collection of illustrative plates is as shown in Figure 5.Display: 182 DEG C start fusion and decomposition.
Adsorption isothermal curve is as shown in Figure 6.Display: 20%RH～80%RH weight is changed to 0.11%.
Embodiment 3
Weigh the Rui Gefeini of 1.00g embodiment 1 preparation in the round-bottomed flask of 250ml, add after 180ml isopropanol super Sound dissolves；Weigh 0.36g p-methyl benzenesulfonic acid in the vial of another 5ml, add ultrasonic dissolution after 4ml isopropanol；Stir Under the conditions of mixing, the aqueous isopropanol of p-methyl benzenesulfonic acid is dropped in the aqueous isopropanol of Rui Gefeini, stir 7 under room temperature little Shi Hou, has white solid to separate out, and filters after continuing stirring 1 hour, and isopropanol washs three times, and 40 DEG C are vacuum dried 10 hours, To 1.21g white solid, productivity 89.2%.
X-ray powder diffraction figure is as shown in Figure 7.Display: Rui Gefeini toluenesulfonate crystal formation T.
PLM collection of illustrative plates is as shown in Figure 8.Display: flat crystal.
TGA collection of illustrative plates is as shown in Figure 9.Display: crystal formation T decomposition temperature is 238 DEG C.
DSC collection of illustrative plates is as shown in Figure 10.Display: crystal formation T starts fusion and decomposition at 237 DEG C.
Adsorption isothermal curve is as shown in figure 11.Display: 20%RH～80%RH weight is changed to 0.04%.
It is to become salt at 1: 1 that HPLC characterizes display, Rui Gefeini and p-methyl benzenesulfonic acid with mol ratio.
Above-mentioned testing result shows: described crystal formation T is the most highly stable, be difficult to moisture absorption, have preferable pattern.
Embodiment 4
Weigh the Rui Gefeini of 1.00g embodiment 1 preparation in the round-bottomed flask of 250ml, add after 180ml isopropanol super Sound dissolves；Weigh 0.36g p-methyl benzenesulfonic acid in the flask of 500ml, add ultrasonic dissolution after 8ml isopropanol；Stirring condition Under, the aqueous isopropanol of Rui Gefeini is dropped in the aqueous isopropanol of p-methyl benzenesulfonic acid, after stirring 6 hours under room temperature, Having white solid to separate out, filter after continuing stirring 1 hour, isopropanol washs three times, and 50 DEG C are vacuum dried 10 hours, obtain 1.20g Rui Gefeini toluenesulfonate crystal formation T, productivity 88.5%.
Embodiment 5
Weigh the Rui Gefeini of 1.01g embodiment 1 preparation in the vial of 50ml, add after 28ml methanol ultrasonic molten Solve；Weigh 0.45g p-methyl benzenesulfonic acid in the vial of another 20ml, add ultrasonic dissolution after 6ml methanol；Stirring condition Under, the methanol solution of p-methyl benzenesulfonic acid is dropped in the methanol solution of Rui Gefeini, after stirring 1 hour under room temperature, have white Color solid separates out and filters, and methanol washs three times, and 50 DEG C are vacuum dried 10 hours, obtain Rui Gefeini toluenesulfonate crystal formation T.Yield is 1.24g, productivity 90.5%.
Embodiment 6
Weigh the Rui Gefeini of 1.03g embodiment 1 preparation in the round-bottomed flask of 500ml, add after 215ml n-butyl alcohol super Sound dissolves；Weigh 0.48g p-methyl benzenesulfonic acid in the vial of another 20ml, add ultrasonic dissolution after 10ml n-butyl alcohol； Under stirring condition, the butanol solution of p-methyl benzenesulfonic acid is dropped in the butanol solution of Rui Gefeini, 50 DEG C of stirrings 10 After hour, having white solid to separate out, filter, n-butyl alcohol washs three times, and 40 DEG C are vacuum dried 10 hours, obtain Rui Gefeini to first Base benzene sulfonate crystal formation T.Yield 1.22g, productivity 87.3%.
Embodiment 7
Weigh the Rui Gefeini of 1.00g embodiment 1 preparation in the round-bottomed flask of 250ml, add after 120ml ethyl acetate Ultrasonic dissolution；Weigh 0.54g p-methyl benzenesulfonic acid in the vial of another 20ml, ultrasonic molten after adding 10ml ethyl acetate Solve；Under stirring condition, the ethyl acetate solution of p-methyl benzenesulfonic acid is delayed in the ethyl acetate solution adding to Rui Gefeini, room temperature After lower stirring 5 hours, having white solid to separate out, filter after continuing stirring 1 hour, ethyl acetate is washed three times, and 40 DEG C of vacuum are done Dry 10 hours, obtain Rui Gefeini toluenesulfonate crystal formation T.Yield 1.23g, productivity 90.7%.
Embodiment 8
Weigh 1.01g embodiment 1 preparation Rui Gefeini in the round-bottomed flask of 250ml, add 162ml isopropyl acetate Rear ultrasonic dissolution；Weigh 0.72g p-methyl benzenesulfonic acid in the vial of another 20ml, super after adding 8ml isopropyl acetate Sound dissolves；Under stirring condition, by molten for the isopropyl acetate that the isopropyl acetate solution of p-methyl benzenesulfonic acid drops to Rui Gefeini In liquid, after stirring 16 hours at-10 DEG C, there is white solid to separate out, filter after continuing stirring 32 hours, isopropyl acetate washing three Secondary, 40 DEG C are vacuum dried 15 hours, obtain Rui Gefeini toluenesulfonate crystal formation T.Yield 1.20g, productivity 87.6%.
Embodiment 9
Weigh the Rui Gefeini of 1.02g embodiment 1 preparation in the round-bottomed flask of 1L, add after 600ml acetone ultrasonic molten Solve；Weigh 0.37g p-methyl benzenesulfonic acid in the vial of another 20ml, add ultrasonic dissolution after 8ml acetone；Stirring condition Under, the acetone soln of p-methyl benzenesulfonic acid is dropped in the acetone soln of Rui Gefeini, after stirring 1 hour under room temperature, have white Color solid separates out, and filters, washing with acetone three times, and 30 DEG C are vacuum dried 10 hours, obtain Rui Gefeini toluenesulfonate brilliant Type T.Yield 0.98g, productivity 70.8%.
Embodiment 10
Weigh the Rui Gefeini of 1.01g embodiment 1 preparation in the round-bottomed flask of 250ml, add after 150ml butanone ultrasonic Dissolve；Weigh 0.36g p-methyl benzenesulfonic acid in the vial of another 20ml, add ultrasonic dissolution after 9ml butanone；Stirring bar Under part, the butanone solution of p-methyl benzenesulfonic acid is dropped in the butanone solution of Rui Gefeini, after-10 DEG C are stirred 13 hours, have White solid separates out, and filters after continuing stirring 35 hours, and butanone washs three times, and 30 DEG C are vacuum dried 24 hours, obtain Rui Gefei Buddhist nun toluenesulfonate crystal formation T.Yield 1.11g, productivity 81.0%.
Embodiment 11
Weigh 1.02g embodiment 1 preparation Rui Gefeini in the round-bottomed flask of 1L, add 450ml methyl tertiary butyl ether(MTBE) Rear ultrasonic dissolution；Weigh 0.37g p-methyl benzenesulfonic acid in the vial of another 20ml, after adding 7ml methyl tertiary butyl ether(MTBE) Ultrasonic dissolution；Under stirring condition, the t-butyl methyl ether solution of p-methyl benzenesulfonic acid is dropped to the methyl-tert fourth of Rui Gefeini In base ethereal solution, after-10 DEG C are stirred 1 hour, having white solid to separate out, filter, methyl tertiary butyl ether(MTBE) washs three times, 30 DEG C of vacuum It is dried 48 hours, obtains Rui Gefeini toluenesulfonate crystal formation T.Yield 0.99g, productivity 71.6%.
Embodiment 12
Weigh the Rui Gefeini of 1.00g embodiment 1 preparation in the round-bottomed flask of 1L, add after 600ml normal heptane ultrasonic Dissolve；Weigh 0.36g p-methyl benzenesulfonic acid in the vial of another 20ml, add ultrasonic dissolution after 10ml normal heptane；Stir Under the conditions of mixing, drop to the n-heptane solution of p-methyl benzenesulfonic acid, in the n-heptane solution of Rui Gefeini, be stirred at room temperature 3 hours Rear filtration, normal heptane washs three times, and 50 DEG C are vacuum dried 10 hours, obtain Rui Gefeini toluenesulfonate crystal formation T.Yield 0.87g, productivity 64.1%.
Embodiment 13
Weigh 1.50g embodiment 1 preparation Rui Gefeini in the vial of 50ml, add 15ml ethanol, 40 DEG C of stirrings Dissolve；Weigh 0.60g p-chlorobenzenesulfonic acid in the vial of another 50ml, add ultrasonic dissolution after 1ml ethanol；Stirring condition Under, the ethanol solution of Rui Gefeini is dropped in the ethanol solution of p-chlorobenzenesulfonic acid, after 40 DEG C are stirred 11 hours, have white solid Body separates out, and filters, washing with alcohol three times after continuing to be stirred at room temperature 37 hours, and 40 DEG C are vacuum dried 72 hours, obtain 2.0g to chlorine Benzene sulfonate productivity 95.3%.
It is to become salt at 1: 1 that HPLC characterizes display, Rui Gefeini and p-chlorobenzenesulfonic acid with mol ratio.
Embodiment 14
Weigh 1.70g embodiment 1 preparation Rui Gefeini in the round-bottomed flask of 100ml, add 60ml sec-butyl alcohol 50 DEG C Stirring and dissolving；Weigh 0.68g p-chlorobenzenesulfonic acid in the flask of another 100ml, add ultrasonic dissolution after 2ml sec-butyl alcohol；Stirring Under the conditions of, the sec-butyl alcohol solution of Rui Gefeini is dropped in the sec-butyl alcohol solution of p-chlorobenzenesulfonic acid, after 50 DEG C are stirred 1 hour, Having white solid to separate out, filter after continuing to be stirred at room temperature 4 hours, sec-butyl alcohol washs three times, and 50 DEG C are vacuum dried 16 hours, obtain 1.96g closilate productivity 82.4%.
It is to become salt at 1: 1 that HPLC characterizes display, Rui Gefeini and p-chlorobenzenesulfonic acid with mol ratio.
Embodiment 15
Weigh 1.01g embodiment 1 preparation Rui Gefeini in the round-bottomed flask of 250ml, add 180ml isopropanol molten Solve；Weigh 0.41g p-chlorobenzenesulfonic acid in the flask of another 250ml, add ultrasonic dissolution after 4ml isopropanol；Under stirring condition, The aqueous isopropanol of Rui Gefeini is dropped in the aqueous isopropanol of p-chlorobenzenesulfonic acid, after 50 DEG C are stirred 1 hour, have white solid Body separates out, and filters after continuing stirring 16 hours, and isopropanol washs three times, and 40 DEG C are vacuum dried 10 hours, obtain 1.29g white solid Body, productivity 91.3%.
X-ray powder diffraction figure is as shown in figure 12.Display: Rui Gefeini closilate crystal formation C.
PLM collection of illustrative plates is as shown in figure 13.Display: little granule crystal.
TGA collection of illustrative plates is as shown in figure 14.Display: crystal formation C is weightlessness 7.98% before 150 DEG C, and decomposition temperature is 230 DEG C.
DSC collection of illustrative plates is as shown in figure 15.Display: crystal formation C starts fusion and decomposition at 186 DEG C.
Adsorption isothermal curve is as shown in figure 16.Display: 20%RH～80%RH weight is changed to 0.38%.
It is to become salt at 1: 1 that HPLC characterizes display, Rui Gefeini and p-chlorobenzenesulfonic acid with mol ratio.
Above-mentioned testing result shows: described crystal formation C at high temperature stablizes, is difficult to moisture absorption.
Embodiment 16
Weigh 1.01g embodiment 1 preparation Rui Gefeini in the round-bottomed flask of 250ml, add 180ml isopropanol molten Solve；Weigh 0.41g p-chlorobenzenesulfonic acid in the flask of another 250ml, add ultrasonic dissolution after 8ml isopropanol；Under stirring condition, The aqueous isopropanol of Rui Gefeini is dropped in the aqueous isopropanol of p-chlorobenzenesulfonic acid, after 50 DEG C are stirred 5 hours, have white solid Body separates out, and filters after continuing stirring 16 hours, and isopropanol washs three times, and 50 DEG C are vacuum dried 10 hours, obtain 1.22g Rui Gefei Buddhist nun closilate crystal formation C, productivity 86.3%.
Embodiment 17
Weigh 1.03g embodiment 1 preparation Rui Gefeini in the round-bottomed flask of 500ml, add 220ml methanol dissolve； Weigh 0.83g p-chlorobenzenesulfonic acid in the burning of another 500ml, add ultrasonic dissolution after 2ml methanol；Under stirring condition, by auspicious lattice The methanol solution of non-Buddhist nun drops in the methanol solution of p-chlorobenzenesulfonic acid, after stirring 5 hours, has white solid to separate out under room temperature, Filtering after continuing stirring 4 hours, methanol washs three times, and 40 DEG C are vacuum dried 16 hours, obtain Rui Gefeini closilate Crystal formation C.Yield 1.20g, productivity 83.3%.
Embodiment 18
Weigh 1.00g embodiment 1 preparation Rui Gefeini in the round-bottomed flask of 500ml, add 215ml n-butyl alcohol molten Solve；Weigh 0.60g p-chlorobenzenesulfonic acid in the flask of another 500ml, add ultrasonic dissolution after 4ml n-butyl alcohol；Under stirring condition, The butanol solution of Rui Gefeini is dropped in the butanol solution of p-chlorobenzenesulfonic acid, after-10 DEG C are stirred 10 hours, have white Solid separates out, and filters after continuing stirring 38 hours, and n-butyl alcohol washs three times, and 30 DEG C are vacuum dried 10 hours, obtain Rui Gefeini Closilate crystal formation C.Yield 1.27g, productivity 90.8%.
Embodiment 19
Weigh 1.01g embodiment 1 preparation Rui Gefeini in the round-bottomed flask of 1L, add 600ml acetic acid ethyl dissolution； Weigh 0.53g p-chlorobenzenesulfonic acid in the flask of another 1L, add ultrasonic dissolution after 8ml ethyl acetate；Under stirring condition, by auspicious The ethyl acetate solution of Ge Feini drops in the ethyl acetate solution of p-chlorobenzenesulfonic acid, after-10 DEG C are stirred 1 hour, has white Solid separates out, and filters, and ethyl acetate is washed three times, and 40 DEG C are vacuum dried 10 hours, obtain Rui Gefeini closilate brilliant Type C.Yield 1.21g, productivity 85.6%.
Embodiment 20
Weigh 1.02g embodiment 1 preparation Rui Gefeini in the round-bottomed flask of 250ml, add 203ml isopropyl acetate Dissolve；Weigh 0.41g p-chlorobenzenesulfonic acid in the flask of another 250ml, add ultrasonic dissolution after 9ml isopropyl acetate；Stirring Under the conditions of, drop to the isopropyl acetate solution of Rui Gefeini, in the isopropyl acetate solution of p-chlorobenzenesulfonic acid, stir under room temperature After mixing 6 hours, having white solid to separate out, filter after continuing stirring 4 hours, isopropyl acetate washs three times, 40 DEG C of vacuum drying 48 hours, obtain Rui Gefeini closilate crystal formation C.Yield 1.17g, productivity 82.0%.
Embodiment 21
Weigh 1.02g embodiment 1 preparation Rui Gefeini in the round-bottomed flask of 150ml, add 60ml acetone solution；Claim Take 0.62g p-chlorobenzenesulfonic acid in the flask of another 150ml, add ultrasonic dissolution after 15ml acetone；Under stirring condition, by auspicious lattice The acetone soln of non-Buddhist nun drops in the acetone soln of p-chlorobenzenesulfonic acid, after stirring 1 hour, has white solid to separate out under room temperature, Filtering after continuing stirring 6 hours, washing with acetone three times, 30 DEG C are vacuum dried 72 hours, obtain Rui Gefeini closilate Crystal formation C.Yield 1.29g, productivity 90.4%.
Embodiment 22
Weigh 1.00g embodiment 1 preparation Rui Gefeini in the round-bottomed flask of 150ml, add 75ml butanone dissolve；Claim Take 0.40g p-chlorobenzenesulfonic acid in the flask of another 150ml, add ultrasonic dissolution after 6ml butanone；Under stirring condition, by auspicious lattice The butanone solution of non-Buddhist nun drops in the butanone solution of p-chlorobenzenesulfonic acid, after-10 DEG C are stirred 7 hours, has white solid to separate out, continues Continuous stirring was filtered after 41 hours, and butanone washs three times, and 30 DEG C are vacuum dried 24 hours, obtain Rui Gefeini closilate brilliant Type C.Yield 1.30g, productivity 92.9%.
Embodiment 23
Weigh 1.01g embodiment 1 preparation Rui Gefeini in the round-bottomed flask of 1L, add 450ml methyl tertiary butyl ether(MTBE) Dissolve；Weigh 0.41g p-chlorobenzenesulfonic acid in the flask of another 1L, add ultrasonic dissolution after 10ml methyl tertiary butyl ether(MTBE)；Stirring Under the conditions of, the t-butyl methyl ether solution of Rui Gefeini is dropped in the t-butyl methyl ether solution of p-chlorobenzenesulfonic acid, room temperature System clarification after stirring 4 hours, after continuing stirring 5 hours, has white solid to separate out, and filters, methyl after continuing stirring 16 hours Tertbutyl ether washs three times, and 30 DEG C are vacuum dried 10 hours, obtain Rui Gefeini closilate crystal formation C.Yield 1.09g, Productivity 77.1%.
Embodiment 24
Weigh 1.01g embodiment 1 preparation Rui Gefeini in the round-bottomed flask of 1L, add 600ml normal heptane dissolve；Claim Take 0.41g p-chlorobenzenesulfonic acid in the vial of another 1L, add ultrasonic dissolution after 10ml normal heptane；Under stirring condition, will The n-heptane solution of Rui Gefeini drops in the n-heptane solution of p-chlorobenzenesulfonic acid, after being stirred at room temperature 10 hours, has white solid Body separates out and filters, and normal heptane washs three times, and 30 DEG C are vacuum dried 10 hours, obtain Rui Gefeini closilate crystal formation C.Produce Amount 0.95g, productivity 67.2%.
Embodiment 25
Weigh 1.50g embodiment 1 preparation Rui Gefeini in the vial of 50ml, add 15ml ethanol, 40 DEG C of stirrings Dissolve；Weigh 0.45g1,5-naphthalenedisulfonic acid in the vial of another 5ml, add ultrasonic dissolution after 4ml ethanol；Stirring bar Under part, by 1, the ethanol solution of 5-naphthalenedisulfonic acid drops in the ethanol solution of Rui Gefeini, after 40 DEG C are stirred 1 hour, has white Color solid separates out, and turns and filters after being stirred at room temperature 4 hours, washing with alcohol three times, and 40 DEG C are vacuum dried 16 hours, obtain 1.86g1,5- Napadisilate productivity 95.5%.
HPLC characterizes display, and Rui Gefeini and 1,5-naphthalenedisulfonic acid is 2: 1 one-tenth salt with mol ratio.
Embodiment 26
Weigh 1.80g embodiment 1 preparation Rui Gefeini in the vial of 100ml, add 64ml sec-butyl alcohol, 50 DEG C are stirred Mix dissolving；Weigh 0.54g1,5-naphthalenedisulfonic acid in the vial of another 5ml, add ultrasonic dissolution after 4ml sec-butyl alcohol；Stir Under the conditions of mixing, by 1, the sec-butyl alcohol solution of 5-naphthalenedisulfonic acid drops in the sec-butyl alcohol solution of Rui Gefeini, and 40 DEG C are stirred 1 hour After, there is white solid to separate out, turn and filter after being stirred at room temperature 4 hours, sec-butyl alcohol washs three times, and 40 DEG C are vacuum dried 48 hours, 2.09g1,5-napadisilate productivity 89.4%.
HPLC characterizes display, and Rui Gefeini and 1,5-naphthalenedisulfonic acid is 2: 1 one-tenth salt with mol ratio.
Embodiment 27
Weigh 1.00g embodiment 1 preparation Rui Gefeini in the round-bottomed flask of 250ml, add 120ml ethyl acetate molten Solve；Weighing 0.60g 1,5-naphthalenedisulfonic acid, in the vial of another 20ml, adds ultrasonic dissolution after 5ml ethyl acetate；Stir Under the conditions of mixing, by 1, the ethyl acetate solution of 5-naphthalenedisulfonic acid drops to, in the ethyl acetate solution of Rui Gefeini, be stirred at room temperature 5 After hour, having white solid to separate out, filter after continuing stirring 1 hour, ethyl acetate is washed three times, and 40 DEG C of vacuum drying 10 are little Time, obtain 1.19g white solid, productivity 91.6%.
X-ray powder diffraction figure is as shown in figure 17.Display: Rui Gefeini 1,5-napadisilate crystal formation N.
PLM collection of illustrative plates is as shown in figure 18.Display: little granule crystal.
TGA collection of illustrative plates is as shown in figure 19.Display: crystal formation N is weightlessness 2.0% before 150 DEG C, and decomposition temperature is 240 DEG C.
DSC collection of illustrative plates is as shown in figure 20.Display: crystal formation N starts fusion and decomposition at 238 DEG C.
Adsorption isothermal curve is as shown in figure 21.Display: 20%RH～80%RH weight is changed to 3.77%.
HPLC characterizes display, and Rui Gefeini and 1,5-naphthalenedisulfonic acid is 2: 1 one-tenth salt with mol ratio.
Above-mentioned testing result shows: described crystal formation N is at high temperature stable.
Embodiment 28
Weigh 1.00g embodiment 1 preparation Rui Gefeini in the round-bottomed flask of 250ml, add 150ml ethyl acetate molten Solve；Weighing 0.30g 1,5-naphthalenedisulfonic acid, in the flask of another 250ml, adds ultrasonic dissolution after 10ml ethyl acetate；Stirring Under the conditions of, the ethyl acetate solution of Rui Gefeini is dropped to 1, in the ethyl acetate solution of 5-naphthalenedisulfonic acid, is stirred at room temperature 6 little Shi Hou, has white solid to separate out, and filters after continuing stirring 1 hour, and ethyl acetate is washed three times, and 30 DEG C are vacuum dried 10 hours, Obtain 1.16g Rui Gefeini 1,5-napadisilate crystal formation N, productivity 89.3%.
Embodiment 29
Weigh 1.01g embodiment 1 preparation Rui Gefeini in the round-bottomed flask of 250ml, add 220ml methanol dissolve； Weighing 0.45g 1,5-naphthalenedisulfonic acid, in the vial of another 5ml, adds ultrasonic dissolution after 4ml methanol；Under stirring condition, By 1, the methanol solution of 5-naphthalenedisulfonic acid drops in the methanol solution of Rui Gefeini, after 50 DEG C are stirred 10 hours, has white solid Body separates out, and filters after continuing stirring 38 hours, and methanol washs three times, and 40 DEG C are vacuum dried 16 hours, get Rui Gefeini 1,5-naphthalene Disulfonate crystal formation N.Yield 1.09g, productivity 83.1%.
Embodiment 30
Weigh 1.03g embodiment 1 preparation Rui Gefeini in the round-bottomed flask of 500ml, add 360ml isopropanol molten Solve；Weighing 0.34g 1,5-naphthalenedisulfonic acid, in the vial of another 5ml, adds ultrasonic dissolution after 4ml isopropanol；Stirring bar Under part, by 1, the aqueous isopropanol of 5-naphthalenedisulfonic acid drops in the aqueous isopropanol of Rui Gefeini, after 50 DEG C are stirred 10 hours, Having white solid to separate out, filter after continuing stirring 1 hour, isopropanol washs three times, and 50 DEG C are vacuum dried 10 hours, get Rui Gefei Buddhist nun 1,5-napadisilate crystal formation N.Yield 1.18g, productivity 88.2%.
Embodiment 31
Weigh 1.02g embodiment 1 preparation Rui Gefeini in the round-bottomed flask of 500ml, add 215ml n-butyl alcohol molten Solve；Weigh 0.34g1,5-naphthalenedisulfonic acid in the vial of another 20ml, add ultrasonic dissolution after 6ml n-butyl alcohol；Stirring bar Under part, by 1, the butanol solution of 5-naphthalenedisulfonic acid drops in the butanol solution of Rui Gefeini, after being stirred at room temperature 1 hour, Having white solid to separate out, filter, n-butyl alcohol washs three times, and 40 DEG C are vacuum dried 24 hours, get Rui Gefeini 1,5-naphthalenedisulfonic acid Salt crystal formation N.Yield 1.20g, productivity 90.6%.
Embodiment 32
Weigh 1.02g embodiment 1 preparation Rui Gefeini in the round-bottomed flask of 250ml, add 180ml isopropyl acetate Dissolve；Weighing 0.40g 1,5-naphthalenedisulfonic acid is in the vial of another 20ml, ultrasonic molten after adding 8ml isopropyl acetate Solve；Under stirring condition, by 1, the isopropyl acetate solution of 5-naphthalenedisulfonic acid drops in the isopropyl acetate solution of Rui Gefeini, After being stirred at room temperature 5 hours, having white solid to separate out, filter after continuing stirring 5 hours, isopropyl acetate washs three times, and 40 DEG C true Empty dry 72 hours, get Rui Gefeini 1,5-napadisilate crystal formation N.Yield 1.15g, productivity 86.8%.
Embodiment 33
Weigh 1.00g embodiment 1 preparation Rui Gefeini in the round-bottomed flask of 250ml, add 60ml acetone solution；Claim Taking 0.30g 1,5-naphthalenedisulfonic acid, in the vial of another 20ml, adds ultrasonic dissolution after 6ml acetone；Under stirring condition, By 1, the acetone soln of 5-naphthalenedisulfonic acid drops in the acetone soln of Rui Gefeini, after being stirred at room temperature 10 hours, has white solid Body separates out, and filters, washing with acetone three times, and 40 DEG C are vacuum dried 48 hours, get Rui Gefeini 1,5-napadisilate crystal formation N.Produce Amount 1.21g, productivity 93.2%.
Embodiment 34
Weigh 1.00g embodiment 1 preparation Rui Gefeini in the round-bottomed flask of 250ml, add 75ml butanone dissolve；Claim Taking 0.30g 1,5-naphthalenedisulfonic acid, in the vial of another 20ml, adds ultrasonic dissolution after 7ml butanone；Under stirring condition, By 1, the butanone solution of 5-naphthalenedisulfonic acid drops in the butanone solution of Rui Gefeini, after-10 DEG C are stirred 10 hours, has white solid Body separates out, and filters after continuing stirring 38 hours, and butanone washs three times, and 40 DEG C are vacuum dried 16 hours, get Rui Gefeini 1,5-naphthalene Disulfonate crystal formation N.Yield 1.19g, productivity 91.6%.
Embodiment 35
Weigh 1.02g embodiment 1 preparation Rui Gefeini in the round-bottomed flask of 1L, add 450ml methyl tertiary butyl ether(MTBE) Dissolve；Weigh 0.31g1,5-naphthalenedisulfonic acid in the vial of another 20ml, ultrasonic molten after adding 10ml methyl tertiary butyl ether(MTBE) Solve；Under stirring condition, by 1, the methyl tertiary butyl ether(MTBE) that the t-butyl methyl ether solution of 5-naphthalenedisulfonic acid drops to Rui Gefeini is molten In liquid, after-10 DEG C are stirred 10 hours, there is white solid to separate out, filter after continuing stirring 1 hour, methyl tertiary butyl ether(MTBE) washing three Secondary, 30 DEG C are vacuum dried 10 hours, get Rui Gefeini 1,5-napadisilate crystal formation N.Yield 0.95g, productivity 71.7%.
Embodiment 36
Weigh 1.00g embodiment 1 preparation Rui Gefeini in the round-bottomed flask of 1L, add 600ml normal heptane dissolve；Claim Taking 0.60g 1,5-naphthalenedisulfonic acid, in the vial of another 5ml, adds ultrasonic dissolution after 4ml normal heptane；Under stirring condition, By 1, the n-heptane solution of 5-naphthalenedisulfonic acid drops to, in the n-heptane solution of Rui Gefeini, after being stirred at room temperature 1 hour, have white Solid separates out, and filters, and normal heptane washs three times, and 40 DEG C are vacuum dried 72 hours, get Rui Gefeini 1,5-napadisilate crystal formation N.Yield 0.88g, productivity 67.8%.
Embodiment 37
Weigh 1.30g embodiment 1 preparation Rui Gefeini in the vial of 50ml, add 13ml ethanol, 40 DEG C of stirrings Dissolve；Weigh 0.26g ethionic acid in the vial of another 5ml, add ultrasonic dissolution after 2ml ethanol；Under stirring condition, The ethanol solution of ethionic acid is dropped in the ethanol solution of Rui Gefeini, after 40 DEG C are stirred 1 hour, have white solid to analyse Going out, turn and filter after being stirred at room temperature 4 hours, washing with alcohol three times, 40 DEG C are vacuum dried 16 hours, obtain 1.51g ethanedisulphonate and produce Rate 97.0%.
It is to become salt at 2: 1 that HPLC characterizes display, Rui Gefeini and ethionic acid with mol ratio.
Embodiment 38
Weigh 1.50g embodiment 1 preparation Rui Gefeini in the round-bottomed flask of 100ml, add 64ml sec-butyl alcohol, 50 DEG C Stirring and dissolving；Weigh 0.30g ethionic acid in the vial of another 5ml, add ultrasonic dissolution after 3ml sec-butyl alcohol；Stirring Under the conditions of, the sec-butyl alcohol solution of ethionic acid is dropped in the sec-butyl alcohol solution of Rui Gefeini, after 50 DEG C are stirred 1 hour, have White solid separates out, and filters, and sec-butyl alcohol washs three times, and 30 DEG C are vacuum dried 10 hours, obtain 1.48g ethanedisulphonate productivity 82.4%.
It is to become salt at 2: 1 that HPLC characterizes display, Rui Gefeini and ethionic acid with mol ratio.
Embodiment 39
Weigh 1.00g embodiment 1 preparation Rui Gefeini in the round-bottomed flask of 500ml, add 225ml isopropanol molten Solve；Weigh 0.40g ethionic acid in the vial of another 5ml, add ultrasonic dissolution after 3ml isopropanol；Under stirring condition, The aqueous isopropanol of ethionic acid is added in the aqueous isopropanol of Rui Gefeini, separate out white after stirring 1 hour under room temperature solid Body, filters, and isopropanol washs three times, and 40 DEG C are vacuum dried 10 hours, obtain 1.12g white solid, productivity 93.6%.
X-ray powder diffraction figure is as shown in figure 22.Display: Rui Gefeini ethanedisulphonate crystal formation E.
PLM collection of illustrative plates is as shown in figure 23.Display: little granule crystal.
TGA collection of illustrative plates is as shown in figure 24.Display: crystal formation E is weightlessness 1.12% before 150 DEG C, and decomposition temperature is 234 DEG C.
DSC collection of illustrative plates is as shown in figure 25.Display: crystal formation E starts fusion and decomposition at 235 DEG C.
Adsorption isothermal curve is as shown in figure 26.Display: 20%RH～80%RH weight is changed to 0.89%.
It is to become salt at 2: 1 that HPLC characterizes display, Rui Gefeini and ethionic acid with mol ratio.
Above-mentioned testing result shows: described crystal formation E at high temperature stablizes, is difficult to moisture absorption.
Embodiment 40
Weigh 1.00g embodiment 1 preparation Rui Gefeini in the round-bottomed flask of 250ml, add 180ml isopropanol molten Solve；Weigh 0.20g ethionic acid in the flask of another 250ml, add ultrasonic dissolution after 6ml isopropanol；Under stirring condition, will The aqueous isopropanol of Rui Gefeini drops in the aqueous isopropanol of ethionic acid, separates out white solid under room temperature after stirring 1 hour Body, filters after continuing stirring 3 hours, and isopropanol washs three times, and 40 DEG C are vacuum dried 24 hours, obtain 1.10g Rui Gefeini second Disulfonate crystal formation E, productivity 91.9%.
Embodiment 41
Weigh 1.00g embodiment 1 preparation Rui Gefeini in the round-bottomed flask of 100ml, add 44ml methanol dissolve；Claim Take 0.24g ethionic acid in the vial of another 5ml, add ultrasonic dissolution after 4ml methanol；Under stirring condition, by second two The methanol solution of sulfonic acid adds in the methanol solution of Rui Gefeini, 50 DEG C stirring 1 hour after separate out white solid, continue stirring 1 Filtering after hour, methanol washs three times, and 40 DEG C are vacuum dried 48 hours, obtain Rui Gefeini ethanedisulphonate crystal formation E.Yield 1.13g, productivity 94.4%.
Embodiment 42
Weigh 1.04g embodiment 1 preparation Rui Gefeini in the round-bottomed flask of 500ml, add 215ml n-butyl alcohol molten Solve；Weigh 0.21g ethionic acid in the vial of another 5ml, add ultrasonic dissolution after 4ml n-butyl alcohol；Under stirring condition, The butanol solution of ethionic acid is added in the butanol solution of Rui Gefeini, separate out white after stirring 3 hours under room temperature solid Body, filters after continuing stirring 45 hours, and n-butyl alcohol washs three times, and 50 DEG C are vacuum dried 10 hours, obtain Rui Gefeini second two sulphur Hydrochlorate crystal formation E.Yield 1.17g, productivity 94.0%.
Embodiment 43
Weigh 1.03g embodiment 1 preparation Rui Gefeini in the round-bottomed flask of 250ml, add 134ml ethyl acetate molten Solve；Weigh 0.31g ethionic acid in the vial of another 5ml, add ultrasonic dissolution after 4ml ethyl acetate；Stirring condition Under, the ethyl acetate solution of ethionic acid is added in the ethyl acetate solution of Rui Gefeini, analyse after stirring 10 hours under room temperature Going out white solid, filter, ethyl acetate is washed three times, and 40 DEG C are vacuum dried 72 hours, obtain Rui Gefeini ethanedisulphonate brilliant Type E.Yield 1.15g, productivity 93.3%.
Embodiment 44
Weigh 1.01g embodiment 1 preparation Rui Gefeini in the round-bottomed flask of 250ml, add 162ml isopropyl acetate Dissolve；Weigh 0.20g ethionic acid in the vial of another 20ml, add ultrasonic dissolution after 5ml isopropyl acetate；Stirring Under the conditions of, the isopropyl acetate solution of ethionic acid is added in the isopropyl acetate solution of Rui Gefeini ,-10 DEG C of stirrings 1 are little Separating out white solid time after, filter after continuing stirring 38 hours, isopropyl acetate washs three times, and 30 DEG C are vacuum dried 10 hours, Obtain Rui Gefeini ethanedisulphonate crystal formation E.Yield 1.10g, productivity 91.0%.
Embodiment 45
Weigh 1.01g embodiment 1 preparation Rui Gefeini in the round-bottomed flask of 150ml, add 60ml acetone solution；Claim Take 0.26g ethionic acid in the glass bottle of another 20ml, add ultrasonic dissolution after 8ml acetone；Under stirring condition, by second two sulphur The acetone soln of acid adds in the acetone soln of Rui Gefeini, separates out white solid, continue stirring 1 under room temperature after stirring 1 hour Filtering after hour, washing with acetone three times, 40 DEG C are vacuum dried 16 hours, obtain Rui Gefeini ethanedisulphonate crystal formation E.Yield 1.15g, productivity 95.1%.
Embodiment 46
Weigh 1.02g embodiment 1 preparation Rui Gefeini in the round-bottomed flask of 1L, add 750ml butanone dissolve；Weigh 0.2g ethionic acid, in the vial of another 20ml, adds ultrasonic dissolution after 7ml butanone；Under stirring condition, by second two sulphur The butanone solution of acid adds in the butanone solution of Rui Gefeini, and-10 DEG C of stirrings separated out white solid after 8 hours, continued stirring 40 Filtering after hour, butanone washs three times, and 40 DEG C are vacuum dried 10 hours, obtain Rui Gefeini ethanedisulphonate crystal formation E.Yield 1.00g white solid, productivity 81.9%.
Embodiment 47
Weigh 1.01g embodiment 1 preparation Rui Gefeini in the round-bottomed flask of 1L, add 450ml methyl tertiary butyl ether(MTBE) Dissolve；Weigh 0.20g ethionic acid in the vial of another 20ml, add ultrasonic dissolution after 6ml methyl tertiary butyl ether(MTBE)；Stir Under the conditions of mixing, being added to by the t-butyl methyl ether solution of ethionic acid in the t-butyl methyl ether solution of Rui Gefeini ,-10 DEG C are stirred Separating out white solid after mixing 1 hour, filter, methyl tertiary butyl ether(MTBE) washs three times, and 40 DEG C are vacuum dried 24 hours, obtain Rui Gefei Buddhist nun ethanedisulphonate crystal formation E.Yield 0.91g, productivity 75.3%
Embodiment 48
Weigh 1.02g embodiment 1 preparation Rui Gefeini in the round-bottomed flask of 1L, add 600ml normal heptane dissolve；Claim Take 0.20g ethionic acid in the vial of another 20ml, add ultrasonic dissolution after 10ml normal heptane；Under stirring condition, will The n-heptane solution of ethionic acid adds in the n-heptane solution of Rui Gefeini, separates out white solid under room temperature after stirring 3 hours Filtering after continuing stirring 5 hours, normal heptane washs three times, and 40 DEG C are vacuum dried 10 hours, obtain Rui Gefeini ethanedisulphonate Crystal formation E.Yield 0.83g, productivity 68.0%.
Embodiment 49
The Rui Gefeini weighing 1.00g embodiment 1 preparation is placed in the round-bottomed flask of 250ml, after adding 200ml isopropanol Ultrasonic dissolution；Weigh 0.42g (concentration is 40% weight ratio) hydrobromic acid in the vial of another 5ml, add 4ml isopropanol Rear ultrasonic dissolution；Under stirring condition, being dropped to by hydrobromic aqueous isopropanol in the aqueous isopropanol of Rui Gefeini, 50 DEG C are stirred Separating out white solid after mixing 1 hour, stir 10 hours under room temperature, filter, isopropanol washs three times, and 40 DEG C of vacuum drying 16 are little Time, obtain 1.08g white solid, productivity 92.5%.
X-ray powder diffraction figure is as shown in figure 27.Display: Rui Gefeini hydrobromate crystal formation H1.
PLM collection of illustrative plates is as shown in figure 28.Display: little granule crystal.
TGA collection of illustrative plates is as shown in figure 29.Display: crystal formation H1 is weightlessness 10.47% before 150 DEG C, and decomposition temperature is 216 DEG C.
DSC collection of illustrative plates is as shown in figure 30.Display: crystal formation H1 starts fusion and decomposition at 172 DEG C.
Adsorption isothermal curve is as shown in figure 31.Display: 20%RH～80%RH weight is changed to 1.57%.
It is to become salt at 1: 1 that HPLC characterizes display, Rui Gefeini and hydrobromic acid with mol ratio.
Above-mentioned testing result shows: described crystal formation H1 is at high temperature stable.
Embodiment 50
The Rui Gefeini weighing 1.00g embodiment 1 preparation is placed in the round-bottomed flask of 250ml, after adding 180ml isopropanol Ultrasonic dissolution；Weigh 0.42g hydrobromic acid (concentration is 40% weight ratio) in the flask of another 250ml, after adding 8ml isopropanol Ultrasonic dissolution；Under stirring condition, the aqueous isopropanol of Rui Gefeini is dropped in hydrobromic aqueous isopropanol, 50 DEG C of stirrings Separating out white solid after 1 hour, filter, isopropanol washs three times, and 30 DEG C are vacuum dried 72 hours, obtain 1.07g Rui Gefeini Hydrobromate crystal formation H1, productivity 91.6%.
Embodiment 51
The Rui Gefeini weighing 1.02g embodiment 1 preparation is placed in the vial of 50ml, ultrasonic molten after adding 22ml methanol Solve；Weigh 0.42g hydrobromic acid (concentration is 40% weight ratio) in the vial of another 5ml, ultrasonic molten after adding 3ml methanol Solve；Under stirring condition, hydrobromic methanol solution is dropped in the methanol solution of Rui Gefeini ,-10 DEG C stirring 1 hour after analyse Going out white solid, filter, methanol washs three times, and 40 DEG C are vacuum dried 10 hours, obtain Rui Gefeini hydrobromate crystal formation H1.Produce Amount 1.04g white solid, productivity 87.3%.
Embodiment 52
The Rui Gefeini weighing 1.02g embodiment 1 preparation is placed in the round-bottomed flask of 500ml, after adding 269ml n-butyl alcohol Ultrasonic dissolution；Weigh 0.64g (concentration is 40% weight ratio) hydrobromic acid in the vial of another 5ml, add 4ml n-butyl alcohol Rear ultrasonic dissolution；Under stirring condition, hydrobromic butanol solution is dropped in the butanol solution of Rui Gefeini, under room temperature Separating out white solid after stirring 10 hours, filter, n-butyl alcohol washs three times, and 50 DEG C are vacuum dried 10 hours, obtain Rui Gefeini Hydrobromate crystal formation H1.Yield 1.07g, productivity 89.8%.
Embodiment 53
The Rui Gefeini weighing 1.03g embodiment 1 preparation is placed in the round-bottomed flask of 250ml, super after adding 120ml acetone Sound dissolves；Weigh 0.55g (concentration is 40% weight ratio) hydrobromic acid in the vial of another 20ml, after adding 7ml acetone Ultrasonic dissolution；Under stirring condition, being dropped to by hydrobromic acetone soln in the acetone soln of Rui Gefeini ,-10 DEG C of stirrings 1 are little Separating out white solid time after, filter, washing with acetone three times, 40 DEG C are vacuum dried 24 hours, obtain Rui Gefeini hydrobromate brilliant Type H1.Yield 1.08g, productivity 89.8%.
Embodiment 54
The Rui Gefeini weighing 1.04g embodiment 1 preparation is placed in the round-bottomed flask of 1L, ultrasonic after adding 750ml butanone Dissolve；Weigh 0.44g hydrobromic acid (concentration is 40% weight ratio) in the vial of another 20ml, super after adding 8ml butanone Sound dissolves；Under stirring condition, hydrobromic butanone solution is dropped in the butanone solution of Rui Gefeini, stir 1 under room temperature little Separating out white solid time after, filter, butanone washs three times, and 40 DEG C are vacuum dried 48 hours, obtain Rui Gefeini hydrobromate brilliant Type H1.Yield 0.97g, productivity 79.9%.
Embodiment 55
The Rui Gefeini weighing 1.02g embodiment 1 preparation is placed in the round-bottomed flask of 1L, super after adding 600ml normal heptane Sound dissolves；Weigh 0.42g hydrobromic acid (concentration is 40% weight ratio) in the vial of another 20ml, add 10ml normal heptane Rear ultrasonic dissolution；Under stirring condition, being dropped to by hydrobromic n-heptane solution in the n-heptane solution of Rui Gefeini, 50 DEG C are stirred Having white solid to separate out after mixing 10 hours, after continuing stirring 38 hours, filter, normal heptane washs three times, 50 DEG C of vacuum drying 10 Hour, obtain Rui Gefeini hydrobromate crystal formation H1.Yield 0.80g, productivity 67.2%.
Embodiment 56
The 0.31g Rui Gefeini hydrobromate crystal formation H1 of Example 49 preparation, is placed in 50ml vial, adds 20ml Ethyl acetate.Stirring 72 hours under room temperature, filter, 40 DEG C are vacuum dried 10 hours, obtain 0.30g white solid, and yield is 96.8%.
X-ray powder diffraction figure is as shown in figure 32.Display: Rui Gefeini hydrobromate crystal formation H2.
Embodiment 57
Ethyl acetate in embodiment 56 is replaced with methyl tertiary butyl ether(MTBE), and other operations, with embodiment 56, obtain Rui Ge Non-Buddhist nun hydrobromate crystal formation H2, yield 0.29g, yield 93.5%.
Embodiment 58
Weigh 1.60g embodiment 1 preparation Rui Gefeini in the vial of 50ml, add 13ml ethanol, 40 DEG C of stirrings Dissolve；Weigh 0.37g ethyl sulfonic acid in the vial of another 5ml, add ultrasonic dissolution after 2ml ethanol；Under stirring condition, will The ethanol solution of ethyl sulfonic acid drops in the ethanol solution of Rui Gefeini, after 40 DEG C are stirred 1 hour, has white solid to separate out, and turns Filtering after being stirred at room temperature 4 hours, washing with alcohol three times, 30 DEG C are vacuum dried 24 hours, obtain 1.9g esilate productivity 96.7%.
It is to become salt at 1: 1 that HPLC characterizes display, Rui Gefeini and ethyl sulfonic acid with mol ratio.
Embodiment 59
Take 1.30g embodiment 1 preparation Rui Gefeini in the round-bottomed flask of 1L, add 450ml methyl tertiary butyl ether(MTBE) molten Solve；Weigh 0.30g ethyl sulfonic acid in the vial of another 20ml, add ultrasonic dissolution after 10ml methyl tertiary butyl ether(MTBE)；Stirring Under the conditions of, drop to the t-butyl methyl ether solution of ethyl sulfonic acid, in the t-butyl methyl ether solution of Rui Gefeini, be stirred at room temperature After 10 hours, having white solid to separate out, filter after continuing stirring 1 hour, methyl tertiary butyl ether(MTBE) washs three times, 40 DEG C of vacuum drying 10 hours, get Rui Gefeini esilate yield 1.12g, productivity 70.2%.
It is to become salt at 1: 1 that HPLC characterizes display, Rui Gefeini and ethyl sulfonic acid with mol ratio.
Embodiment 60
The Rui Gefeini free alkali weighing 1.00g embodiment 1 preparation is placed in the round-bottomed flask of 250ml, adds 134ml second Ultrasonic dissolution after acetoacetic ester；Weigh 0.23g ethyl sulfonic acid to be placed in the vial of another 5ml, add 3ml ethyl acetate ultrasonic molten Solve；Under stirring condition, the ethyl acetate solution of ethyl sulfonic acid is dropped in the molten clear liquid of ethyl acetate of Rui Gefeini, 50 DEG C of stirrings Within 5 hours, having white solid to separate out, filter after continuing stirring 43 hours, ethyl acetate is washed three times, and 50 DEG C are vacuum dried 16 hours, Obtain 1.18g white solid, productivity 96.1%.
X-ray powder diffraction figure is as shown in figure 33.Display: Rui Gefeini esilate crystal formation Et1.
PLM collection of illustrative plates is as shown in figure 34.Display: little granule crystal.
TGA collection of illustrative plates is as shown in figure 35.Display: crystal formation Et1 is weightlessness 0.45% before 150 DEG C, and decomposition temperature is 224 DEG C.
DSC collection of illustrative plates is as shown in figure 36.Display: crystal formation Et1 starts fusion and decomposition at 201 DEG C.
Adsorption isothermal curve is as shown in figure 37.Display: 20%RH～80%RH weight is changed to 0.54%.
It is to become salt at 1: 1 that HPLC characterizes display, Rui Gefeini and ethyl sulfonic acid with mol ratio.
Above-mentioned testing result shows: described crystal formation Et1 is at high temperature stable, is difficult to moisture absorption.
Embodiment 61
The Rui Gefeini free alkali weighing 1.00g embodiment 1 preparation is placed in the round-bottomed flask of 250ml, adds 120ml second Ultrasonic dissolution after acetoacetic ester；Weigh 0.23g ethyl sulfonic acid to be placed in the flask of another 250ml, add 6ml ethyl acetate ultrasonic molten Solve；Under stirring condition, the ethyl acetate solution of Rui Gefeini is added to the molten clear liquid of ethyl acetate of ethyl sulfonic acid, 50 DEG C of stirrings Within 5 hours, having white solid to separate out, filter after continuing stirring 5 hours, ethyl acetate is washed three times, and 40 DEG C are vacuum dried 24 hours, Obtain 1.04g Rui Gefeini esilate crystal formation Et1, productivity 84.7%.
Embodiment 62
The Rui Gefeini free alkali weighing 1.01g embodiment 1 preparation is placed in the round-bottomed flask of 50ml, adds 25ml ethanol Rear ultrasonic dissolution；Weigh 0.46g ethyl sulfonic acid to be placed in the vial of another 5ml, add 2ml EtOH Sonicate and dissolve；Stirring bar Under part, drop to the ethanol solution of ethyl sulfonic acid, in the molten clear liquid of ethanol of Rui Gefeini, be stirred at room temperature 5 hours and have white solid to analyse Going out, filter, washing with alcohol three times after continuing stirring 1 hour, 40 DEG C are vacuum dried 72 hours, obtain Rui Gefeini esilate brilliant Type Et1.Yield 1.19g, productivity 95.9%.
Embodiment 63
The Rui Gefeini free alkali weighing 1.02g embodiment 1 preparation is placed in the round-bottomed flask of 250ml, adds 180ml different Ultrasonic dissolution after propanol；Weigh 0.28g ethyl sulfonic acid to be placed in the vial of another 5ml, add 3ml isopropanol ultrasonic dissolution； Under stirring condition, drop to the aqueous isopropanol of ethyl sulfonic acid, in the molten clear liquid of isopropanol of Rui Gefeini, be stirred at room temperature 1 hour and have White solid separates out, and filters, and isopropanol washs three times, and 40 DEG C are vacuum dried 10 hours, obtain Rui Gefeini esilate crystal formation Et1.Yield 1.18g, productivity 94.2%.
Embodiment 64
The Rui Gefeini free alkali weighing 1.00g embodiment 1 preparation is placed in the round-bottomed flask of 500ml, is just adding 215ml Ultrasonic dissolution after butanol；Weigh 0.35g ethyl sulfonic acid to be placed in the vial of another 5ml, add 3ml n-butyl alcohol ultrasonic dissolution； Under stirring condition, being dropped to by the butanol solution of ethyl sulfonic acid in the molten clear liquid of n-butyl alcohol of Rui Gefeini, 50 DEG C are stirred 15 hours Having white solid to separate out, filter after continuing stirring 33 hours, n-butyl alcohol washs three times, and 40 DEG C are vacuum dried 48 hours, obtain auspicious Ge Feini esilate crystal formation Et1.Yield 1.13g, productivity 92.0%.
Embodiment 65
The Rui Gefeini free alkali weighing 1.01g embodiment 1 preparation is placed in the round-bottomed flask of 250ml, adds 120ml third Ultrasonic dissolution after ketone；Weigh 0.24g ethyl sulfonic acid to be placed in the vial of another 5ml, add 4ml acetone ultrasonic dissolution；Stirring Under the conditions of, the acetone soln of ethyl sulfonic acid is dropped in the molten clear liquid of acetone of Rui Gefeini ,-10 DEG C of stirrings have white solid for 2 hours Body separates out, and filters, washing with acetone three times after continuing stirring 46 hours, and 40 DEG C are vacuum dried 10 hours, obtain Rui Gefeini second sulphur Hydrochlorate crystal formation Et1.Yield 1.15g, productivity 92.7%.
Embodiment 66
The Rui Gefeini free alkali weighing 1.00g embodiment 1 preparation is placed in the round-bottomed flask of 1L, adds 750ml butanone Rear ultrasonic dissolution；Weigh 0.46g ethyl sulfonic acid to be placed in the vial of another 5ml, add 4ml butanone ultrasonic dissolution；Stirring bar Under part, drop to the butanone solution of ethyl sulfonic acid, in the molten clear liquid of butanone of Rui Gefeini, be stirred at room temperature 10 hours and have white solid Separating out, filter, butanone washs three times, and 40 DEG C are vacuum dried 24 hours, obtain Rui Gefeini esilate crystal formation Et1.Yield 0.98g, productivity 79.8%.
Embodiment 67
The 0.33g Rui Gefeini esilate crystal formation Et1 of Example 60 preparation, is placed in 50ml bottle, adds 20ml Methyl tertiary butyl ether(MTBE).Stirring 72 hours under room temperature, filter, 40 DEG C are vacuum dried 10 hours, obtain 0.32g white solid, yield It is 97.0%.
X-ray powder diffraction figure is as shown in figure 38.Display: Rui Gefeini esilate crystal formation Et2.
Embodiment 68
Methyl tertiary butyl ether(MTBE) in embodiment 67 is replaced with normal heptane, and other operations, with embodiment 67, obtain Rui Gefei Buddhist nun esilate crystal formation Et2, yield 0.31g, yield 93.9%.
Embodiment 69
The Rui Gefeini free alkali weighing 1.00g embodiment 1 preparation is placed in the round-bottomed flask of 250ml, adds 180ml different Propanol dissolves；Weigh 0.44g 2-LOMAR PWA EINECS 246-676-2 to be placed in the vial of another 5ml, add 4ml isopropanol ultrasonic dissolution；By 2- The aqueous isopropanol of LOMAR PWA EINECS 246-676-2 drops in the molten clear liquid of isopropanol of Rui Gefeini, and holding 2 hour is stirred at room temperature, and volatilization eliminates molten Agent, adds that 50ml normal heptane is ultrasonic separates out white solid at once, filters after stirring 1 hour under room temperature, and isopropanol washs three times, 30 DEG C It is vacuum dried 24 hours, obtains 1.30g white solid, productivity 90.8%.
X-ray powder diffraction figure is as shown in figure 39.Display: the 2-naphthalene sulfonate crystal formation Na of Rui Gefeini.
PLM collection of illustrative plates is as shown in figure 40.Display: little granule crystal.
TGA collection of illustrative plates is as shown in figure 41.Display: crystal formation Na is 235 DEG C in decomposition temperature.
DSC collection of illustrative plates is as shown in figure 42.Display: crystal formation Na starts fusion and decomposition at 193 DEG C.
Adsorption isothermal curve is as shown in figure 43.Display: 20%RH～80%RH weight is changed to 0.26%.
HPLC characterizes display, Rui Gefeini with 2-LOMAR PWA EINECS 246-676-2 is to become salt at 1: 1 with mol ratio.
Above-mentioned testing result shows: described crystal formation Na is at high temperature stable, is difficult to moisture absorption.
Embodiment 70
The Rui Gefeini free alkali weighing 1.00g embodiment 1 preparation is placed in the round-bottomed flask of 500ml, adds 225ml different Propanol；Weigh 0.44g 2-LOMAR PWA EINECS 246-676-2 to be placed in the flask of another 500ml, add 8ml isopropanol ultrasonic dissolution；By Rui Gefeini Aqueous isopropanol add in the molten clear liquid of isopropanol of 2-LOMAR PWA EINECS 246-676-2,50 DEG C of stirrings keep 2 hours, and volatilization eliminates solvent, adds 25ml normal heptane is ultrasonic separates out white solid at once, filters after stirring 10 hours under room temperature, and isopropanol washs three times, 40 DEG C of vacuum It is dried 10 hours, obtains the 2-naphthalene sulfonate crystal formation Na of 1.36g Rui Gefeini, productivity 95.0%.
Embodiment 71
The Rui Gefeini free alkali weighing 1.01g embodiment 1 preparation is placed in the round-bottomed flask of 500ml, adds 220ml first Alcohol dissolves；Weigh 0.88g 2-LOMAR PWA EINECS 246-676-2 to be placed in the vial of another 5ml, add 4ml methanol ultrasonic dissolution；By 2-naphthalene sulphur The methanol solution of acid drops in the molten clear liquid of methanol of Rui Gefeini, and holding 2 hour is stirred at room temperature, and volatilization eliminates solvent, adds The ultrasonic white solid that separates out at once of 110ml normal heptane ,-10 DEG C of stirrings filter after 1 hour, and methanol washs three times, and 50 DEG C of vacuum are done Dry 10 hours, obtain the 2-naphthalene sulfonate crystal formation Na of Rui Gefeini, yield 1.23g, yield 85.1%.
Embodiment 72
The Rui Gefeini free alkali weighing 1.00g embodiment 1 preparation is placed in the round-bottomed flask of 500ml, is just adding 215ml Butanol dissolves；Weigh 0.53g 2-LOMAR PWA EINECS 246-676-2 to be placed in the vial of another 5ml, add 4ml n-butyl alcohol ultrasonic dissolution；By 2- The butanol solution of LOMAR PWA EINECS 246-676-2 drops in the molten clear liquid of n-butyl alcohol of Rui Gefeini, and holding 1 hour is stirred at room temperature, and quickly volatilization removes To the greatest extent solvent, adds the ultrasonic white solid that separates out at once of 50ml normal heptane, and 50 DEG C of stirrings were filtered after 1 hour, and n-butyl alcohol washs three times, and 40 DEG C vacuum drying 48 hours, obtain the 2-naphthalene sulfonate crystal formation Na of Rui Gefeini, yield 1.28g, yield 89.4%.
Embodiment 73
The Rui Gefeini free alkali weighing 1.02g embodiment 1 preparation is placed in the round-bottomed flask of ml100ml, adds 67ml Acetone solution；Weigh 0.66g 2-LOMAR PWA EINECS 246-676-2 to be placed in the vial of another 5ml, add 4ml acetone ultrasonic dissolution；By 2-naphthalene The acetone soln of sulfonic acid drops in the molten clear liquid of acetone of Rui Gefeini, and holding 2 hour is stirred at room temperature, and volatilization eliminates solvent, adds The ultrasonic white solid that separates out at once of 34ml normal heptane ,-10 DEG C of stirrings filter after 48 hours, and washing with acetone three times, 40 DEG C of vacuum are done Dry 16 hours, obtain the 2-naphthalene sulfonate crystal formation Na of Rui Gefeini, obtain 1.27g, yield 87.0%.
Embodiment 74
The Rui Gefeini free alkali weighing 1.01g embodiment 1 preparation is placed in the round-bottomed flask of 500ml, adds 360ml fourth Ketone dissolves；Weigh 0.44g 2-LOMAR PWA EINECS 246-676-2 to be placed in the vial of another 5ml, add 4ml butanone ultrasonic dissolution；By 2-naphthalene sulphur The butanone solution of acid drops in the molten clear liquid of butanone of Rui Gefeini, and 50 DEG C of stirrings keep 48 hours, and quickly volatilization eliminates solvent, Adding the ultrasonic white solid that separates out at once of 180ml normal heptane ,-10 DEG C of stirrings were filtered after 4 hours, and butanone washs three times, 30 DEG C of vacuum It is dried 10 hours, obtains the 2-naphthalene sulfonate crystal formation Na of Rui Gefeini, obtain 1.24g, yield 85.8%.
Embodiment 75
The Rui Gefeini free alkali weighing 1.01g embodiment 1 preparation is placed in the round-bottomed flask of 250ml, adds 120ml second Acetoacetic ester dissolves；Weigh 0.44g 2-LOMAR PWA EINECS 246-676-2 to be placed in the vial of another 5ml, add 4ml ethyl acetate ultrasonic dissolution； Being dropped to by the ethyl acetate solution of 2-LOMAR PWA EINECS 246-676-2 in the molten clear liquid of ethyl acetate of Rui Gefeini ,-10 DEG C of stirrings keep 1 hour, Quickly volatilization eliminates solvent, adds that 24ml normal heptane is ultrasonic separates out white solid at once, filters, acetic acid under room temperature after stirring 1 hour Ethyl ester washs three times, and 40 DEG C are vacuum dried 72 hours, obtain the 2-naphthalene sulfonate crystal formation Na of Rui Gefeini, yield 1.28g, yield 88.5%.
Embodiment 76
The Rui Gefeini free alkali weighing 1.02g embodiment 1 preparation is placed in the round-bottomed flask of 250ml, adds 162ml second Isopropyl propionate dissolves；Weigh 0.44g 2-LOMAR PWA EINECS 246-676-2 to be placed in the vial of another 5ml, add 4ml isopropyl acetate ultrasonic Dissolve；Drop to the isopropyl acetate solution of 2-LOMAR PWA EINECS 246-676-2, in the molten clear liquid of isopropyl acetate of Rui Gefeini, guarantor is stirred at room temperature Holding 2 hours, quickly volatilization eliminates solvent, adds that 17ml normal heptane is ultrasonic separates out white solid at once, after stirring 10 hours under room temperature Filtering, isopropyl acetate washs three times, and 50 DEG C are vacuum dried 10 hours, obtain the 2-naphthalene sulfonate crystal formation Na of Rui Gefeini, produce Amount 1.29g, yield 88.4%.
Embodiment 77
The Rui Gefeini free alkali weighing 1.01g embodiment 1 preparation is placed in the round-bottomed flask of 1L, adds 450ml methyl Tertbutyl ether dissolves；Weigh 0.44g2-LOMAR PWA EINECS 246-676-2 to be placed in the vial of another 5ml, add 4ml methyl tertiary butyl ether(MTBE) ultrasonic Dissolve；Being dropped to by the t-butyl methyl ether solution of 2-LOMAR PWA EINECS 246-676-2 in the molten clear liquid of methyl tertiary butyl ether(MTBE) of Rui Gefeini, room temperature is stirred Mixing holding 4 hours, quickly volatilization eliminates solvent, adds the ultrasonic white solid that separates out at once of 90ml normal heptane, after 40 DEG C are stirred 1 hour Filtering, methyl tertiary butyl ether(MTBE) washs three times, and 40 DEG C are vacuum dried 10 hours, obtain the 2-naphthalene sulfonate crystal formation Na of Rui Gefeini, Yield 0.96g, yield 66.4%.
Embodiment 78
The preparation of aseptic IV solution: the T crystal formation Rui Gefeini toluenesulfonate present invention prepared, with aseptic note Penetrate and be configured to 7 mg/ml solution with water, add solubilizing agent pluronic (Pluronic) F-of 2% percentage by weight simultaneously 68, and regulate pH (pH is transferred between low dose of 4-9, heavy dose of pH as close possible to normal human blood) on demand.
The administration of aseptic IV solution: above-mentioned aseptic IV solution is diluted to 2 mg/ml with 5% aseptic dextrose, and uses Within 60 minutes, venous transfusion is administered.
Embodiment 79-86
The preparation of sterile solution: the T crystal formation Rui Gefeini toluenesulfonate in embodiment 78 is replaced with respectively this The C crystal form Rui Gefeini closilate of invention preparation, N crystal form Rui Gefeini 1,5-napadisilate, crystal form E Rui Gefeini Ethanedisulphonate, H1 crystal formation Rui Gefeini hydrobromate, H2 crystal formation Rui Gefeini hydrobromate, Et1 crystal formation Rui Gefeini second sulphur Hydrochlorate, Et2 crystal formation Rui Gefeini esilate crystal formation and Na crystal formation Rui Gefeini 2-naphthalene sulfonate, in formula in various salt form Free alkali is identical with the mole dosage of free alkali in toluenesulfonate, filler in various salt form formula and salt form total Measuring identical with in embodiment 78, other operations are with embodiment 78.
Embodiment 87
The preparation of freeze-dried powder: the T crystal formation Rui Gefei prepared by the present invention of (i) 135-1350 milligram freeze-dried powder form Buddhist nun's toluenesulfonate, after dissolving with appropriate water for injection, aseptic filtration, it is sub-packed in ampere, seals after lyophilization, leakage Gas inspection and get final product.
The intravenously administrable of freeze-dried powder: by the freeze-dried powder of above-mentioned T crystal formation Rui Gefeini toluenesulfonate, with aseptic Water for injection or 5% dextrose reproduce into the solution that concentration is 21 mg/ml, further with normal saline or 5% dextrose It is diluted to the solution of 0.5 mg/ml, and was administered by vein set bolus or venous perfusion with 15-60 minute.
Embodiment 88-95
Preparation for the freeze-dried powder of intravenously administrable: by the T crystal formation Rui Gefeini p-methyl benzenesulfonic acid in embodiment 87 Salt replaces with C crystal form Rui Gefeini closilate, N crystal form Rui Gefeini 1 prepared by the present invention, 5-naphthalenedisulfonic acid respectively Salt, crystal form E Rui Gefeini ethanedisulphonate, H1 crystal formation Rui Gefeini hydrobromate, H2 crystal formation Rui Gefeini hydrobromate, Et1 Crystal formation Rui Gefeini esilate, Et2 crystal formation Rui Gefeini esilate crystal formation and Na crystal formation Rui Gefeini 2-naphthalene sulfonate, join In side, the free alkali in various salt form is identical with the mole dosage of free alkali in toluenesulfonate, in various salt form formula Filler is identical with in embodiment 87 with the total amount of salt form, and other operations are with embodiment 87.
Embodiment 96
The preparation of intramuscular suspension:
T crystal formation Rui Gefeini toluenesulfonate prepared by the 50 mg/ml present invention
5 mg/ml sodium carboxymethyl cellulose
4 mg/ml Tween80
9 mg/ml sodium chloride
9 mg/ml benzylated polyols
(as follows)
Sodium carboxymethyl cellulose is first dissolved by suitable quantity of water, standby；By Tween80, sodium chloride, benzylated polyol suitable quantity of water Mix homogeneously in sodium carboxymethyl cellulose solution is added after dissolving；T crystal formation Rui Gefeini toluenesulfonate is added mixed Close dispersed with stirring in solution uniform, to obtain final product.
Embodiment 97-105
The preparation of intramuscular suspension: the T crystal formation Rui Gefeini toluenesulfonate in embodiment 96 is replaced with respectively C crystal form Rui Gefeini closilate prepared by the present invention, N crystal form Rui Gefeini 1,5-napadisilate, crystal form E Rui Gefei Buddhist nun's ethanedisulphonate, H1 crystal formation Rui Gefeini hydrobromate, H2 crystal formation Rui Gefeini hydrobromate, Et1 crystal formation Rui Gefeini second Sulfonate, Et2 crystal formation Rui Gefeini esilate crystal formation and Na crystal formation Rui Gefeini 2-naphthalene sulfonate, in formula in various salt form Free alkali identical with the mole dosage of free alkali in toluenesulfonate, filler in various salt form formula and salt form Total amount is identical with in embodiment 96, and other operations are with embodiment 96.
Embodiment 106
The preparation of hard-shell capsule: by filling traditional two-piece type hard capsule, prepare capsule particle.By 100 milligrams of powder Shape active component Rui Gefeini (i.e. T crystal formation Rui Gefeini toluenesulfonate prepared by the 135mg present invention) and 150 milligrams of breasts Sugar, 50 milligrams of cellulose mix homogeneously, add 6 milligrams of magnesium stearate, fills capsule, to obtain final product after mixing.
Embodiment 107-114
The preparation of hard-shell capsule: the T crystal formation Rui Gefeini toluenesulfonate in embodiment 106 is replaced with respectively this The C crystal form Rui Gefeini closilate of invention preparation, N crystal form Rui Gefeini 1,5-napadisilate, crystal form E Rui Gefeini Ethanedisulphonate, H1 crystal formation Rui Gefeini hydrobromate, H2 crystal formation Rui Gefeini hydrobromate, Et1 crystal formation Rui Gefeini second sulphur Hydrochlorate, Et2 crystal formation Rui Gefeini esilate crystal formation and Na crystal formation Rui Gefeini 2-naphthalene sulfonate, in formula in various salt form Free alkali is identical with the mole dosage of free alkali in toluenesulfonate, filler in various salt form formula and salt form total Measuring identical with in embodiment 106, other operations are with embodiment 106.
Embodiment 115
The preparation of Perle: add gelatin, glycerol, preservative in water, be stirred and heated to about 80 DEG C and make shape Become transparent glue, glue adds lucifuge agent, coloring agent etc. and stirs, the glue configured is incubated at 60 DEG C, standby； The T crystal formation Rui Gefeini toluenesulfonate present invention prepared adds in the vegetable oil such as soybean oil, Oleum Gossypii semen or olive oil Stir, be allowed to be formed containing 100 milligrams of active component Rui Gefeini (i.e. 135mgT crystal formation Rui Gefeini p-methyl benzenesulfonic acids Salt) suspension type soft capsule content；T crystal formation Rui Gefeini toluenesulfonate also can be dissolved in Polyethylene Glycol etc. water-soluble Property liquid diluent forms transparent water-soluble soft capsule content；By pump, glue is inputted with soft capsule content Suppressing soft capsule in encapsulating machine, capsule drying i.e. obtains satisfactory soft capsule after cleaning.
Embodiment 116-123
The preparation of Perle: the T crystal formation Rui Gefeini toluenesulfonate in embodiment 115 is replaced with respectively C crystal form Rui Gefeini closilate prepared by the present invention, N crystal form Rui Gefeini 1,5-napadisilate, crystal form E Rui Gefei Buddhist nun's ethanedisulphonate, H1 crystal formation Rui Gefeini hydrobromate, H2 crystal formation Rui Gefeini hydrobromate, Et1 crystal formation Rui Gefeini second Sulfonate, Et2 crystal formation Rui Gefeini esilate crystal formation and Na crystal formation Rui Gefeini 2-naphthalene sulfonate, in formula in various salt form Free alkali identical with the mole dosage of free alkali in toluenesulfonate, filler in various salt form formula and salt form Total amount is identical with in embodiment 115, and other operations are with embodiment 115.
Embodiment 124
The preparation of tablet: prepare a large amount of tablet by common process.By 100 milligrams of active component Rui Gefeini (i.e. 135mg T crystal formation Rui Gefeini toluenesulfonate prepared by the present invention), 98.8 milligrams of lactose, 11 milligrams of starch, 2 milligrams of carboxymethyls Starch Sodium and 275 milligrams of microcrystalline Cellulose mix in mixer, use water as wetting agent pelletize, wet granular be dried in an oven to Moisture, below 3%, adds 2 milligrams of carboxymethyl starch sodium and 5 milligrams of magnesium stearate, mix homogeneously, measures in backward dry granule Principal agent composition in granule, determines tablet weight, tabletting.
Embodiment 125-132
The preparation of tablet: the T crystal formation Rui Gefeini toluenesulfonate in embodiment 124 is replaced with the present invention respectively The C crystal form Rui Gefeini closilate of preparation, N crystal form Rui Gefeini 1,5-napadisilate, crystal form E Rui Gefeini second two Sulfonate, H1 crystal formation Rui Gefeini hydrobromate, H2 crystal formation Rui Gefeini hydrobromate, Et1 crystal formation Rui Gefeini esilate, Et2 crystal formation Rui Gefeini esilate crystal formation and Na crystal formation Rui Gefeini 2-naphthalene sulfonate, dissociating in various salt form in formula Alkali is identical with the mole dosage of free alkali in toluenesulfonate, filler in various salt form formula and the total amount of salt form and Identical in embodiment 124, other operations are with embodiment 124.
Embodiment 133
The preparation of immediate release pharmaceutical tablets/capsule: (i.e. T prepared by the 135mg present invention is brilliant by 100 milligrams of active component Rui Gefeini Type Rui Gefeini toluenesulfonate) mix homogeneously with 162mg lactose, 100mg microcrystalline Cellulose, 3mg magnesium stearate is added Enter above-mentioned mixed powder adds after mixing tabletting in tablet machine and i.e. obtain immediate release pharmaceutical tablets；By 100 milligrams of active component Rui Gefeini (i.e. 135mgT crystal formation Rui Gefeini toluenesulfonate) mix homogeneously with 115mg pregelatinized Starch after add in capsule filling machine Carry out capsule fill quick-release capsules.
Embodiment 134
The preparation of immediate release pharmaceutical tablets/capsule: the T crystal formation Rui Gefeini toluenesulfonate in embodiment 133 is replaced respectively Being changed to C crystal form Rui Gefeini closilate, N crystal form Rui Gefeini 1 prepared by the present invention, 5-napadisilate, crystal form E are auspicious Ge Feini ethanedisulphonate, H1 crystal formation Rui Gefeini hydrobromate, H2 crystal formation Rui Gefeini hydrobromate, Et1 crystal formation Rui Gefei Buddhist nun's esilate, Et2 crystal formation Rui Gefeini esilate crystal formation and Na crystal formation Rui Gefeini 2-naphthalene sulfonate, various salt in formula Free alkali in type is identical with the mole dosage of free alkali in toluenesulfonate, the filler in various salt form formula and salt The total amount of type is identical with in embodiment 133, and other operations are with embodiment 133.
Embodiment 135
Take respectively the toluenesulfonate crystal formation T of Rui Gefeini prepared by the present invention, closilate crystal formation C, 1, 5-napadisilate crystal formation N, ethanedisulphonate crystal formation E, hydrobromate crystal formation H1, hydrobromate crystal formation H2, ethyl sulfonic acid crystal formation Et1, the monohydrate of ethyl sulfonic acid crystal formation Et2,2-naphthalene sulfonate crystal formation Na Yu Rui Gefeini carry out dissolubility, 20%-80%RH Weight change, fusing point, decomposition temperature and the comparison of pattern.
In 20%-80%RH RH range, weight change is to be obtained by DVS detection.
Fusing point compares: obtained by DSC detection.
Decomposition temperature compares: obtained by TGA detection.
Pattern compares: obtained by PLM detection.
Dissolubility compares: use dodecylbenzene sodium sulfonate solubilising to combine HPLC detection method.Take respectively 10mg sample and 50mg dodecylbenzene sodium sulfonate, in 20ml vial, adds 15ml deionized water, 40Khz ultrasound works power ultrasonic 60min, sampling filtering is also settled in 5ml volumetric flask, after removing water, uses acetonitrile constant volume, HPLC detectable concentration.The results are shown in Table 1.
The performance comparison result of the Rui Gefeini of the different salt form of table 1
As seen from Table 1, the Rui Gefeini toluenesulfonate crystal formation T that prepared by the present invention, closilate crystal formation C, 1,5-napadisilate crystal formation N, ethanedisulphonate crystal formation E, hydrobromate crystal formation H1, ethyl sulfonic acid crystal formation Et1,2-naphthalene sulfonate The monohydrate of crystal formation Na with Rui Gefeini compares, and has the advantages such as decomposition temperature height is good with solubilizing effect, and its solubilizing effect is 10～95 times of monohydrate.
All patents, patent application publication, patent application and non-patent publications cited in this specification, all passes through Quote and be incorporated by the application with it.
The general description of the above-mentioned invention to relating in the application and the description to its detailed description of the invention should not be understood For being the restriction to this inventive technique forecast scheme configuration.Those skilled in the art, according to disclosure herein, can not disobey On the premise of invention element involved by the back of the body, general describe or/and detailed description of the invention (including embodiment) to above-mentioned In public technology feature carry out increasing, reduce or combining, formed and belong to other technical scheme of described invention.The present invention's Protection domain should be as the criterion with the protection domain that claims are limited.

Claims (107)

1. Rui Gefeini toluenesulfonate crystal formation T, its structural formula is as follows:
It is characterized in that, use Cu-K α radiation, its X-ray powder diffraction figure 2 θ be 4.5 ± 0.2 °, 13.4 ± 0.2 °, 18.1 At ± 0.2 °, 20.8 ± 0.2 °, 21.9 ± 0.2 ° and 23.0 ± 0.2 °, there is characteristic peak.
Rui Gefeini toluenesulfonate crystal formation T the most according to claim 1, it is characterised in that its X-ray powder diffraction Figure 2 θ be 4.5 ± 0.2 °, 11.0 ± 0.2 °, 11.5 ± 0.2 °, 13.4 ± 0.2 °, 14.8 ± 0.2 °, 16.6 ± 0.2 °, 18.1 At ± 0.2 °, 20.4 ± 0.2 °, 20.8 ± 0.2 °, 21.9 ± 0.2 °, 23.0 ± 0.2 ° and 25.0 ± 0.2 °, there is characteristic peak.
Rui Gefeini toluenesulfonate crystal formation T the most according to claim 2, it is characterised in that its X-ray powder diffraction Characteristic peak and the relative intensity thereof of figure are as follows:
4. the preparation method of Rui Gefeini toluenesulfonate crystal formation T, described method according to any one of claims 1 to 3 Including: form Rui Gefeini and p-methyl benzenesulfonic acid solution system in soluble solvent respectively, Rui Gefeini and to methylbenzene The mol ratio of sulfonic acid is 1:1～1:2, mixes two individual system and forms suspension, crystallize at a temperature of-10 DEG C～50 DEG C, obtains Described crystal formation T.
The preparation method of Rui Gefeini toluenesulfonate crystal formation T the most according to claim 4, it is characterised in that institute State soluble solvent selected from C1～C4Alcohol, C4～C5Ester, C3～C4Ketone, methyl tertiary butyl ether(MTBE) or normal heptane.
The preparation method of Rui Gefeini toluenesulfonate crystal formation T the most according to claim 4, it is characterised in that institute The concentration of the soluble solvent solution stating Rui Gefeini is its under recrystallization temperature in soluble solvent 0.1～1 times of dissolubility.
The preparation method of Rui Gefeini toluenesulfonate crystal formation T the most according to claim 6, it is characterised in that institute The concentration of the soluble solvent solution stating Rui Gefeini is its under recrystallization temperature in soluble solvent 0.5～1 times of dissolubility.
The preparation method of Rui Gefeini toluenesulfonate crystal formation T the most according to claim 4, it is characterised in that institute The concentration of the soluble solvent solution stating p-methyl benzenesulfonic acid be its under recrystallization temperature in soluble solvent the 0.5～1 of dissolubility Times.
The preparation method of Rui Gefeini toluenesulfonate crystal formation T the most according to claim 4, it is characterised in that institute The mol ratio stating Rui Gefeini and p-methyl benzenesulfonic acid is 1:1～1:1.5.
The preparation method of Rui Gefeini toluenesulfonate crystal formation T the most according to claim 4, it is characterised in that institute Stating recrystallization temperature is room temperature.
The preparation method of 11. Rui Gefeini toluenesulfonate crystal formation T according to claim 4, it is characterised in that institute Stating the crystallize time is 1～48 hour.
The preparation method of 12. Rui Gefeini toluenesulfonate crystal formation T according to claim 11, it is characterised in that The described crystallize time is 1～10 hour.
13. Rui Gefeini closilate crystal formation C, its structural formula is as follows:
It is characterized in that, use Cu-K α radiation, its X-ray powder diffraction figure 2 θ be 9.0 ± 0.2 °, 9.9 ± 0.2 °, 18.2 At ± 0.2 °, 19.9 ± 0.2 °, 23.1 ± 0.2 ° and 27.4 ± 0.2 °, there is characteristic peak.
14. according to Rui Gefeini closilate crystal formation C described in claim 13, it is characterised in that its X-ray powder diffraction Figure 2 θ be 9.0 ± 0.2 °, 9.9 ± 0.2 °, 12.4 ± 0.2 °, 15.7 ± 0.2 °, 18.2 ± 0.2 °, 19.9 ± 0.2 °, 21.9 At ± 0.2 °, 23.1 ± 0.2 °, 24.1 ° ± 0.2 °, 25.2 ± 0.2 °, 25.5 ± 0.2 ° and 27.4 ± 0.2 °, there is characteristic peak.
15. according to Rui Gefeini closilate crystal formation C described in claim 14, it is characterised in that its X-ray powder diffraction Characteristic peak and the relative intensity thereof of figure are as follows:
The preparation method of Rui Gefeini closilate crystal formation C, described method according to any one of 16. claim 13～15 Including: form Rui Gefeini and p-chlorobenzenesulfonic acid solution system in soluble solvent, Rui Gefeini and p-chlorobenzenesulfonic acid respectively Mol ratio 1:1～1:2, mix two individual system formed suspensions, crystallize at a temperature of-10 DEG C～50 DEG C, obtain described crystalline substance Type C.
The preparation method of 17. Rui Gefeini closilate crystal formation C according to claim 16, it is characterised in that institute State soluble solvent selected from C1～C4Alcohol, C4～C5Ester, C3～C4Ketone, methyl tertiary butyl ether(MTBE) or normal heptane.
The preparation method of 18. Rui Gefeini closilate crystal formation C according to claim 16, it is characterised in that institute The concentration of the soluble solvent solution stating Rui Gefeini is its under recrystallization temperature in soluble solvent 0.1～1 times of dissolubility.
The preparation method of 19. Rui Gefeini closilate crystal formation C according to claim 18, it is characterised in that institute The concentration of the soluble solvent solution stating Rui Gefeini is its under recrystallization temperature in soluble solvent 0.5～1 times of dissolubility.
The preparation method of 20. Rui Gefeini closilate crystal formation C according to claim 16, it is characterised in that institute The concentration of the soluble solvent solution stating p-chlorobenzenesulfonic acid is its under recrystallization temperature in soluble solvent 0.5～1 times of dissolubility.
The preparation method of 21. Rui Gefeini closilate crystal formation C according to claim 16, it is characterised in that institute The mol ratio stating Rui Gefeini and p-chlorobenzenesulfonic acid is 1:1～1:1.5.
The preparation method of 22. Rui Gefeini closilate crystal formation C according to claim 16, it is characterised in that institute Stating recrystallization temperature is room temperature.
The preparation method of 23. Rui Gefeini closilate crystal formation C according to claim 16, it is characterised in that institute Stating the crystallize time is 1～48 hour.
The preparation method of 24. Rui Gefeini closilate crystal formation C according to claim 23, it is characterised in that institute Stating the crystallize time is 1～10 hour.
25. Rui Gefeini 1,5-napadisilate crystal formation N, its structural formula is as follows:
It is characterized in that, use Cu-K α radiation, its X-ray powder diffraction figure 2 θ be 7.3 ± 0.2 °, 10.3 ± 0.2 °, 12.8 At ± 0.2 °, 15.1 ± 0.2 °, 18.8 ± 0.2 ° and 26.1 ± 0.2 °, there is characteristic peak.
26. according to Rui Gefeini 1 described in claim 25,5-napadisilate crystal formation N, it is characterised in that its x-ray powder spreads out Penetrate figure 2 θ be 7.3 ± 0.2 °, 8.3 ± 0.2 °, 9.6 ± 0.2 °, 10.3 ± 0.2 °, 11.6 ± 0.2 °, 12.8 ± 0.2 °, 13.7 Have at ± 0.2 °, 15.1 ± 0.2 °, 16.5 ± 0.2 °, 18.8 ± 0.2 °, 19.8 ± 0.2 °, 21.1 ± 0.2 ° and 26.1 ± 0.2 ° There is characteristic peak.
27. according to Rui Gefeini 1 described in claim 26,5-napadisilate crystal formation N, it is characterised in that its x-ray powder spreads out Characteristic peak and the relative intensity thereof of penetrating figure are as follows:
The preparation method of Rui Gefeini 1,5-napadisilate crystal formation N, described side according to any one of 28. claim 25～27 Method includes: form Rui Gefeini and 1,5-naphthalenedisulfonic acid solution system in soluble solvent, Rui Gefeini and 1,5-naphthalene respectively The mol ratio of disulfonic acid is 1:1～2:1, mixes two individual system and forms suspension, crystallize at a temperature of-10 DEG C～50 DEG C, obtains To described crystal formation N.
The preparation method of 29. Rui Gefeini 1 according to claim 28,5-napadisilate crystal formation N, it is characterised in that Described soluble solvent is selected from C1～C4Alcohol, C4～C5Ester, C3～C4Ketone, methyl tertiary butyl ether(MTBE) or normal heptane.
The preparation method of 30. Rui Gefeini 1 according to claim 28,5-napadisilate crystal formation N, it is characterised in that The concentration of the soluble solvent solution of described Rui Gefeini is its under recrystallization temperature in soluble solvent 0.1～1 times of dissolubility.
The preparation method of 31. Rui Gefeini 1 according to claim 30,5-napadisilate crystal formation N, it is characterised in that The concentration of the soluble solvent solution of described Rui Gefeini is its under recrystallization temperature in soluble solvent 0.5～1 times of dissolubility.
The preparation method of 32. Rui Gefeini 1 according to claim 28,5-napadisilate crystal formation N, it is characterised in that The concentration of the soluble solvent solution of described 1,5-naphthalenedisulfonic acid be its under recrystallization temperature in soluble solvent dissolubility 0.5～ 1 times.
The preparation method of 33. Rui Gefeini 1 according to claim 28,5-napadisilate crystal formation N, it is characterised in that The mol ratio of described Rui Gefeini and 1,5-naphthalenedisulfonic acid is 2:1.5～2:1.
The preparation method of 34. Rui Gefeini 1 according to claim 28,5-napadisilate crystal formation N, it is characterised in that Described recrystallization temperature is room temperature.
The preparation method of 35. Rui Gefeini 1 according to claim 28,5-napadisilate crystal formation N, it is characterised in that The described crystallize time is 1～48 hour.
The preparation method of 36. Rui Gefeini 1 according to claim 35,5-napadisilate crystal formation N, it is characterised in that The described crystallize time is 1～10 hour.
37. Rui Gefeini ethanedisulphonate crystal formation E, its structural formula is as follows:
It is characterized in that, use Cu-K α radiation, its X-ray powder diffraction figure 2 θ be 10.6 ± 0.2 °, 12.1 ± 0.2 °, At 17.0 ± 0.2 °, 18.1 ± 0.2 °, 22.7 ± 0.2 ° and 23.6 ± 0.2 °, there is characteristic peak.
38. according to Rui Gefeini ethanedisulphonate crystal formation E described in claim 37, it is characterised in that its X-ray powder diffraction figure 2 θ be 10.6 ± 0.2 °, 12.1 ± 0.2 °, 14.1 ± 0.2 °, 15.8 ± 0.2 °, 17.0 ± 0.2 °, 18.1 ± 0.2 °, 20.1 At ± 0.2 °, 21.3 ± 0.2 °, 22.7 ± 0.2 °, 23.6 ± 0.2 °, 24.3 ± 0.2 ° and 27.8 ± 0.2 °, there is characteristic peak.
39. according to Rui Gefeini ethanedisulphonate crystal formation E described in claim 38, it is characterised in that its X-ray powder diffraction figure Characteristic peak and relative intensity as follows:
The preparation method of Rui Gefeini ethanedisulphonate crystal formation E, described method bag according to any one of 40. claim 37～39 Include: formed respectively Rui Gefeini and ethionic acid solution system in soluble solvent, Rui Gefeini and ethionic acid mole Ratio is 1:1～2:1, mixes two individual system and forms suspensions, crystallize at a temperature of-10 DEG C～50 DEG C, obtains described crystal formation E.
The preparation method of 41. Rui Gefeini ethanedisulphonate crystal formation E according to claim 40, it is characterised in that described Soluble solvent is selected from C1～C4Alcohol, C4～C5Ester, C3～C4Ketone, methyl tertiary butyl ether(MTBE) or normal heptane.
The preparation method of 42. Rui Gefeini ethanedisulphonate crystal formation E according to claim 40, it is characterised in that described The concentration of the soluble solvent solution of Rui Gefeini is its under recrystallization temperature in soluble solvent 0.1～1 times of dissolubility.
The preparation method of 43. Rui Gefeini ethanedisulphonate crystal formation E according to claim 42, it is characterised in that described The concentration of the soluble solvent solution of Rui Gefeini is its under recrystallization temperature in soluble solvent 0.5～1 times of dissolubility.
The preparation method of 44. Rui Gefeini ethanedisulphonate crystal formation E according to claim 40, it is characterised in that described The concentration of the soluble solvent solution of ethionic acid is its under recrystallization temperature in soluble solvent 0.5～1 times of dissolubility.
The preparation method of 45. Rui Gefeini ethanedisulphonate crystal formation E according to claim 40, it is characterised in that described The mol ratio of Rui Gefeini and ethionic acid is 2:1.5～2:1.
The preparation method of 46. Rui Gefeini ethanedisulphonate crystal formation E according to claim 40, it is characterised in that described Recrystallization temperature is room temperature.
The preparation method of 47. Rui Gefeini ethanedisulphonate crystal formation E according to claim 40, it is characterised in that described The crystallize time is 1～48 hour.
The preparation method of 48. Rui Gefeini ethanedisulphonate crystal formation E according to claim 47, it is characterised in that described Recrystallization temperature is 1～10 hour.
49. Rui Gefeini hydrobromate crystal formation H1, its structural formula is as follows:
It is characterized in that, use Cu-K α radiation, its X-ray powder diffraction figure 2 θ be 5.1 ± 0.2 °, 10.1 ± 0.2 °, 15.1 At ± 0.2 °, 18.2 ± 0.2 °, 19.5 ± 0.2 ° and 24.8 ± 0.2 °, there is characteristic peak.
50. according to Rui Gefeini hydrobromate crystal formation H1 described in claim 49, it is characterised in that its X-ray powder diffraction figure 2 θ be 5.1 ± 0.2 °, 10.1 ± 0.2 °, 15.1 ± 0.2 °, 18.2 ± 0.2 °, 19.5 ± 0.2 °, 20.3 ± 0.2 °, 23.2 ± At 0.2 °, 24.8 ± 0.2 °, 25.2 ± 0.2 ° and 30.0 ± 0.2 °, there is characteristic peak.
51. according to Rui Gefeini hydrobromate crystal formation H1 described in claim 50, it is characterised in that its X-ray powder diffraction figure Characteristic peak and relative intensity as follows:
The preparation method of Rui Gefeini hydrobromate crystal formation H1, described method bag according to any one of 52. claim 49～51 Include: form Rui Gefeini respectively and hydrobromic acid solution system in soluble solvent, Rui Gefeini and hydrobromic mol ratio are 1:1～1:2, mixes two individual system and forms suspension, crystallize at a temperature of-10 DEG C～50 DEG C, obtain described crystal formation H1.
The preparation method of 53. Rui Gefeini hydrobromate crystal formation H1 according to claim 52, it is characterised in that described can Solvent is selected from C1～C4Alcohol, C3～C4Ketone or normal heptane.
The preparation method of 54. Rui Gefeini hydrobromate crystal formation H1 according to claim 52, it is characterised in that described auspicious Ge Feini concentration of solution in soluble solvent is its under recrystallization temperature in soluble solvent 0.1～1 times of dissolubility.
The preparation method of 55. Rui Gefeini hydrobromate crystal formation H1 according to claim 54, it is characterised in that described auspicious Ge Feini concentration of solution in soluble solvent is its under recrystallization temperature in soluble solvent 0.5～1 times of dissolubility.
The preparation method of 56. Rui Gefeini hydrobromate crystal formation H1 according to claim 52, it is characterised in that described hydrogen The concentration of the soluble solvent solution of bromic acid is its under recrystallization temperature in soluble solvent 0.5～1 times of dissolubility.
The preparation method of 57. Rui Gefeini hydrobromate crystal formation H1 according to claim 52, it is characterised in that described auspicious Ge Feini and hydrobromic mol ratio are 1:1～1:1.5.
The preparation method of 58. Rui Gefeini hydrobromate crystal formation H1 according to claim 52, it is characterised in that described analysis Brilliant temperature is room temperature.
The preparation method of 59. Rui Gefeini hydrobromate crystal formation H1 according to claim 52, it is characterised in that described analysis The brilliant time is 1～48 hour.
The preparation method of 60. Rui Gefeini hydrobromate crystal formation H1 according to claim 59, it is characterised in that described analysis The brilliant time is 1～10 hour.
61. Rui Gefeini hydrobromate crystal formation H2, it is characterised in that using Cu-K α radiation, its X-ray powder diffraction figure is at 2 θ It is, at 10.6 ± 0.2 °, 12.0 ± 0.2 °, 16.8 ± 0.2 °, 19.2 ± 0.2 °, 21.3 ± 0.2 ° and 24.4 ± 0.2 °, there is spy Levy peak.
62. according to Rui Gefeini hydrobromate crystal formation H2 described in claim 61, it is characterised in that its X-ray powder diffraction figure 2 θ be 10.6 ± 0.2 °, 12.0 ± 0.2 °, 16.8 ± 0.2 °, 17.0 ± 0.2 °, 18.9 ± 0.2 °, 19.2 ± 0.2 °, 20.2 Have at ± 0.2 °, 20.5 ± 0.2 °, 21.3 ± 0.2 °, 24.1 ± 0.2 °, 24.4 ± 0.2 °, 25.7 ± 0.2 ° and 26.5 ± 0.2 ° There is characteristic peak.
63. according to Rui Gefeini hydrobromate crystal formation H2 described in claim 62, it is characterised in that its X-ray powder diffraction figure Characteristic peak and relative intensity as follows:
The preparation method of Rui Gefeini hydrobromate crystal formation H2, described method bag according to any one of 64. claim 61～63 Include: Rui Gefeini hydrobromate crystal formation H1 is formed suspension in a solvent, and described suspension is at a temperature of-10 DEG C～50 DEG C Crystallize, obtains described crystal formation H2, and wherein said solvent is selected from ethyl acetate, methyl tertiary butyl ether(MTBE) or its mixture.
The preparation method of 65. Rui Gefeini hydrobromate crystal formation H2 according to claim 64, it is characterised in that described auspicious The consumption of Ge Feini hydrobromate crystal formation H1 is its under recrystallization temperature in described dicyandiamide solution 1.1～20 times of dissolubility.
The preparation method of 66. Rui Gefeini hydrobromate crystal formation H2 according to claim 65, it is characterised in that described auspicious The consumption of Ge Feini hydrobromate crystal formation H1 is its under recrystallization temperature in described dicyandiamide solution 1.5～10 times of dissolubility.
The preparation method of 67. Rui Gefeini hydrobromate crystal formation H2 according to claim 64, it is characterised in that described analysis Brilliant temperature is room temperature.
The preparation method of 68. Rui Gefeini hydrobromate crystal formation H2 according to claim 64, it is characterised in that described analysis The brilliant time is 1～72 hour.
The preparation method of 69. Rui Gefeini hydrobromate crystal formation H2 according to claim 68, it is characterised in that described analysis The brilliant time is 1～10 hour.
70. Rui Gefeini esilate crystal formation Et1, its structural formula is as follows:
It is characterized in that, use Cu-K α radiation, its X-ray powder diffraction figure 2 θ be 8.2 ± 0.2 °, 8.9 ± 0.2 °, 13.0 At ± 0.2 °, 18.8 ± 0.2 °, 23.6 ± 0.2 ° and 24.6 ± 0.2 °, there is characteristic peak.
71. according to Rui Gefeini esilate crystal formation Et1 described in claim 70, it is characterised in that its X-ray powder diffraction figure 2 θ be 8.2 ± 0.2 °, 8.9 ± 0.2 °, 12.2 ± 0.2 °, 13.0 ± 0.2 °, 14.4 ± 0.2 °, 16.2 ± 0.2 °, 17.9 ± At 0.2 °, 18.8 ± 0.2 °, 20.1 ± 0.2 °, 22.0 ± 0.2 °, 23.6 ± 0.2 ° and 24.6 ± 0.2 °, there is characteristic peak.
72. according to Rui Gefeini esilate crystal formation Et1 described in claim 71, it is characterised in that its X-ray powder diffraction figure Substantially 2 θ characteristic peaks and relative intensity thereof are as follows:
The preparation method of Rui Gefeini esilate crystal formation Et1, described method bag according to any one of 73. claim 70～72 Include: forming Rui Gefeini and ethyl sulfonic acid solution system in soluble solvent respectively, the mol ratio of Rui Gefeini and ethyl sulfonic acid is 1:1～1:2, mixes two individual system and forms suspension, crystallize at a temperature of-10 DEG C～50 DEG C, obtain described crystal formation Et1.
74. according to the preparation method of the Rui Gefeini esilate crystal formation Et1 described in claim 73, it is characterised in that described Soluble solvent is selected from C1～C4Alcohol, C3～C4Ketone or C4～C5Ester.
75. according to the preparation method of the Rui Gefeini esilate crystal formation Et1 described in claim 73, it is characterised in that described The concentration of the soluble solvent solution of Rui Gefeini is its under recrystallization temperature in soluble solvent 0.1～1 times of dissolubility.
76. according to the preparation method of the Rui Gefeini esilate crystal formation Et1 described in claim 75, it is characterised in that described The concentration of the soluble solvent solution of Rui Gefeini is its under recrystallization temperature in soluble solvent 0.5～1 times of dissolubility.
77. according to the preparation method of the Rui Gefeini esilate crystal formation Et1 described in claim 73, it is characterised in that described The concentration of the soluble solvent solution of ethyl sulfonic acid is its under recrystallization temperature in soluble solvent 0.5～1 times of dissolubility.
78. according to the preparation method of the Rui Gefeini esilate crystal formation Et1 described in claim 73, it is characterised in that described The mol ratio of Rui Gefeini and ethyl sulfonic acid is 1:1～1:1.5.
79. according to the preparation method of the Rui Gefeini esilate crystal formation Et1 described in claim 73, it is characterised in that described Recrystallization temperature is room temperature.
80. according to the preparation method of the Rui Gefeini esilate crystal formation Et1 described in claim 73, it is characterised in that described The crystallize time is 1～48 hour.
The preparation method of 81. Rui Gefeini esilate crystal formation Et1 described in 0 according to Claim 8, it is characterised in that described The crystallize time is 1～10 hour.
82. Rui Gefeini esilate crystal formation Et2, it is characterised in that using Cu-K α radiation, its X-ray powder diffraction figure is at 2 θ It is, at 12.3 ± 0.2 °, 13.6 ± 0.2 °, 16.0 ± 0.2 °, 20.5 ± 0.2 °, 24.3 ± 0.2 ° and 24.5 ± 0.2 °, there is spy Levy peak.
83. Rui Gefeini esilate crystal formation Et2 described in 2 according to Claim 8, it is characterised in that its X-ray powder diffraction figure 2 θ be 7.4 ± 0.2 °, 8.2 ± 0.2 °, 12.3 ± 0.2 °, 13.6 ± 0.2 °, 16.0 ± 0.2 °, 16.9 ± 0.2 °, 18.5 ± At 0.2 °, 20.5 ± 0.2 °, 20.9 ± 0.2 °, 22.1 ° ± 0.2,24.3 ± 0.2 ° and 24.5 ± 0.2 °, there is characteristic peak.
84. Rui Gefeini esilate crystal formation Et2 described in 3 according to Claim 8, it is characterised in that its X-ray powder diffraction figure Substantially 2 θ characteristic peaks and relative intensity thereof are as follows:
The preparation method of Rui Gefeini esilate crystal formation Et2, described method bag according to any one of 85. claim 82～84 Include: Rui Gefeini esilate crystal formation Et1 is formed suspension in a solvent, and described suspension is crystallize at-10 DEG C～50 DEG C, Obtaining described crystal formation Et2, wherein said solvent is selected from methyl tertiary butyl ether(MTBE), normal heptane or its mixture.
The preparation method of 86. Rui Gefeini esilate crystal formation Et2 described in 5 according to Claim 8, it is characterised in that described Consumption is the dissolubility in described dicyandiamide solution under its recrystallization temperature 1.1～the 20 of Rui Gefeini esilate crystal formation Et1 Times.
The preparation method of 87. Rui Gefeini esilate crystal formation Et2 described in 6 according to Claim 8, it is characterised in that described Consumption is the dissolubility in described dicyandiamide solution under its recrystallization temperature 1.5～the 10 of Rui Gefeini esilate crystal formation Et1 Times.
The preparation method of 88. Rui Gefeini esilate crystal formation Et2 described in 5 according to Claim 8, it is characterised in that described Recrystallization temperature is room temperature.
The preparation method of 89. Rui Gefeini esilate crystal formation Et2 described in 5 according to Claim 8, it is characterised in that described The crystallize time is 1～72 hour.
The preparation method of 90. Rui Gefeini esilate crystal formation Et2 described in 9 according to Claim 8, it is characterised in that described The crystallize time is 1～10 hour.
91. Rui Gefeini 2-LOMAR PWA EINECS 246-676-2 crystal formation Na, its structural formula is as follows:
It is characterized in that, use Cu-K α radiation, its X-ray powder diffraction figure 2 θ be 4.7 ± 0.2 °, 13.7 ± 0.2 °, 16.4 At ± 0.2 °, 18.0 ± 0.2 °, 20.2 ± 0.2 ° and 21.9 ± 0.2 °, there is characteristic peak.
92. according to the Rui Gefeini 2-naphthalene sulfonate crystal formation Na described in claim 91, it is characterised in that its x-ray powder spreads out Figure 2 θ be 4.7 ± 0.2 °, 10.5 ± 0.2 °, 11.1 ± 0.2 °, 13.7 ± 0.2 °, 14.3 ± 0.2 °, 16.4 ± 0.2 °, 18.0 At ± 0.2 °, 20.2 ± 0.2 °, 21.5 ± 0.2 °, 21.9 ± 0.2 °, 22.5 ± 0.2 ° and 24.0 ± 0.2 °, there is characteristic peak.
93. according to the Rui Gefeini 2-naphthalene sulfonate crystal formation Na described in claim 92, it is characterised in that its x-ray powder spreads out Penetrate figure substantially 2 θ characteristic peak and relative intensity be as follows:
The preparation method of Rui Gefeini 2-naphthalene sulfonate crystal formation Na, described method according to any one of 94. claim 91～93 Including: form Rui Gefeini and 2-LOMAR PWA EINECS 246-676-2 solution system in soluble solvent, rubbing of Rui Gefeini and 2-LOMAR PWA EINECS 246-676-2 respectively Your ratio is 1:1～1:2, and by two individual system mixing, gained mixed liquor stirs at-10 DEG C～50 DEG C, removes soluble solvent, adds Normal heptane forms suspension, and described suspension is crystallize at-10 DEG C～50 DEG C, obtains described crystal formation Na.
95. according to the preparation method of the Rui Gefeini 2-naphthalene sulfonate crystal formation Na described in claim 94, it is characterised in that described Soluble solvent is selected from C1～C4Alcohol, C4～C5Ester, C3～C4Ketone or methyl tertiary butyl ether(MTBE).
96. according to the preparation method of the Rui Gefeini 2-naphthalene sulfonate crystal formation Na described in claim 94, it is characterised in that described The consumption of Rui Gefeini is its under recrystallization temperature 0.1～1 times of the dissolubility in soluble solvent.
97. according to the preparation method of the Rui Gefeini 2-naphthalene sulfonate crystal formation Na described in claim 96, it is characterised in that described The consumption of Rui Gefeini is its under recrystallization temperature 0.5～1 times of the dissolubility in soluble solvent.
98. according to the preparation method of the Rui Gefeini 2-naphthalene sulfonate crystal formation Na described in claim 94, it is characterised in that described The consumption of normal heptane is 0.1～0.5 times of Rui Gefeini soluble solvent.
99. according to the preparation method of the Rui Gefeini 2-naphthalene sulfonate crystal formation Na described in claim 94, it is characterised in that described The consumption of 2-LOMAR PWA EINECS 246-676-2 is its under recrystallization temperature in soluble solvent 0.5～1 times of dissolubility.
100. according to the preparation method of the Rui Gefeini 2-naphthalene sulfonate crystal formation Na described in claim 94, it is characterised in that institute The mol ratio stating Rui Gefeini and 2-LOMAR PWA EINECS 246-676-2 is 1:1～1:1.5.
101. according to the preparation method of the Rui Gefeini 2-naphthalene sulfonate crystal formation Na described in claim 94, it is characterised in that institute State mixed liquor and be stirred at room temperature 1 minute to 48 hours.
102. according to the preparation method of the Rui Gefeini 2-naphthalene sulfonate crystal formation Na described in claim 101, it is characterised in that institute State mixed liquor and be stirred at room temperature 1～10 hour.
103. according to the preparation method of the Rui Gefeini 2-naphthalene sulfonate crystal formation Na described in claim 94, it is characterised in that institute State suspension and be stirred at room temperature 1～48 hour.
104. according to the preparation method of the Rui Gefeini 2-naphthalene sulfonate crystal formation Na described in claim 103, it is characterised in that institute State suspension and be stirred at room temperature 1～10 hour.
105. 1 kinds of pharmaceutical compositions, one or more comprising treatment and/or prevention effective dose are appointed in claim 1-3 According to any one of one described Rui Gefeini toluenesulfonate crystal formation T, claim 13～15, Rui Gefeini is to chlorobenzene Rui Gefeini 1,5-napadisilate crystal formation N, claim 37 according to any one of sulfonate crystal formation C, claim 25～27 ～Rui Gefeini hydrogen according to any one of Rui Gefeini ethanedisulphonate crystal formation E, claim 49～51 according to any one of 39 Rui Gefeini hydrobromate crystal formation H2, claim 70～72 according to any one of bromate crystal formation H1, claim 61～63 According to any one of Rui Gefeini ethyl sulfonic acid according to any one of Rui Gefeini esilate crystal formation Et1, claim 82～84 Rui Gefeini 2-naphthalene sulfonate crystal formation Na according to any one of salt crystal formation Et2, claim 91～93, and at least one can medicine Carrier.
Rui Gefeini toluenesulfonate crystal formation T according to any one of 106. claims 1 to 3, claim 13～15 According to any one of Rui Gefeini 1,5-according to any one of Rui Gefeini closilate crystal formation C, claim 25～27 Rui Gefeini ethanedisulphonate crystal formation E, claim 49 according to any one of napadisilate crystal formation N, claim 37～39 ～Rui Gefeini hydrogen bromine according to any one of Rui Gefeini hydrobromate crystal formation H1, claim 61～63 according to any one of 51 In Rui Gefeini esilate crystal formation Et1, claim 82～84 according to any one of hydrochlorate crystal formation H2, claim 70～72 Rui Gefeini 2-LOMAR PWA EINECS 246-676-2 according to any one of Rui Gefeini esilate crystal formation Et2, claim 91～93 described in any one Pharmaceutical composition described in salt crystal formation Na or claim 105 is used for treating and/or preventing the medicine of higher proliferation disease in preparation In purposes, wherein said higher proliferation disease be selected from lymphoma, sarcoma, leukemia, breast carcinoma, respiratory cancer, the brain cancer, reproduction Organ cancer, digestive tract cancer, carcinoma of urethra, cancer eye, hepatocarcinoma, skin carcinoma, head and neck cancer, thyroid carcinoma and/or parathyroid carcinoma.
107. according to the purposes described in claim 106, it is characterised in that described higher proliferation disease is transitivity colorectum Cancer.
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Citations (4)

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WO2011113366A1 (en) * 2010-03-18 2011-09-22 苏州泽璟生物制药有限公司 Method for preparing deuterated diphenylurea
WO2012012404A1 (en) * 2010-07-19 2012-01-26 Bayer Healthcare Llc Drug combinations with fluoro-substituted omega-carboxyaryl diphenyl urea for the treatment and prevention of diseases and conditions
CN103079567A (en) * 2010-04-17 2013-05-01 拜尔健康护理有限责任公司 Synthetic metabolites of fluoro substituted omega-carboxyaryl diphenyl urea for the treatment and prevention diseases and conditions

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1856469A (en) * 2003-07-23 2006-11-01 拜尔医药品股份有限公司 Fluoro substituted omega-carboxyaryl diphenyl urea for the treatment and prevention of diseases and conditions
WO2011113366A1 (en) * 2010-03-18 2011-09-22 苏州泽璟生物制药有限公司 Method for preparing deuterated diphenylurea
CN103079567A (en) * 2010-04-17 2013-05-01 拜尔健康护理有限责任公司 Synthetic metabolites of fluoro substituted omega-carboxyaryl diphenyl urea for the treatment and prevention diseases and conditions
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