CN105315266A - Crystal forms of 1-{2-fluoro-4-[5-(4-isobutyl phenyl)-1,2,4-oxadiazole-3-yl]-benzyl}-3-azetidinecarboxylic acid - Google Patents

Crystal forms of 1-{2-fluoro-4-[5-(4-isobutyl phenyl)-1,2,4-oxadiazole-3-yl]-benzyl}-3-azetidinecarboxylic acid Download PDF

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CN105315266A
CN105315266A CN201410376027.0A CN201410376027A CN105315266A CN 105315266 A CN105315266 A CN 105315266A CN 201410376027 A CN201410376027 A CN 201410376027A CN 105315266 A CN105315266 A CN 105315266A
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oxadiazole
fluoro
benzyl
base
azetidinecarboxylic acid
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CN105315266B (en
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郑伟
潘武宾
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SUZHOU KANGNAIDE BIO-PHARMACEUTICAL Co Ltd
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SUZHOU KANGNAIDE BIO-PHARMACEUTICAL Co Ltd
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Abstract

The invention discloses crystal forms of a drug, i.e., 1-{2-fluoro-4-[5-(4-isobutyl phenyl)-1,2,4-oxadiazole-3-yl]-benzyl}-3-azetidinecarboxylic acid, for diseases or conditions mediated by an S1P1 receptor. The invention also discloses preparation methods for the crystal forms, a pharmaceutical composition of the crystal forms and application of the crystal forms in preparation of drugs used for treatment and/or prevention of diseases or conditions mediated by the S1P1 receptor.

Description

The fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } crystal formation of-3-azetidinecarboxylic acid
Technical field
The application belongs to pharmaceutical chemistry crystallization technique field.Specifically, relate to the fluoro-4-of the medicine 1-{2-[5-(4-isobutyl phenenyl)-1 by the receptor-mediated disease of S1P1 or illness, 2,4-oxadiazole-3-base]-benzyl } crystal formation of-3-azetidinecarboxylic acid, also relate to the preparation method of described crystal formation, its pharmaceutical composition and purposes.
Background technology
Polymorphic is the character of some molecules and molecular composition.Identical molecule may form different crystal because of different spread patterns.Described polymorphic has different crystalline structure and physical properties, as solubleness, stability, thermal properties, mechanical properties, purification capacity, X ray diffracting spectrum, infrared absorption pattern, Raman spectrum and solid-state nmr etc.One or more analyzing and testing modes can be used for the different crystal forms distinguishing same compound.
The crystal formation that discovery active constituents of medicine is new can provide (comprising anhydride, hydrate, solvate) material of advantage working properties, find that new anhydrous crystal forms and solvate can provide the material with better physicochemical property, such as better bioavailability, stable storing, easily processing treatment, the easy intermediate crystal form of purifying or being converted into other crystal formations as promotion.The new crystal of the compound of pharmaceutically useful also can help improve the performance of medicine.It expands formulation science man to optimize the kenel of preparation performance and available raw material, such as, improve dissolution rate, improve shelf life, more easily process.
The fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid has S1P1 receptor agonist activity and selects specificity, and having the Half-life in vivo significantly shortened, and is therefore high-quality s-generation S1P1 receptor stimulant.Large quantity research shows, there is multiple S1P1 receptor stimulant, and they can be attached to homoreceptor that lymphocyte is expressed and cause S1P1 receptor internalisation, then stops lymphocyte to be derived.So S1P1 receptor stimulant starts immunoreactive ability by stoping lymphocytic transport to reduce human body, thus can be used for the treatment of various autoimmune disorder as immunosuppressor.The fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } chemical formula of-3-azetidinecarboxylic acid is C 23h 24fN 3o 3; Molecular weight 409.45; Chemical structural formula is as follows:
The fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 is disclosed in patent documentation CN103450171A (it is incorporated in the application by way of reference), 2,4-oxadiazole-3-base]-benzyl the confirmation of-3-azetidinecarboxylic acid, preparation, composition and purposes.Particularly, the preparation method of this compound is disclosed in example 2.
In view of prior art remains deficiency, research 1-{2-fluoro-4-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } crystal formation of-3-azetidinecarboxylic acid is of great practical significance.
Summary of the invention
The object of this invention is to provide the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } crystal formation of-3-azetidinecarboxylic acid and unformed, and its preparation method, its pharmaceutical composition and purposes are provided.
According to object of the present invention, the invention provides the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the crystal formation I (hereinafter referred to as " crystal formation I ") and preparation method thereof of-3-azetidinecarboxylic acid, described crystal formation I is semihydrate.
Use Cu-K α radiation, the X-ray powder diffraction pattern of described crystal formation I is that 4.8 ± 0.2 °, 5.5 ± 0.2 °, 8.2 ± 0.2 °, 15.0 ± 0.2 °, 17.0 ± 0.2 ° and 18.6 ± 0.2 ° of places have characteristic peak at diffraction angle 2 θ.
Preferably, the X-ray powder diffraction pattern of described crystal formation I is that 4.8 ± 0.2 °, 5.5 ± 0.2 °, 8.2 ± 0.2 °, 10.1 ± 0.2 °, 11.1 ± 0.2 °, 12.1 ± 0.2 °, 15.0 ± 0.2 °, 17.0 ± 0.2 °, 18.6 ± 0.2 °, 24.0 ± 0.2 °, 24.9 ± 0.2 ° and 27.0 ± 0.2 ° of places have characteristic peak at diffraction angle 2 θ.
Further, the X-ray powder diffraction pattern of described crystal formation I is that following position has characteristic peak and relative intensity thereof at diffraction angle 2 θ:
Nonrestrictive, in a specific embodiments of the present invention, the X-ray powder diffraction pattern of described crystal formation I as shown in Figure 1.
Described crystal formation I also has the following characteristic of at least one:
Nonrestrictive, in a specific embodiments of the present invention, the FT-IR figure of described crystal formation I as shown in Figure 5.
Described crystal formation I adopts any one preparation in following method:
(1) by fluoro-for 1-{2-4-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid forms suspension in following solvent system, stirring and crystallizing, by the crystal separation of precipitation, drying, obtain the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the crystal formation I of-3-azetidinecarboxylic acid, wherein said solvent system is selected from the mixture of water or water and organic solvent, and described organic solvent is selected from C 1~ C 4alcohol, C 5~ C 6ether, C 3~ C 4ketone, ethyl acetate, Nitromethane 99Min., methylene dichloride, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, acetonitrile, chloroform, toluene, methyl-sulphoxide, C 7alkane and composition thereof;
Preferably, described organic solvent is selected from methyl alcohol, ethanol, propyl alcohol, butanols, methyl tertiary butyl ether, isopropyl ether, acetone, butanone, ethyl acetate, Nitromethane 99Min., methylene dichloride, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, acetonitrile, chloroform, toluene, methyl-sulphoxide, methylcyclohexane or normal heptane;
Preferably, in the mixture of described water and organic solvent, the volume content of water is at least 0.01%, is more preferably at least 0.1%;
Preferably, the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is 1.1 ~ 50 times of its solubleness in described solvent system under service temperature, is more preferably 1.5 ~ 10 times;
Preferably, described recrystallization temperature is room temperature to 60 DEG C, is more preferably room temperature;
Preferably, described service temperature is room temperature;
Preferably, the described crystallization time is 3-14 days, is more preferably 3-7 days;
(2) under certain temperature, by fluoro-for 1-{2-4-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid forms solution in the mixed system of water and tetrahydrofuran (THF), cooling is stirring and crystallizing also, by the crystal separation of precipitation, drying, obtains the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the crystal formation I of-3-azetidinecarboxylic acid;
Preferably, in the mixed system of described water and tetrahydrofuran (THF), the volume content of water is 0.01% ~ 50%, is more preferably 0.1% ~ 50%;
Preferably, in described solution, the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is 0.1 ~ 1 times of its solubleness in described mixed system under certain temperature, is more preferably 0.5 ~ 1 times;
Preferably, described certain temperature is 40 DEG C ~ 50 DEG C;
Preferably, described cooled temperature is room temperature;
Preferably, the described crystallization time is 0.5 ~ 72 hour, is more preferably 0.5 ~ 10 hour;
(3) to the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } add water in the solution that formed in organic solvent of-3-azetidinecarboxylic acid, stirring and crystallizing, by the crystal separation of precipitation, drying, obtain the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the crystal formation I of-3-azetidinecarboxylic acid, wherein said organic solvent is selected from ethanol and trifluoroethanol mixture, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, methyl-sulphoxide or its mixture;
Preferably, described organic solvent is selected from trifluoroethanol solution (volume content of ethanol is 66%), tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane or the methyl-sulphoxide of ethanol;
Preferably, the volume ratio of described water and organic solvent is 1:1 ~ 50:1, is more preferably 1:1 ~ 10:1;
Preferably, in described solution, the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is 0.1 ~ 1 times of its solubleness in described organic solvent under service temperature; Be more preferably 0.5 ~ 1 times;
Preferably, described service temperature is room temperature;
Preferably, described recrystallization temperature is room temperature to 60 DEG C, is more preferably room temperature;
Preferably, the described crystallization time is 0.5 ~ 72 hour, is more preferably 0.5 ~ 10 hour;
(4) by fluoro-for 1-{2-4-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the solution evaporation crystallization of-3-azetidinecarboxylic acid in the mixed system of water and organic solvent, by the crystal separation of precipitation, drying, obtain the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the crystal formation I of-3-azetidinecarboxylic acid; Wherein said organic solvent is selected from propyl alcohol, acetone, tetrahydrofuran (THF) or its mixture;
Preferably, described organic solvent is selected from Virahol, acetone or tetrahydrofuran (THF);
Preferably, in the mixture of described water and organic solvent, the volume content of water is 0.01% ~ 50%, is more preferably at least 0.1% ~ 50%;
Preferably, the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is 0.1 ~ 1 times of its solubleness in described solvent system under service temperature, is more preferably 0.5 ~ 1 times;
Preferably, described service temperature is room temperature;
Preferably, described recrystallization temperature is room temperature to 60 DEG C, is more preferably room temperature;
Preferably, the described crystallization time is 1 ~ 7 day, is more preferably 3 ~ 7 days;
In the preparation method of above-mentioned (1) ~ (4) crystal formation I, described drying temperature is room temperature ~ 60 DEG C, is preferably 40 DEG C; Described time of drying is 1 ~ 48 hour, is preferably 1 ~ 24 hour.
Described crystal formation I has following beneficial effect:
(1) place 1 month under described crystal formation I, room temperature-97%RH, room temperature-75%RH uncovered in drying at room temperature device, room temperature or room temperature-44%RH, crystal formation is constant;
(2) described crystal formation I quality change in 20 ~ 80%RH range of humidity variation is only about 0.8%, not easily moisture absorption;
(3) described crystal formation I is crystal formation the most stable under Aquo System, and therefore it has better using value in wet granulation or mixed suspension form.
(4) preparation prepared for raw material with crystal formation I is in placement after 6 months, and its crystal formation and dissolution rate all do not change, and the application of its applicable formulation products is described.
The above-mentioned character of described crystal formation I shows: the stability of crystal form of crystal formation I of the present invention is good, water absorbability is low, the problems such as the uneven and purity drop of the content caused due to the factor such as time, humidity in the processes such as medicine manufacture, storage and transport can be resisted better, reduce changed by active substance crystal formation, the unstable and foreign matter content of content increases the curative effect downside risk and security risk that bring; And crystal formation I of the present invention is crystal formation the most stable in Aquo System, is more suitable for the wet granulation technology of solid preparation or makes suspensoid, there is good preparation processing suitability, production favorable reproducibility, and be conducive to storage and the transport in later stage.
According to object of the present invention, the invention provides the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } form IV (hereinafter referred to as " form IV ") and preparation method thereof of-3-azetidinecarboxylic acid, described form IV is anhydride.
Use Cu-K α radiation, the X-ray powder diffraction pattern of described form IV is that 4.8 ± 0.2 °, 9.0 ± 0.2 °, 15.1 ± 0.2 °, 15.9 ± 0.2 °, 17.5 ± 0.2 ° and 17.7 ± 0.2 ° of places have characteristic peak at diffraction angle 2 θ.
Preferably, the X-ray powder diffraction pattern of described form IV is that 4.8 ± 0.2 °, 9.0 ± 0.2 °, 9.8 ± 0.2 °, 12.4 ± 0.2 °, 13.7 ± 0.2 °, 14.8 ± 0.2 °, 15.1 ± 0.2 °, 15.9 ± 0.2 °, 17.5 ± 0.2 °, 17.7 ± 0.2 °, 18.2 ± 0.2 ° and 19.8 ± 0.2 ° of places have characteristic peak at diffraction angle 2 θ.
Further, the X-ray powder diffraction pattern of described form IV is that following position has characteristic peak and relative intensity thereof at diffraction angle 2 θ:
Nonrestrictive, in a specific embodiments of the present invention, the X-ray powder diffraction pattern of described form IV as shown in Figure 6.
Described form IV also has the following characteristic of at least one:
Nonrestrictive, in a specific embodiments of the present invention, the FT-IR figure of described form IV as shown in Figure 10.
Described form IV adopts any one preparation in following method:
(1) by fluoro-for 1-{2-4-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid forms suspension in following organic solvent system, stirring and crystallizing, by the crystal separation of precipitation, drying, obtain the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } form IV of-3-azetidinecarboxylic acid, wherein said organic solvent is selected from C 2~ C 3alcohol, acetone, C 4~ C 5ester, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, acetonitrile and composition thereof;
Preferably, described organic solvent is selected from acetone, ethyl acetate, isopropyl acetate, 1, the ethanolic soln (volume content of acetonitrile is 50%) of the ethanolic soln (volume content of acetone is 50%) of 4-dioxane, acetonitrile, acetone, the ethanolic soln (volume content of tetrahydrofuran (THF) is 50%) of tetrahydrofuran (THF) and acetonitrile, be more preferably acetone, ethyl acetate, isopropyl acetate, Isosorbide-5-Nitrae-dioxane and acetonitrile;
Preferably, the process of described organic solvent drying, the volume content of Water in Organic Solvents is less than 0.001%;
Preferably, the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is 1.1 ~ 50 times of its solubleness in described solvent system under service temperature, is more preferably 1.5 ~ 10 times;
Preferably, described service temperature is room temperature;
Preferably, described recrystallization temperature is room temperature to 60 DEG C, is more preferably room temperature;
Preferably, the described crystallization time is 3-14 days, is more preferably 3-7 days;
(2) under certain temperature, by fluoro-for 1-{2-4-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl-3-azetidinecarboxylic acid forms solution in organic solvent, cooling stirring and crystallizing, by separate out crystal separation, drying, obtain the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } form IV of-3-azetidinecarboxylic acid, wherein said organic solvent is selected from C 1~ C 4alcohol, C 3~ C 4ketone, C 4~ C 5ester, Isosorbide-5-Nitrae-dioxane, acetonitrile, toluene and composition thereof;
Preferably, described organic solvent is selected from methyl alcohol, ethanol, Virahol, n-propyl alcohol, sec-butyl alcohol, propyl carbinol, acetone, butanone, ethyl acetate, isopropyl acetate, 1, the acetonitrile solution (volume content of ethanol is 25%) of 4-dioxane, toluene and ethanol, be more preferably methyl alcohol, ethanol, Virahol, propyl carbinol, acetone, butanone, ethyl acetate, isopropyl acetate, Isosorbide-5-Nitrae-dioxane, toluene;
Preferably, the process of described organic solvent drying, the volume content of Water in Organic Solvents is less than 0.001%;
Preferably, in described solution, the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is its 0.1 ~ 1 times of solubleness in described organic solvent under certain temperature, is more preferably 0.5 ~ 1 times;
Preferably, described certain temperature is 40 DEG C ~ 80 DEG C, is more preferably 50 DEG C ~ 80 DEG C;
Preferably, described cooled temperature is room temperature;
Preferably, the described crystallization time is 0.5 ~ 72 hour, is more preferably 0.5 ~ 10 hour;
(3) to the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } add slightly soluble or insoluble solvent in the solution that formed in soluble solvent of-3-azetidinecarboxylic acid, stirring and crystallizing, by the crystal separation of precipitation, drying, obtain the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } form IV of-3-azetidinecarboxylic acid, wherein said soluble solvent is selected from trifluoroethanol, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, methyl-sulphoxide or its mixture; Described slightly soluble or insoluble solvent are selected from C 3~ C 4alcohol, C 4~ C 5ester, isopropyl ether, normal heptane or its mixture;
Preferably, described soluble solvent is selected from trifluoroethanol, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane or methyl-sulphoxide;
Preferably, described slightly soluble or insoluble solvent are selected from n-propyl alcohol, propyl carbinol, sec-butyl alcohol, ethyl acetate, isopropyl acetate, isopropyl ether or normal heptane;
Preferably, the equal drying process of described solvent, the volume content of Water in Organic Solvents is less than 0.001%;
Preferably, the volume ratio of described slightly soluble or insoluble solvent and soluble solvent is 1:1 ~ 50:1, is more preferably 1:1 ~ 10:1;
Preferably, in described solution, the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is 0.1 ~ 1 times of its solubleness in described soluble solvent under service temperature; Be more preferably 0.5 ~ 1 times;
Preferably, described service temperature is room temperature;
Preferably, described recrystallization temperature is room temperature to 60 DEG C, is more preferably room temperature;
Preferably, the described crystallization time is 0.5 ~ 72 hour, is more preferably 0.5 ~ 10 hour;
(4) by fluoro-for 1-{2-4-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid solution evaporation crystallization in organic solvent, by the crystal separation of precipitation, drying, obtain the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } form IV of-3-azetidinecarboxylic acid; Wherein said organic solvent is selected from C 1~ C 4alcohol, C 4~ C 5ester, butanone, tetrahydrofuran (THF), methyl-sulphoxide or its mixture;
Preferably, described organic solvent is selected from methyl alcohol, ethanol, Virahol, n-propyl alcohol, sec-butyl alcohol, propyl carbinol, butanone, ethyl acetate, isopropyl acetate, tetrahydrofuran (THF) or methyl-sulphoxide;
Preferably, the process of described organic solvent drying, the volume content of Water in Organic Solvents is less than 0.001%;
Preferably, the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is 0.1 ~ 1 times of its solubleness in described solvent system under service temperature, is more preferably 0.5 ~ 1 times;
Preferably, described service temperature is room temperature;
Preferably, described recrystallization temperature is room temperature to 60 DEG C, is more preferably room temperature;
Preferably, the described crystallization time is 1 ~ 7 day, is more preferably 3 ~ 7 days;
In the preparation method of above-mentioned (1) ~ (4) form IV, described drying temperature is room temperature ~ 60 DEG C, is preferably 40 DEG C; Described time of drying is 1 ~ 48 hour, is preferably 1 ~ 24 hour.
Described form IV has following beneficial effect:
(1) place 1 month under described form IV, room temperature-97%RH, room temperature-75%RH uncovered in drying at room temperature device, room temperature or room temperature-44%RH, crystal formation is constant;
(2) described form IV turns to about 1.6% in the quantitative change of 20 ~ 80%RH range of humidity variation endoplasm;
(3) described form IV is crystal formation the most stable under pure organic solvent condition;
(4) described form IV is rod-shpaed particle, and particle is comparatively large, good fluidity;
(5) with form IV be the preparation prepared of raw material in placement after 6 months, its crystal formation and dissolution rate all do not change, and the application of its applicable formulation products is described.
The above-mentioned character of described form IV shows: the stability of crystal form of form IV of the present invention is good, water absorbability is low, the problems such as the uneven and purity drop of the content caused due to the factor such as time, humidity in the processes such as medicine manufacture, storage and transport can be resisted better, reduce changed by active substance crystal formation, the unstable and foreign matter content of content increases the curative effect downside risk and security risk that bring; And form IV of the present invention is crystal formation the most stable in pure organic solvent, there is good preparation processing suitability, production favorable reproducibility, and be conducive to storage and the transport in later stage; The granule-morphology of crystal form V I of the present invention is good, good fluidity, and be conducive to the accurate quantitative analysis in preparation preparation and topple over, production favorable reproducibility, has good preparation processing suitability.
According to object of the present invention, the invention provides the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the crystal form X II (hereinafter referred to as " crystal form X II ") and preparation method thereof of-3-azetidinecarboxylic acid, described crystal form X II is anhydride.
Use Cu-K α radiation, the X-ray powder diffraction pattern of described crystal form X II is that 6.3 ± 0.2 °, 9.5 ± 0.2 °, 12.7 ± 0.2 °, 18.0 ± 0.2 ° and 19.3 ± 0.2 ° of places have characteristic peak at diffraction angle 2 θ.
Preferably, the X-ray powder diffraction pattern of described crystal form X II is that 6.3 ± 0.2 °, 9.5 ± 0.2 °, 12.7 ± 0.2 °, 18.0 ± 0.2 °, 19.3 ± 0.2 °, 21.8 ± 0.2 °, 22.1 ± 0.2 °, 22.4 ± 0.2 °, 24.2 ± 0.2 °, 24.6 ± 0.2 ° and 25.7 ± 0.2 ° of places have characteristic peak at diffraction angle 2 θ.
Further, the X-ray powder diffraction pattern of described crystal form X II is that following position has characteristic peak and relative intensity thereof at diffraction angle 2 θ:
Nonrestrictive, in a specific embodiments of the present invention, the X-ray powder diffraction pattern of described crystal form X II as shown in figure 11.
Described crystal form X II also has the following characteristic of at least one:
Nonrestrictive, in a specific embodiments of the present invention, the FT-IR figure of described crystal form X II as shown in figure 15.
Described crystal form X II adopts following method to prepare:
By fluoro-for 1-{2-4-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid forms suspension in anhydrous methanol, stirring and crystallizing, by the crystal separation of precipitation, drying, obtain the fluoro-4-of described 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the crystal form X II of-3-azetidinecarboxylic acid;
Preferably, the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is 1.1 ~ 50 times of its solubleness in anhydrous methanol under service temperature, is more preferably 1.5 ~ 10 times;
Preferably, described recrystallization temperature is room temperature to 60 DEG C, is more preferably room temperature;
Preferably, described service temperature is room temperature;
Preferably, the described crystallization time is 3-14 days, is more preferably 3-7 days;
In the preparation method of above-mentioned crystal form X II, described drying temperature is room temperature ~ 60 DEG C, is preferably 40 DEG C; Described time of drying is 1 ~ 48 hour, is preferably 1 ~ 24 hour.
Described crystal form X II has following beneficial effect:
(1) place 1 month under described crystal form X II, room temperature-97%RH, room temperature-75%RH uncovered in drying at room temperature device, room temperature or room temperature-44%RH, crystal formation is constant;
(2) described crystal form X II quality change in 20 ~ 80%RH range of humidity variation is only about 1.3%;
(3) described crystal form X II has good stability in water;
(4) preparation prepared for raw material with crystal form X II is in placement after 6 months, and its crystal formation and dissolution rate all do not change, and the application of its applicable formulation products is described.
The above-mentioned character of described crystal form X II shows: the stability of crystal form of crystal form X II of the present invention is good, water absorbability is low, the problems such as the uneven and purity drop of the content caused due to the factor such as time, humidity in the processes such as medicine manufacture, storage and transport can be resisted better, reduce changed by active substance crystal formation, the unstable and foreign matter content of content increases the curative effect downside risk and security risk that bring; And crystal form X II of the present invention has certain stability in water, be more suitable for the wet granulation technology of solid preparation or make suspensoid, there is good preparation processing suitability, production favorable reproducibility, and being conducive to storage and the transport in later stage.
According to object of the present invention, the invention provides the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } crystal form II (hereinafter referred to as " crystal form II ") of-3-azetidinecarboxylic acid and preparation method thereof.
Use Cu-K α radiation, the X-ray powder diffraction pattern of described crystal form II is that 5.3 ± 0.2 °, 12.8 ± 0.2 °, 14.7 ± 0.2 °, 16.9 ± 0.2 °, 19.1 ± 0.2 ° and 19.5 ± 0.2 ° of places have characteristic peak at diffraction angle 2 θ.
Preferably, the X-ray powder diffraction pattern of described crystal form II is that 5.3 ± 0.2 °, 6.3 ± 0.2 °, 8.1 ± 0.2 °, 9.8 ± 0.2 °, 12.8 ± 0.2 °, 14.7 ± 0.2 °, 15.6 ± 0.2 °, 16.9 ± 0.2 °, 18.5 ± 0.2 °, 19.1 ± 0.2 °, 19.5 ± 0.2 ° and 21.7 ± 0.2 ° of places have characteristic peak at diffraction angle 2 θ.
Further, the X-ray powder diffraction pattern of described crystal form II is that following position has characteristic peak and relative intensity thereof at diffraction angle 2 θ:
Nonrestrictive, in a specific embodiments of the present invention, the X-ray powder diffraction pattern of described crystal form II as shown in figure 16.
Described crystal form II also has the following characteristic of at least one:
Nonrestrictive, in a specific embodiments of the present invention, the FT-IR figure of described crystal form II as shown in figure 17.
Described crystal form II adopts following method to prepare:
By fluoro-for 1-{2-4-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the crystal formation I of-3-azetidinecarboxylic acid is warming up to and sloughs crystal water completely, then room temperature crystallization is naturally cooled to, namely the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 is obtained, 2,4-oxadiazole-3-base]-benzyl } crystal form II of-3-azetidinecarboxylic acid;
Preferably, described temperature-rising method is TGA, DSC, thermal station or baking oven;
Preferably, the temperature risen to described in is 100 DEG C ~ 150 DEG C;
Preferably, the described crystallization time is 0.5-24 hour.
According to object of the present invention, the invention provides the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the crystal form II I (hereinafter referred to as " crystal form II I ") of-3-azetidinecarboxylic acid and preparation method thereof.
Use Cu-K α radiation, the X-ray powder diffraction pattern of described crystal form II I is that 4.1 ± 0.2 °, 4.9 ± 0.2 °, 8.2 ± 0.2 °, 8.8 ± 0.2 °, 11.3 ± 0.2 ° and 12.3 ± 0.2 ° of places have characteristic peak at diffraction angle 2 θ.
Preferably, the X-ray powder diffraction pattern of described crystal form II I is that 4.1 ± 0.2 °, 4.9 ± 0.2 °, 8.2 ± 0.2 °, 8.8 ± 0.2 °, 9.8 ± 0.2 °, 11.3 ± 0.2 °, 12.3 ± 0.2 °, 19.8 ± 0.2 °, 22.0 ± 0.2 ° and 24.8 ± 0.2 ° of places have characteristic peak at diffraction angle 2 θ.
Further, the X-ray powder diffraction pattern of described crystal form II I is that following position has characteristic peak and relative intensity thereof at diffraction angle 2 θ:
Nonrestrictive, in a specific embodiments of the present invention, the X-ray powder diffraction pattern of described crystal form II I as shown in figure 18.
Described crystal form II I also has the following characteristic of at least one:
Nonrestrictive, in a specific embodiments of the present invention, the FT-IR figure of described crystal form II I as shown in figure 19.
Described crystal form II I adopts any one preparation in following method:
(1) to the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } add solvent resistant in the solution that formed in trifluoroethanol of-3-azetidinecarboxylic acid, stirring and crystallizing, by crystal separation, the non-drying separated out, obtain the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the crystal form II I of-3-azetidinecarboxylic acid, wherein said solvent resistant is selected from water, C 3~ C 4ketone, C 4ester, C 5~ C 6ether, acetonitrile or its mixture;
Preferably, described solvent resistant is selected from water, acetone, ethyl acetate, isopropyl ether, methyl tertiary butyl ether, acetonitrile;
Preferably, the volume ratio of described solvent resistant and trifluoroethanol is 1:1 ~ 50:1, is more preferably 1:1 ~ 10:1;
Preferably, in described solution, the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is 0.1 ~ 1 times of its solubleness in trifluoroethanol under service temperature; Be more preferably 0.5 ~ 1 times;
Preferably, described service temperature is room temperature;
Preferably, described recrystallization temperature is room temperature to 60 DEG C, is more preferably room temperature;
Preferably, the described crystallization time is 0.5 ~ 72 hour, is more preferably 0.5 ~ 10 hour;
(2) by fluoro-for 1-{2-4-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the solution evaporation crystallization of-3-azetidinecarboxylic acid in trifluoroethanol, by crystal separation, the non-drying separated out, obtain the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the crystal form II I of-3-azetidinecarboxylic acid;
Preferably, the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is 0.1 ~ 1 times of its solubleness in trifluoroethanol under service temperature, is more preferably 0.5 ~ 1 times;
Preferably, described service temperature is room temperature;
Preferably, described recrystallization temperature is room temperature;
Preferably, the described crystallization time is 1 ~ 7 day, is more preferably 3 ~ 7 days.
According to object of the present invention, the invention provides the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } crystal form V (hereinafter referred to as " crystal form V ") of-3-azetidinecarboxylic acid and preparation method thereof.
Use Cu-K α radiation, the X-ray powder diffraction pattern of described crystal form V is that 6.2 ± 0.2 °, 11.4 ± 0.2 °, 13.5 ± 0.2 °, 17.2 ± 0.2 °, 17.8 ± 0.2 ° and 18.9 ± 0.2 ° of places have characteristic peak at diffraction angle 2 θ.
Preferably, the X-ray powder diffraction pattern of described crystal form V is that 6.2 ± 0.2 °, 8.0 ± 0.2 °, 11.4 ± 0.2 °, 12.6 ± 0.2 °, 13.5 ± 0.2 °, 16.2 ± 0.2 °, 17.2 ± 0.2 °, 17.8 ± 0.2 °, 18.9 ± 0.2 °, 20.4 ± 0.2 ° and 22.6 ± 0.2 ° of places have characteristic peak at diffraction angle 2 θ.
Further, the X-ray powder diffraction pattern of described crystal form V is that following position has characteristic peak and relative intensity thereof at diffraction angle 2 θ:
Nonrestrictive, in a specific embodiments of the present invention, the X-ray powder diffraction pattern of described crystal form V as shown in figure 20.
Described crystal form V also has the following characteristic of at least one:
Nonrestrictive, in a specific embodiments of the present invention, the FT-IR figure of described crystal form V as shown in figure 21.
Described crystal form V adopts following method to prepare:
By fluoro-for 1-{2-4-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid forms suspension in propyl carbinol, stirring and crystallizing, by the crystal separation of precipitation, drying, obtain the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } crystal form V of-3-azetidinecarboxylic acid;
Preferably, the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is 1.1 ~ 50 times of its solubleness in propyl carbinol under service temperature, is more preferably 1.5 ~ 10 times;
Preferably, described service temperature is room temperature;
Preferably, described recrystallization temperature is room temperature to 60 DEG C, is more preferably room temperature;
Preferably, the described crystallization time is 3-14 days, is more preferably 3-7 days;
In the preparation method of above-mentioned crystal form V, described drying temperature is room temperature ~ 60 DEG C, is preferably 40 DEG C; Described time of drying is 1 ~ 48 hour, is preferably 1 ~ 24 hour.
According to object of the present invention, the invention provides the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the crystal form V I (hereinafter referred to as " crystal form V I ") of-3-azetidinecarboxylic acid and preparation method thereof.
Use Cu-K α radiation, the X-ray powder diffraction pattern of described crystal form V I is that 6.8 ± 0.2 °, 7.2 ± 0.2 °, 8.9 ± 0.2 °, 17.2 ± 0.2 ° and 17.7 ± 0.2 ° of places have characteristic peak at diffraction angle 2 θ.
Preferably, the X-ray powder diffraction pattern of described crystal form V I is that 5.7 ± 0.2 °, 6.2 ± 0.2 °, 6.8 ± 0.2 °, 7.2 ± 0.2 °, 8.9 ± 0.2 °, 13.6 ± 0.2 °, 14.5 ± 0.2 °, 17.2 ± 0.2 °, 17.7 ± 0.2 °, 18.4 ± 0.2 ° and 19.4 ± 0.2 ° of places have characteristic peak at diffraction angle 2 θ.
Further, the X-ray powder diffraction pattern of described crystal form V I is that following position has characteristic peak and relative intensity thereof at diffraction angle 2 θ:
Nonrestrictive, in a specific embodiments of the present invention, the X-ray powder diffraction pattern of described crystal form V I as shown in figure 22.
Described crystal form V I adopts following method to prepare:
By fluoro-for 1-{2-4-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid forms suspension in ethanol, stirring and crystallizing, by the crystal separation of precipitation, drying, obtain the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the crystal form V I of-3-azetidinecarboxylic acid;
Preferably, the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is 1.1 ~ 50 times of its solubleness in ethanol under service temperature, is more preferably 1.5 ~ 10 times;
Preferably, described service temperature is room temperature;
Preferably, described recrystallization temperature is room temperature to 60 DEG C, is more preferably room temperature;
Preferably, the described crystallization time is 3-14 days, is more preferably 3-7 days;
In the preparation method of above-mentioned crystal form V I, described drying temperature is room temperature ~ 60 DEG C, is preferably 40 DEG C; Described time of drying is 1 ~ 48 hour, is preferably 1 ~ 24 hour.
According to object of the present invention, the invention provides the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the crystal form V II (hereinafter referred to as " crystal form V II ") of-3-azetidinecarboxylic acid and preparation method thereof.
Use Cu-K α radiation, the X-ray powder diffraction pattern of described crystal form V II is that 5.6 ± 0.2 °, 8.4 ± 0.2 °, 11.3 ± 0.2 °, 19.9 ± 0.2 °, 22.8 ± 0.2 ° and 25.8 ± 0.2 ° of places have characteristic peak at diffraction angle 2 θ.
Further, the X-ray powder diffraction pattern of described crystal form V II is that following position has characteristic peak and relative intensity thereof at diffraction angle 2 θ:
Nonrestrictive, in a specific embodiments of the present invention, the X-ray powder diffraction pattern of described crystal form V II as shown in figure 23.
Described crystal form V II also has the following characteristic of at least one:
Nonrestrictive, in a specific embodiments of the present invention, the FT-IR figure of described crystal form V II as shown in figure 24.
Described crystal form V II adopts following method to prepare:
Form the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } solution of-3-azetidinecarboxylic acid in methyl-sulphoxide, water-filled closed atmosphere is placed in by uncovered for the reaction flask of solution, treat crystallization in water vapor diffusion to dimethyl sulfoxide solution, by crystal separation, the non-drying separated out, obtain the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the crystal form V II of-3-azetidinecarboxylic acid;
Preferably, the volume ratio of described water and methyl-sulphoxide is 1:1 ~ 50:1, is more preferably 1:1 ~ 10:1;
Preferably, the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is 0.1 ~ 1 times of its solubleness in methyl-sulphoxide under service temperature; Be more preferably 0.5 ~ 1 times;
Preferably, described service temperature is room temperature;
Preferably, described recrystallization temperature is room temperature to 60 DEG C, is more preferably room temperature;
Preferably, the described crystallization time is 3-14 days, is more preferably 7-14 days.
According to object of the present invention, the invention provides the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the crystal form V III (hereinafter referred to as " crystal form V III ") and preparation method thereof of-3-azetidinecarboxylic acid.
Use Cu-K α radiation, the X-ray powder diffraction pattern of described crystal form V III is that 3.5 ± 0.2 °, 7.2 ± 0.2 °, 14.5 ± 0.2 °, 17.7 ± 0.2 °, 18.5 ± 0.2 ° and 19.5 ± 0.2 ° of places have characteristic peak at diffraction angle 2 θ.
Preferably, the X-ray powder diffraction pattern of described crystal form V III is that 3.5 ± 0.2 °, 7.2 ± 0.2 °, 9.8 ± 0.2 °, 12.7 ± 0.2 °, 14.5 ± 0.2 °, 16.8 ± 0.2 °, 17.2 ± 0.2 °, 17.7 ± 0.2 °, 18.2 ± 0.2 °, 18.5 ± 0.2 ° and 19.5 ± 0.2 ° of places have characteristic peak at diffraction angle 2 θ.
Further, the X-ray powder diffraction pattern of described crystal form V III is that following position has characteristic peak and relative intensity thereof at diffraction angle 2 θ:
Nonrestrictive, in a specific embodiments of the present invention, the X-ray powder diffraction pattern of described crystal form V III as shown in figure 25.
Described crystal form V III also has the following characteristic of at least one:
Nonrestrictive, in a specific embodiments of the present invention, the FT-IR figure of described crystal form V III as shown in figure 26.
Described crystal form V III adopts following method to prepare:
By fluoro-for 1-{2-4-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the crystal form V I of-3-azetidinecarboxylic acid forms suspension in ethanol, stirring and crystallizing, by the crystal separation of precipitation, drying, obtain the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the crystal form V III of-3-azetidinecarboxylic acid;
Preferably, the consumption of crystal form V I is 1.1 ~ 50 times of its solubleness in ethanol under service temperature, is more preferably 1.5 ~ 10 times;
Preferably, described service temperature is room temperature;
Preferably, described recrystallization temperature is room temperature to 60 DEG C, is more preferably room temperature;
Preferably, the described crystallization time is 3-14 days, is more preferably 3-7 days;
In the preparation method of above-mentioned crystal form V III, described drying temperature is room temperature ~ 60 DEG C, is preferably 40 DEG C; Described time of drying is 1 ~ 48 hour, is preferably 1 ~ 24 hour.
According to object of the present invention, the invention provides the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the crystal formation IX (hereinafter referred to as " crystal formation IX ") of-3-azetidinecarboxylic acid and preparation method thereof.
Use Cu-K α radiation, the X-ray powder diffraction pattern of described crystal formation IX is that 6.2 ± 0.2 °, 7.0 ± 0.2 °, 12.5 ± 0.2 °, 17.1 ± 0.2 °, 17.5 ± 0.2 ° and 17.9 ± 0.2 ° of places have characteristic peak at diffraction angle 2 θ.
Preferably, the X-ray powder diffraction pattern of described crystal formation IX is that 4.8 ± 0.2 °, 6.2 ± 0.2 °, 7.0 ± 0.2 °, 8.2 ± 0.2 °, 9.7 ± 0.2 °, 11.5 ± 0.2 °, 12.5 ± 0.2 °, 13.4 ± 0.2 °, 14.3 ± 0.2 °, 17.1 ± 0.2 °, 17.5 ± 0.2 ° and 17.9 ± 0.2 ° of places have characteristic peak at diffraction angle 2 θ.
Further, the X-ray powder diffraction pattern of described crystal formation IX is that following position has characteristic peak and relative intensity thereof at diffraction angle 2 θ:
Nonrestrictive, in a specific embodiments of the present invention, the X-ray powder diffraction pattern of described crystal formation IX as shown in figure 27.
Described crystal formation IX also has the following characteristic of at least one:
Nonrestrictive, in a specific embodiments of the present invention, the FT-IR figure of described crystal formation IX as shown in figure 28.
Described crystal formation IX adopts following method to prepare:
By fluoro-for 1-{2-4-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid forms suspension in Virahol, stirring and crystallizing, by the crystal separation of precipitation, drying, obtain the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the crystal formation IX of-3-azetidinecarboxylic acid;
Preferably, the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is 1.1 ~ 50 times of its solubleness in Virahol under service temperature, is more preferably 1.5 ~ 10 times;
Preferably, described service temperature is room temperature;
Preferably, described recrystallization temperature is room temperature to 60 DEG C, is more preferably room temperature;
Preferably, the described crystallization time is 3-14 days, is more preferably 3-7 days;
In the preparation method of above-mentioned crystal formation IX, described drying temperature is room temperature ~ 60 DEG C, is preferably 40 DEG C; Described time of drying is 1 ~ 48 hour, is preferably 1 ~ 24 hour.
According to object of the present invention, the invention provides the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } crystal form X (hereinafter referred to as " crystal form X ") of-3-azetidinecarboxylic acid and preparation method thereof.
Use Cu-K α radiation, the X-ray powder diffraction pattern of described crystal form X is that 3.1 ± 0.2 °, 5.9 ± 0.2 °, 6.4 ± 0.2 °, 17.7 ± 0.2 ° and 18.1 ± 0.2 ° of places have characteristic peak at diffraction angle 2 θ.
Preferably, the X-ray powder diffraction pattern of described crystal form X is that 3.1 ± 0.2 °, 5.9 ± 0.2 °, 6.4 ± 0.2 °, 14.5 ± 0.2 °, 16.5 ± 0.2 °, 17.7 ± 0.2 °, 18.1 ± 0.2 °, 18.4 ± 0.2 °, 19.2 ± 0.2 ° and 22.2 ± 0.2 ° of places have characteristic peak at diffraction angle 2 θ.
Further, the X-ray powder diffraction pattern of described crystal form X is that following position has characteristic peak and relative intensity thereof at diffraction angle 2 θ:
Nonrestrictive, in a specific embodiments of the present invention, the X-ray powder diffraction pattern of described crystal form X as shown in figure 29.
Described crystal form X also has the following characteristic of at least one:
Nonrestrictive, in a specific embodiments of the present invention, the FT-IR figure of described crystal form X as shown in figure 30.
Described crystal form X adopts following method to prepare:
By fluoro-for 1-{2-4-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid is 1, solution evaporation crystallization in 4-dioxane, by the crystal separation of precipitation, drying, obtain the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } crystal form X of-3-azetidinecarboxylic acid;
Preferably, the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is 0.1 ~ 1 times of its solubleness in Isosorbide-5-Nitrae-dioxane under service temperature, is more preferably 0.5 ~ 1 times;
Preferably, described service temperature is room temperature;
Preferably, described recrystallization temperature is room temperature to 60 DEG C, is more preferably 60 DEG C;
Preferably, the described crystallization time is 1 ~ 7 day, is more preferably 3 ~ 7 days;
In the preparation method of above-mentioned crystal form X, described drying temperature is room temperature ~ 60 DEG C, is preferably 40 DEG C; Described time of drying is 1 ~ 48 hour, is preferably 1 ~ 24 hour.
According to object of the present invention, the invention provides the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the crystal form X I (hereinafter referred to as " crystal form X I ") of-3-azetidinecarboxylic acid and preparation method thereof.
Use Cu-K α radiation, the X-ray powder diffraction pattern of described crystal form X I is that 8.9 ± 0.2 °, 15.0 ± 0.2 °, 15.7 ± 0.2 °, 18.2 ± 0.2 ° and 18.7 ± 0.2 ° of places have characteristic peak at diffraction angle 2 θ.
Preferably, the X-ray powder diffraction pattern of described crystal form X I is that 8.9 ± 0.2 °, 9.6 ± 0.2 °, 15.0 ± 0.2 °, 15.7 ± 0.2 °, 16.4 ± 0.2 °, 17.0 ± 0.2 °, 17.3 ± 0.2 °, 17.7 ± 0.2 °, 18.2 ± 0.2 ° and 18.7 ± 0.2 ° of places have characteristic peak at diffraction angle 2 θ.
Further, the X-ray powder diffraction pattern of described crystal form X I is that following position has characteristic peak and relative intensity thereof at diffraction angle 2 θ:
Nonrestrictive, in a specific embodiments of the present invention, the X-ray powder diffraction pattern of described crystal form X I as shown in figure 31.
Described crystal form X I also has the following characteristic of at least one:
Nonrestrictive, in a specific embodiments of the present invention, the FT-IR figure of described crystal form X I as shown in figure 32.
Described crystal form X I adopts following method to prepare:
By fluoro-for 1-{2-4-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid forms suspension in toluene, stirring and crystallizing, by the crystal separation of precipitation, drying, obtain the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the crystal form X I of-3-azetidinecarboxylic acid;
Preferably, the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is 1.1 ~ 50 times of its solubleness in toluene under service temperature, is more preferably 1.5 ~ 10 times;
Preferably, described service temperature is 60 DEG C;
Preferably, described recrystallization temperature is room temperature to 60 DEG C, is more preferably 60 DEG C;
Preferably, the described crystallization time is 3-14 days, is more preferably 3-7 days;
In the preparation method of above-mentioned crystal form X I, described drying temperature is room temperature ~ 60 DEG C, is preferably 40 DEG C; Described time of drying is 1 ~ 48 hour, is preferably 1 ~ 24 hour.
In the above-mentioned preparation method of crystal formation I of the present invention, form IV, crystal form X II, crystal form II, crystal form II I, crystal form V, crystal form V I, crystal form V II, crystal form V III, crystal formation IX, crystal form X and crystal form X I, described stirring can adopt the ordinary method of this area to carry out, such as magnetic agitation, mechanical stirring etc.Stir speed (S.S.) is 50 ~ 1800 revs/min, preferably 300 ~ 900 revs/min.
In the above-mentioned preparation method of crystal formation I of the present invention, form IV, crystal form X II, crystal form II, crystal form II I, crystal form V, crystal form V I, crystal form V II, crystal form V III, crystal formation IX, crystal form X and crystal form X I, this area ordinary method is adopted to be carried out by the crystal of precipitation being separated, washing and drying.Described separation, adopts the ordinary method of this area such as to filter, centrifugal etc.; The concrete operations of filtering are: be placed on filter paper by the sample for being separated, decompress filter; Centrifugal concrete operations are: the sample for being separated is placed in centrifuge tube, and high speed rotating is until solid is all sink to bottom centrifuge tube afterwards, and centrifugation rate is such as 6000 revs/min.The solvent of described washing preferably with solvent phase used in this crystal formation preparation method with the consumption of, cleaning solvent be the 2-10 of recrystallisation solvent doubly.Described drying, adopts the such as seasoning of this area ordinary method, forced air drying or drying under reduced pressure; Drying plant is stink cupboard, convection oven or vacuum drying oven; Drying is in decompression or carry out under not reducing pressure, and is preferably pressure and is less than 0.09Mpa; Drying temperature is about room temperature to 60 DEG C; Time of drying is 1 ~ 48 hour, is preferably 1 ~ 24 hour.
In the present invention, described " room temperature " refers to about 10 ~ 30 DEG C.
In the present invention, " crystal ", " crystal formation " or " amorphous article " refer to by shown X-ray diffractogram characterize confirm.The experimental error that it will be appreciated by those skilled in the art that wherein depends on the purity of the condition of instrument, the preparation of sample and sample.Particularly, as well known to those skilled in the art, X-ray diffractogram can change along with the condition of instrument usually to some extent.Special needs to be pointed out is, the relative intensity of X-ray diffractogram also may change along with the change of experiment condition, so the order of peak intensity can not as unique or deciding factor.In addition, the experimental error of peak angle is usually 5% or less, and the error of these angles also should be considered into, usually allows ± the error of 0.2 °.In addition, due to the impact of the empirical factors such as height of specimen, the overall offset of peak angle can be caused, usually allow certain skew.Thus, it will be appreciated by persons skilled in the art that any have all belong in scope with the same or analogous crystal formation in TuPu method peak of the present invention.Described " single crystal form " refers to that detecting through X-ray powder diffraction is single crystal form.
Crystal formation I of the present invention, form IV, crystal form X II, crystal form II, crystal form II I, crystal form V, crystal form V I, crystal form V II, crystal form V III, crystal formation IX, crystal form X, crystal form X I are pure, single, substantially do not mix any other crystal formation or amorphous article.In the present invention, " substantially do not have " when being used to refer to new crystal, refer to that other crystal formations of containing in this new crystal or amorphous article are less than 20% (weight), more refer to be less than 10% (weight), especially be less than 5% (weight), refer to especially and be less than 1% (weight).
The fluoro-4-of starting raw material 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid can be obtained with reference to the preparation method of patent documentation CN103450171A.
Further, the invention provides a kind of pharmaceutical composition, described pharmaceutical composition comprises one or more the crystal formation of the present invention and crystal formation that is unformed or that prepared by the inventive method that treat and/or prevent significant quantity and unformed and the pharmaceutically acceptable carrier of at least one.Wherein, the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl-3-azetidinecarboxylic acid crystal formation and unformedly comprise crystal formation I, form IV, crystal form X II, crystal form II, crystal form II I, crystal form V, crystal form V I, crystal form V II, crystal form V III, crystal formation IX, crystal form X, crystal form X I and unformed.In addition, described pharmaceutical composition can also comprise the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } other pharmaceutically useful crystal formation of-3-azetidinecarboxylic acid or amorphous article or the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the pharmaceutically useful crystal formation of other salt of-3-azetidinecarboxylic acid or amorphous article.Pharmaceutical composition as herein described itself can be a kind of pharmaceutical preparation, also can again with other auxiliary materials or Pharmaceutical formulations pharmaceutical preparations or drug combination preparation.
Aforementioned pharmaceutical compositions can be made into certain formulation, preferred oral administration administration, administered parenterally (comprising subcutaneous, intramuscular and intravenously), rectal administration, transdermal administration, containing the formulation taking the form such as administration, nose administration, include but not limited to solid dosage, liquid dosage form, semiliquid formulation, aerosol or suppository etc.Such as, be applicable to peroral administration formulation and comprise tablet, capsule, granule, powder, pill, pulvis, lozenge, syrup or suspensoid; Be applicable to the formulation of administered parenterally and comprise water-based or nonaqueous solution or emulsion; The formulation being applicable to rectal administration comprises the suppository using wetting ability or hydrophobic carrier; The formulation being applicable to transdermal administration comprises paste, creme; The formulation being applicable to nose administration comprises aerosol, spray.As required, above-mentioned formulation can be suitable for the quick release of activeconstituents, delayed release or adjustment release.
Pharmaceutically acceptable carrier of the present invention comprises solid-state carrier, specifically include but not limited to: thinner, such as starch, pregelatinized Starch, lactose, Solka-floc, Microcrystalline Cellulose, secondary calcium phosphate, tricalcium phosphate, N.F,USP MANNITOL, sorbyl alcohol, sugar etc.; Tackiness agent, such as gum arabic, guar gum, gelatin, polyvinylpyrrolidone, hydroxypropylcellulose, Vltra tears, polyoxyethylene glycol etc.; Disintegrating agent, such as starch, sodium starch glycollate, pregelatinized Starch, polyvinylpolypyrrolidone, croscarmellose sodium, colloid silica etc.; Lubricant, such as stearic acid, Magnesium Stearate, Zinic stearas, Sodium Benzoate, sodium acetate etc.; Glidant, such as colloid silica etc.; Complex forming agents, the cyclodextrin of such as various rank and resin; Release rate control agent, such as hydroxypropylcellulose, Walocel MT 20.000PV, Vltra tears, ethyl cellulose, methylcellulose gum, methyl methacrylate, wax etc.Pharmaceutically acceptable carrier of the present invention also comprises liquid carrier, specifically includes but not limited to: solvent such as sterilized water, normal saline solution, glucose solution, mannitol solution, vegetables oil, Oils,glyceridic,cod-liver, ethanol, propyl alcohol, the glycerine etc. of water-based, oiliness or alcohol solution.In addition, the carrier such as polyoxyethylene glycol, polypropylene glycol can also be used.Also can other pharmaceutically acceptable carriers of choice for use according to the difference of formulation, such as include but not limited to membrane-forming agent, softening agent, tinting material, seasonings, viscosity modifier, sanitas, antioxidant, permeate agent, buffer reagent etc.Each carrier must be acceptable, can be compatible and harmless for sufferer with other compositions in formula.
Described pharmaceutical composition can use the method for well known to a person skilled in the art to prepare.During pharmaceutical compositions, crystal formation I of the present invention, form IV, crystal form X II, crystal form II, crystal form II I, crystal form V, crystal form V I, crystal form V II, crystal form V III, crystal formation IX, crystal form X, crystal form X I, unformed or its combination mix mutually with one or more pharmaceutically acceptable carriers, optionally, mix mutually with one or more other active constituents of medicine.Solid preparation can be prepared by techniques such as mixing, granulations, and liquid or semiliquid formulation can be prepared by techniques such as mixing, dissolving, dispersion, emulsifications.
Further, the invention provides crystal formation of the present invention and crystal formation that is unformed or that obtained by preparation method of the present invention and unformed for the preparation for the treatment of and/or preventing by the purposes in the medicine of the receptor-mediated disease of S1P1 or illness.Wherein said crystal formation and unformedly comprise the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl the crystal formation I of-3-azetidinecarboxylic acid, form IV, crystal form X II, crystal form II, crystal form II I, crystal form V, crystal form V I, crystal form V II, crystal form V III, crystal formation IX, crystal form X, crystal form X I, unformed or its combination.Describedly be selected from rheumatoid arthritis by the receptor-mediated disease of S1P1 or illness, multiple sclerosis, inflammatory enteritis, autoimmune disorder, chronic inflammatory disease, asthma, inflammatory neuropathies, sacroiliitis, transplant, Crohn disease, ulcerative colitis, lupus erythematosus, psoriasis, ischemia reperfusion injury, noumenal tumour, with the disease of associated angiogenesis, vascular disease, antalgesic, acute viral diseases, inflammatory bowel, Regular Insulin and non-insulin-dependent diabetes mellitus (NIDDM) and other related immunological diseases, preferably, described disease or illness are selected from multiple sclerosis, rheumatoid arthritis, inflammatory enteritis and psoriasis.
Further, the invention provides a kind of method treated and/or prevented by the receptor-mediated disease of S1P1 or illness, described method comprises the crystal formation of the present invention of subject and/or the prevention significant quantity giving needs and unformed or its combination or its pharmaceutical composition, wherein said crystal formation and unformedly comprise the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal formation I of-3-azetidinecarboxylic acid, form IV, crystal form X II, crystal form II, crystal form II I, crystal form V, crystal form V I, crystal form V II, crystal form V III, crystal formation IX, crystal form X, crystal form X I, unformed or its combination.Describedly be selected from rheumatoid arthritis by the receptor-mediated disease of S1P1 or illness, multiple sclerosis, inflammatory enteritis, autoimmune disorder, chronic inflammatory disease, asthma, inflammatory neuropathies, sacroiliitis, transplant, Crohn disease, ulcerative colitis, lupus erythematosus, psoriasis, ischemia reperfusion injury, noumenal tumour, with the disease of associated angiogenesis, vascular disease, antalgesic, acute viral diseases, inflammatory bowel, Regular Insulin and non-insulin-dependent diabetes mellitus (NIDDM) and other related immunological diseases, preferably, described disease or illness are selected from multiple sclerosis, rheumatoid arthritis, inflammatory enteritis and psoriasis.Described experimenter includes but not limited to Mammals.Crystal formation provided by the invention and unformed or its combination or its pharmaceutical composition jointly can use with other therapies or therapeutical agent.And, implement treatment, prevent or the dosage of the compound that to alleviate etc. needed for effect or pharmaceutical composition usually depend on use particular compound, patient, disease specific or illness and severity, route of administration and frequency etc., and need to be judged as the case may be by attending doctor.
Accompanying drawing explanation
Fig. 1 is the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the XRPD collection of illustrative plates of the crystal formation I of-3-azetidinecarboxylic acid.
Fig. 2 is the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the PLM collection of illustrative plates of the crystal formation I of-3-azetidinecarboxylic acid.
Fig. 3 is the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the TGA/DSC collection of illustrative plates of the crystal formation I of-3-azetidinecarboxylic acid.
Fig. 4 is the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the DVS isothermal adsorption figure of the crystal formation I of-3-azetidinecarboxylic acid.
Fig. 5 is the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the FT-IR collection of illustrative plates of the crystal formation I of-3-azetidinecarboxylic acid.
Fig. 6 is the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the XRPD collection of illustrative plates of the form IV of-3-azetidinecarboxylic acid.
Fig. 7 is the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the PLM collection of illustrative plates of the form IV of-3-azetidinecarboxylic acid.
Fig. 8 is the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the TGA/DSC collection of illustrative plates of the form IV of-3-azetidinecarboxylic acid.
Fig. 9 is the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the DVS isothermal adsorption figure of the form IV of-3-azetidinecarboxylic acid.
Figure 10 is the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the FT-IR collection of illustrative plates of the form IV of-3-azetidinecarboxylic acid.
Figure 11 is the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the XRPD collection of illustrative plates of the crystal form X II of-3-azetidinecarboxylic acid.
Figure 12 is the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the PLM collection of illustrative plates of the crystal form X II of-3-azetidinecarboxylic acid.
Figure 13 is the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the TGA/DSC collection of illustrative plates of the crystal form X II of-3-azetidinecarboxylic acid.
Figure 14 is the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the DVS isothermal adsorption figure of the crystal form X II of-3-azetidinecarboxylic acid.
Figure 15 is the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the FT-IR collection of illustrative plates of the crystal form X II of-3-azetidinecarboxylic acid.
Figure 16 is the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the XRPD collection of illustrative plates of the crystal form II of-3-azetidinecarboxylic acid.
Figure 17 is the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the FT-IR collection of illustrative plates of the crystal form II of-3-azetidinecarboxylic acid.
Figure 18 is the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the XRPD collection of illustrative plates of the crystal form II I of-3-azetidinecarboxylic acid.
Figure 19 is the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the FT-IR collection of illustrative plates of the crystal form II I of-3-azetidinecarboxylic acid.
Figure 20 is the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the XRPD collection of illustrative plates of the crystal form V of-3-azetidinecarboxylic acid.
Figure 21 is the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the FT-IR collection of illustrative plates of the crystal form V of-3-azetidinecarboxylic acid.
Figure 22 is the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the XRPD collection of illustrative plates of the crystal form V I of-3-azetidinecarboxylic acid.
Figure 23 is the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the XRPD collection of illustrative plates of the crystal form V II of-3-azetidinecarboxylic acid.
Figure 24 is the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the FT-IR collection of illustrative plates of the crystal form V II of-3-azetidinecarboxylic acid.
Figure 25 is the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the XRPD collection of illustrative plates of the crystal form V III of-3-azetidinecarboxylic acid.
Figure 26 is the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the FT-IR collection of illustrative plates of the crystal form V III of-3-azetidinecarboxylic acid.
Figure 27 is the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the XRPD collection of illustrative plates of the crystal formation IX of-3-azetidinecarboxylic acid.
Figure 28 is the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the FT-IR collection of illustrative plates of the crystal formation IX of-3-azetidinecarboxylic acid.
Figure 29 is the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the XRPD collection of illustrative plates of the crystal form X of-3-azetidinecarboxylic acid.
Figure 30 is the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the FT-IR collection of illustrative plates of the crystal form X of-3-azetidinecarboxylic acid.
Figure 31 is the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the XRPD collection of illustrative plates of the crystal form X I of-3-azetidinecarboxylic acid.
Figure 32 is the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the FT-IR collection of illustrative plates of the crystal form X I of-3-azetidinecarboxylic acid.
Figure 33 is the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the unformed XRPD collection of illustrative plates of-3-azetidinecarboxylic acid.
Figure 34 is the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the unformed FT-IR collection of illustrative plates of-3-azetidinecarboxylic acid.
Embodiment
To contribute to understanding the present invention further by following embodiment, but be not used in restriction the present invention.Detecting instrument and method:
X-ray powder diffraction (XPRD): the instrument used is BrukerD8Advancediffractometer, copper target wavelength is adopted to be the KaX-ray of 1.54nm, under the operational condition of 40kV and 40mA, θ-2 θ goniometer, Mo monochromator, Lynxeye detector.Instrument is calibrated with silicon carbide before use.Acquisition software is DiffracPlusXRDCommander.Sample is tested at ambient temperature, is placed on no reflection events plate needing the sample detected.Detailed testing conditions is as follows, angular range: 3 – 40 ° 2 θ, step-length: 0.02 ° of 2 θ, speed: 0.2 second/step.
Differential thermal analysis (DSC): data acquisition is certainly in TAInstrumentsQ200MDSC, and instrument control software is ThermalAdvantage, and analysis software is UniversalAnalysis.Usually the sample getting 1-10 milligram is positioned in aluminium dish, with the heat-up rate of 10 DEG C/min at the dry N of 40mL/min 2protection under sample is risen to 250 DEG C from room temperature.
Thermogravimetric analysis (TGA): data acquisition is certainly in TAInstrumentsQ500TGA, and instrument control software is ThermalAdvantage, and analysis software is UniversalAnalysis.Usually the sample getting 1-15 milligram is positioned in platinum crucible, adopts the mode of segmentation high resolution detection, with the heat-up rate of 10 DEG C/min at the dry N of 40mL/min 2protection under sample is risen to 300 DEG C from room temperature.
Adsorption isothermal curve (DVS): data acquisition is certainly in TAInstrumentsQ5000TGA, and instrument control software is ThermalAdvantage, and analysis software is UniversalAnalysis.Usually the sample getting 1-10 milligram is positioned in platinum crucible, the changes in weight of TA software records sample relative humidity from 0% to 90% to 0% change procedure.Particular case per sample, also can adopt different absorption and De contamination step to sample.
Hydrogen nuclear magnetic resonance modal data ( 1hNMR) pick up from BrukerAvanceIIDMX400MHZ nuclear magnetic resonance spectrometer.Weigh 1-5mg sample, with 0.5mL deuterochloroform (CDCl 3) dissolve, be made into the solution of 2mg/mL – 10mg/mL.
FTIR spectrum analyzes (FT-IR) data acquisition certainly in BrukerTensor27, and instrument control software and data analysis software are all OPUS.Usual employing ATR equipment, at 600-4000cm -1in scope, gather infrared absorption spectrum, the sweep time of sample and blank background is 32 seconds, instrumental resolution 4cm -1.All ingredients used in embodiment is commercially available if no special instructions.
Ultrasound procedure in embodiment can promote sample dissolution, and equipment is ultrasonic cleaner, carries out 15 minutes under 40kHz power.
preparation example 1
The fluoro-4-of compound 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid can refer to patent documentation CN103450171A embodiment 2 preparation method obtain.Be specially: under room temperature, by fluoro-for 2-4-[5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-phenyl aldehyde (0.90g, 2.78mmol), 3-azetidinecarboxylic acid (0.28g, 2.78mmol) and methyl alcohol-tetrahydrofuran (THF) (20mL/20mL) solution stirring 2 hours of acetic acid (1mL), add sodium cyanoborohydride (1.03g, methanol solution (60mL) 16.35mmol) afterwards room temperature continues stirring 16 hours, filter, with methyl alcohol (10mL) washing leaching cake, dry the fluoro-4-of white solid product 1-{2-[5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid (compound 2) (0.20g).1H-NMR(400MHz，CD3OD)δ：8.13(d,J＝8.4Hz,2H),8.05(m,1H),7.97(m,1H),7.68(t,J＝8.0Hz,7.6Hz,1H),7.42(d,J＝8.4Hz,2H),4.40(s,2H),4.15(m,4H),3.41(m,1H),2.61(d,J＝7.2Hz,2H),1.95(m,1H),0.94(d,J＝7.2Hz,6H).
X-ray powder diffraction pattern as shown in figure 33, is amorphous article.
FT-IR collection of illustrative plates as shown in figure 34.
embodiment 1
Under room temperature, the fluoro-4-of 130.1mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 20mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 13.0mL aqueous acetone solution (volume of water content 67%), within ultrasonic 15 minutes, obtain white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is its at room temperature 50 times of solubleness in aqueous acetone solution), stirred at ambient temperature 7 days crystallizatioies, filter, by solid 40 DEG C of vacuum-dryings of obtaining 48 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal formation I of-3-azetidinecarboxylic acid.Output is 120.1mg; Productive rate is 95%.
X-ray powder diffraction pattern as shown in Figure 1, is crystal formation I.
PLM collection of illustrative plates as shown in Figure 2.Display: fine crystals.
DSC and TGA collection of illustrative plates as shown in Figure 3.Display: crystal formation I has a roomy endotherm(ic)peak (solvent peak) at 3 ~ 115 DEG C, and sloughing the sample fusing point after water is 179 DEG C; Crystal formation I is ladder weightlessness about 2.2% before 50 ~ 125 DEG C, and semihydrate theoretical value (2.2%) meets, and decomposition temperature is 182 DEG C.
DVS collection of illustrative plates as shown in Figure 4.Display: 20%RH ~ 80%RH changes in weight is 0.8%.
FT-IR collection of illustrative plates as shown in Figure 5.
Above-mentioned detected result shows: described crystal formation I is semihydrate, not easily moisture absorption.
embodiment 2
Under room temperature, the fluoro-4-of 0.9mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 20mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 18.0mL water, within ultrasonic 15 minutes, obtain white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is its at room temperature 50 times of solubleness in water), 7 days crystallizatioies are stirred at 60 DEG C, filter, by the solid room temperature vacuum-drying that obtains 24 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal formation I of-3-azetidinecarboxylic acid.Output is 0.7mg; Productive rate is 78%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1.
embodiment 3
Under room temperature, the fluoro-4-of 15.4mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 2.5mL aqueous ethanolic solution (volume of water content 50%), within ultrasonic 15 minutes, obtain white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is its at room temperature 10 times of solubleness in aqueous ethanolic solution), stirred at ambient temperature 3 days crystallizatioies, filter, by solid 40 DEG C of vacuum-dryings of obtaining 24 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal formation I of-3-azetidinecarboxylic acid.Output is 13.1mg; Productive rate is 85%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1.
embodiment 4
Under room temperature, the fluoro-4-of 1.3mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 3.0mL methanol aqueous solution (volume of water content 67%), within ultrasonic 15 minutes, obtain white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is its at room temperature 1.1 times of solubleness in methanol aqueous solution), stirred at ambient temperature 3 days crystallizatioies, filter, by the solid room temperature vacuum-drying that obtains 24 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal formation I of-3-azetidinecarboxylic acid.Output is 0.1mg; Productive rate is 0.8%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1.
embodiment 5
Under room temperature, the fluoro-4-of 0.6mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and the 1.3mL n-propyl alcohol aqueous solution (volume of water content 1.0%), within ultrasonic 15 minutes, obtain white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is its at room temperature 1.5 times of solubleness in the n-propyl alcohol aqueous solution), stirred at ambient temperature 7 days crystallizatioies, centrifugal, by solid 40 DEG C of vacuum-dryings of obtaining 48 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal formation I of-3-azetidinecarboxylic acid.Output is 0.3mg; Productive rate is 50%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1.
embodiment 6
Under room temperature, the fluoro-4-of 3.1mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 1.0mL isopropanol water solution (volume of water content 5.0%), within ultrasonic 15 minutes, obtain white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is its at room temperature 10 times of solubleness in isopropanol water solution), stirred at ambient temperature 7 days crystallizatioies, filter, by solid 40 DEG C of vacuum-dryings of obtaining 48 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal formation I of-3-azetidinecarboxylic acid.Output is 2.7mg; Productive rate is 87%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1.
embodiment 7
Under room temperature, the fluoro-4-of 3.2mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 1.6mL n-butanol aqueous solution (volume of water content 0.01%), within ultrasonic 15 minutes, obtain white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is its at room temperature 10 times of solubleness in n-butanol aqueous solution), 7 days crystallizatioies are stirred at 60 DEG C, filter, by solid 60 DEG C of vacuum-dryings of obtaining 48 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal formation I of-3-azetidinecarboxylic acid.Output is 2.5mg; Productive rate is 78%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1.
embodiment 8
Under room temperature, the fluoro-4-of 3.0mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and the 1.5mL sec-butyl alcohol aqueous solution (volume of water content 0.1%), within ultrasonic 15 minutes, obtain white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is its at room temperature 10 times of solubleness in the sec-butyl alcohol aqueous solution), stirred at ambient temperature 14 days crystallizatioies, centrifugal, by solid 60 DEG C of vacuum-dryings of obtaining 24 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal formation I of-3-azetidinecarboxylic acid.Output is 2.7mg; Productive rate is 90%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1.
embodiment 9
Under room temperature, the fluoro-4-of 3.0mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 100mL single port bottle, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and the 60mL methyl tertiary butyl ether aqueous solution (volume of water content 0.1%), within ultrasonic 15 minutes, obtain white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is its at room temperature 50 times of solubleness in the methyl tertiary butyl ether aqueous solution), stirred at ambient temperature 14 days crystallizatioies, centrifugal, by solid 60 DEG C of vacuum-dryings of obtaining 24 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal formation I of-3-azetidinecarboxylic acid.Output is 2.7mg; Productive rate is 90%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1.
embodiment 10
Under room temperature, the fluoro-4-of 2.9mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 100mL single port bottle, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and the 60mL isopropyl ether aqueous solution (volume of water content 0.01%), within ultrasonic 15 minutes, obtain white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is its at room temperature 50 times of solubleness in the isopropyl ether aqueous solution), stirred at ambient temperature 7 days crystallizatioies, filter, by the solid room temperature vacuum-drying that obtains 1 hour, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal formation I of-3-azetidinecarboxylic acid.Output is 2.0mg; Productive rate is 69%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1.
embodiment 11
Under room temperature, the fluoro-4-of 4.1mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and the 2.0mL butanone aqueous solution (volume of water content 0.1%), within ultrasonic 15 minutes, obtain white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is its at room temperature 10 times of solubleness in the butanone aqueous solution), stirred at ambient temperature 3 days crystallizatioies, centrifugal, by solid 40 DEG C of vacuum-dryings of obtaining 1 hour, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal formation I of-3-azetidinecarboxylic acid.Output is 3.3mg; Productive rate is 80%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1.
embodiment 12
Under room temperature, the fluoro-4-of 2.5mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 5.0mL ethyl acetate aqueous solution (volume of water content 0.01%), within ultrasonic 15 minutes, obtain white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is its at room temperature 50 times of solubleness in ethyl acetate aqueous solution), stirred at ambient temperature 7 days crystallizatioies, centrifugal, by solid 40 DEG C of vacuum-dryings of obtaining 1 hour, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal formation I of-3-azetidinecarboxylic acid.Output is 2.1mg; Productive rate is 84%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1.
embodiment 13
Under room temperature, the fluoro-4-of 1.8mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and the 3.6mL Nitromethane 99Min. aqueous solution (volume of water content 1.0%), within ultrasonic 15 minutes, obtain white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is its at room temperature 50 times of solubleness in the Nitromethane 99Min. aqueous solution), 7 days crystallizatioies are stirred at 40 DEG C, filter, by solid 40 DEG C of vacuum-dryings of obtaining 24 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal formation I of-3-azetidinecarboxylic acid.Output is 1.3mg; Productive rate is 72%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1.
embodiment 14
Under room temperature, the fluoro-4-of 2.0mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and the 5.0mL methylene dichloride aqueous solution (volume of water content 0.1%), within ultrasonic 15 minutes, obtain white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is its at room temperature 40 times of solubleness in the methylene dichloride aqueous solution), 7 days crystallizatioies are stirred at 40 DEG C, filter, by the solid room temperature vacuum-drying that obtains 1 hour, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal formation I of-3-azetidinecarboxylic acid.Output is 0.8mg; Productive rate is 40%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1.
embodiment 15
Under room temperature, the fluoro-4-of 5.8mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 1.0mL1, the 4-dioxane aqueous solution (volume of water content 20%), within ultrasonic 15 minutes, obtain white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is that it is at room temperature 1, 10 times of solubleness in the 4-dioxane aqueous solution), 7 days crystallizatioies are stirred at 60 DEG C, centrifugal, by solid 60 DEG C of vacuum-dryings of obtaining 24 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal formation I of-3-azetidinecarboxylic acid.Output is 4.9mg; Productive rate is 84%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1.
embodiment 16
Under room temperature, the fluoro-4-of 4.7mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 4.7mL acetonitrile solution (volume of water content 40%), within ultrasonic 15 minutes, obtain white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is its at room temperature 10 times of solubleness in acetonitrile solution), stirred at ambient temperature 14 days crystallizatioies, filter, by solid 40 DEG C of vacuum-dryings of obtaining 24 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal formation I of-3-azetidinecarboxylic acid.Output is 3.0mg; Productive rate is 64%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1.
embodiment 17
Under room temperature, the fluoro-4-of 3.0mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 1.0mL chloroform water solution (volume of water content 0.01%), within ultrasonic 15 minutes, obtain white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is its at room temperature 5 times of solubleness in chloroform water solution), stirred at ambient temperature 7 days crystallizatioies, filter, by the solid room temperature vacuum-drying that obtains 24 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal formation I of-3-azetidinecarboxylic acid.Output is 2.3mg; Productive rate is 77%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1.
embodiment 18
Under room temperature, the fluoro-4-of 1.8mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and the 3.6mL toluene aqueous solution (volume of water content 0.1%), within ultrasonic 15 minutes, obtain white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is its at room temperature 50 times of solubleness in the toluene aqueous solution), 7 days crystallizatioies are stirred at 40 DEG C, filter, by solid 60 DEG C of vacuum-dryings of obtaining 48 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal formation I of-3-azetidinecarboxylic acid.Output is 0.5mg; Productive rate is 28%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1.
embodiment 19
Under room temperature, the fluoro-4-of 2.3mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and the 1.5mL methyl-sulphoxide aqueous solution (volume of water content 10%), within ultrasonic 15 minutes, obtain white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is its at room temperature 1.5 times of solubleness in the methyl-sulphoxide aqueous solution), 7 days crystallizatioies are stirred at 40 DEG C, filter, by solid 60 DEG C of vacuum-dryings of obtaining 48 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal formation I of-3-azetidinecarboxylic acid.Output is 0.6mg; Productive rate is 26%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1.
embodiment 20
Under room temperature, the fluoro-4-of 16.1mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 1.0mL tetrahydrofuran aqueous solution (volume of water content 10%), within ultrasonic 15 minutes, obtain white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is its at room temperature 10 times of solubleness in tetrahydrofuran aqueous solution), stirred at ambient temperature 7 days crystallizatioies, filter, by the solid room temperature vacuum-drying that obtains 24 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal formation I of-3-azetidinecarboxylic acid.Output is 13.0mg; Productive rate is 81%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1.
embodiment 21
Under room temperature, the fluoro-4-of 1.7mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 50mL single port bottle, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and the 34.0mL methylcyclohexane aqueous solution (volume of water content 0.01%), within ultrasonic 15 minutes, obtain white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is its at room temperature 50 times of solubleness in the methylcyclohexane aqueous solution), 7 days crystallizatioies are stirred at 40 DEG C, filter, by solid 40 DEG C of vacuum-dryings of obtaining 24 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal formation I of-3-azetidinecarboxylic acid.Output is 1.0mg; Productive rate is 59%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1.
embodiment 22
Under room temperature, the fluoro-4-of 1.9mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 50mL single port bottle, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and the 38.0mL normal heptane aqueous solution (volume of water content 0.1%), within ultrasonic 15 minutes, obtain white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is its at room temperature 50 times of solubleness in the normal heptane aqueous solution), stirred at ambient temperature 7 days crystallizatioies, filter, by solid 60 DEG C of vacuum-dryings of obtaining 24 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal formation I of-3-azetidinecarboxylic acid.Output is 0.7mg; Productive rate is 37%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1.
embodiment 23
Under room temperature, the fluoro-4-of 2.5mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 1.0mL tetrahydrofuran aqueous solution (volume content 50% of water) heating in water bath to 50 DEG C, be stirred to sample and dissolve (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 completely, 2, 4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is 0.5 times of its solubleness in described tetrahydrofuran aqueous solution at 50 DEG C), close after water-bath naturally cools to room temperature and continue stirring 10 hours, obtain white solid, filter, 40 DEG C of vacuum-drying 24 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal formation I of-3-azetidinecarboxylic acid.Output is 1.2mg; Productive rate is 48%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1.
embodiment 24
Under room temperature, the fluoro-4-of 5.1mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 20mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 10.0mL tetrahydrofuran aqueous solution (volume content 0.1% of water) heating in water bath to 40 DEG C, be stirred to sample and dissolve (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 completely, 2, 4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is 0.1 times of its solubleness in described tetrahydrofuran aqueous solution at 40 DEG C), close after water-bath naturally cools to room temperature and continue stirring 72 hours, obtain white solid, filter, 60 DEG C of vacuum-drying 72 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal formation I of-3-azetidinecarboxylic acid.Output is 3.0mg; Productive rate is 59%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1.
embodiment 25
Under room temperature, the fluoro-4-of 7.9mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 1.0mL tetrahydrofuran aqueous solution (volume content 0.01% of water) heating in water bath to 50 DEG C, be stirred to sample and dissolve (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 completely, 2, 4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is 1 times of its solubleness in described tetrahydrofuran aqueous solution at 50 DEG C), close after water-bath naturally cools to room temperature and continue stirring 1 hour, obtain white solid, centrifugal, 40 DEG C of vacuum-drying 1 hour, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal formation I of-3-azetidinecarboxylic acid.Output is 3.7mg; Productive rate is 47%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1.
embodiment 26
Under room temperature, the fluoro-4-of 1.6mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 20mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 1.0mL tetrahydrofuran (THF), after ultrasonic 5min, sample dissolves (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 completely, 2, 4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is 1 times of its solubleness in tetrahydrofuran (THF) under room temperature), in wherein dripping water 10mL, obtain white solid at once, stirred at ambient temperature 10 hours, centrifugal, 40 DEG C of vacuum-drying 1 hour, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal formation I of-3-azetidinecarboxylic acid.Output is 1.0mg; Productive rate is 62%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1.
embodiment 27
Under room temperature, the fluoro-4-of 1.5mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 150mL single port bottle, 2, 4-oxadiazole-3-base]-benzyl } the trifluoroethanol solution (volume content of ethanol is 66%) of-3-azetidinecarboxylic acid and 1.0mL ethanol, after ultrasonic 5min, sample dissolves (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 completely, 2, 4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is 0.5 times of its solubleness in the trifluoroethanol solution of ethanol under room temperature), in wherein dripping water 100mL, obtain white solid at once, stirred at ambient temperature 72 hours, filter, 40 DEG C of vacuum-drying 24 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal formation I of-3-azetidinecarboxylic acid.Output is 1.3mg; Productive rate is 87%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1.
embodiment 28
Under room temperature, the fluoro-4-of 1.7mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 50mL single port bottle, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 28.0mL1, 4-dioxane, after ultrasonic 5min, sample dissolves (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 completely, 2, 4-oxadiazole-3-base]-benzyl the amount of-3-azetidinecarboxylic acid be under room temperature its 1, 0.1 times of solubleness in 4-dioxane), by fluoro-for 1-{2-4-[5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl-3-azetidinecarboxylic acid 1, 4-dioxane solution drops in 10.0mL water, obtain white solid at once, stir 0.5 hour at 60 DEG C, filter, 60 DEG C of vacuum-drying 1 hour, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal formation I of-3-azetidinecarboxylic acid.Output is 0.7mg; Productive rate is 41%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1.
embodiment 29
Under room temperature, the fluoro-4-of 1.9mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 20mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 1.9mL methyl-sulphoxide, after ultrasonic 5min, sample dissolves (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 completely, 2, 4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is 1 times of its solubleness in methyl-sulphoxide under room temperature), in wherein dripping water 10mL, obtain white solid at once, stirred at ambient temperature 0.5 hour, filter, 40 DEG C of vacuum-drying 24 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal formation I of-3-azetidinecarboxylic acid.Output is 1.4mg; Productive rate is 74%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1.
embodiment 30
Under room temperature, the fluoro-4-of 1.9mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 20mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 6.3mL isopropanol water solution (volume content of water is 50%), within ultrasonic 15 minutes, obtain colorless cleared solution (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this solution, 2, 4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is its 1 times of solubleness in isopropanol water solution at such a temperature), with 0.45 μm of organic filter membrane filtration, filtrate is placed in 5mL vial 60 DEG C of lower open mouth volatilization crystallizatioies, by solid 40 DEG C of vacuum-dryings of obtaining 48 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal formation I of-3-azetidinecarboxylic acid.Output is 1.4mg; Productive rate is 74%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1.
embodiment 31
Under room temperature, the fluoro-4-of 1.7mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 20mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 10.0mL tetrahydrofuran aqueous solution (volume content of water is 0.1%), within ultrasonic 15 minutes, obtain colorless cleared solution (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this solution, 2, 4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is its at room temperature 0.1 times of solubleness in tetrahydrofuran aqueous solution), with 0.45 μm of organic filter membrane filtration, filtrate is placed in the uncovered volatilization of 20mL vial room temperature 3 days crystallizatioies, by the solid room temperature vacuum-drying that obtains 24 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal formation I of-3-azetidinecarboxylic acid.Output is 0.4mg; Productive rate is 24%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1.
embodiment 32
Under room temperature, the fluoro-4-of 0.8mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 20mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 8.0mL aqueous acetone solution (volume content of water is 0.01%), within ultrasonic 15 minutes, obtain colorless cleared solution (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this solution, 2, 4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is its at room temperature 0.5 times of solubleness in aqueous acetone solution), with 0.45 μm of organic filter membrane filtration, filtrate is placed in the uncovered volatilization of 20mL vial room temperature 1 day crystallization, by solid 60 DEG C of vacuum-dryings of obtaining 1 hour, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal formation I of-3-azetidinecarboxylic acid.Output is 0.4mg; Productive rate is 40%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1.
embodiment 33
Under room temperature, the fluoro-4-of 30.1mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 3.0mL acetone (volume content of water is 0.0000%), within ultrasonic 15 minutes, obtain white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is 50 times of its at room temperature solubleness in acetone), stirred at ambient temperature 7 days crystallizatioies, filter, by the solid room temperature vacuum-drying that obtains 72 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } form IV of-3-azetidinecarboxylic acid.Output is 27.5mg; Productive rate is 91%.
X-ray powder diffraction pattern as shown in Figure 6, is form IV.
PLM collection of illustrative plates as shown in Figure 7.Display: rhabdolith.
DSC and TGA collection of illustrative plates as shown in Figure 8.Display: form IV fusing point is 174 DEG C; Form IV is substantially without weightless before 125 DEG C, and decomposition temperature is 183 DEG C.
DVS collection of illustrative plates as shown in Figure 9.Display: 20%RH ~ 80%RH changes in weight is 1.6%.
FT-IR collection of illustrative plates as shown in Figure 10.
Above-mentioned detected result shows: described form IV is anhydride, has good pattern, at high temperature stablizes.
embodiment 34
Under room temperature, the fluoro-4-of 3.7mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 20mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 7.4mL ethyl acetate (volume content of water is 0.0000%), within ultrasonic 15 minutes, obtain white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is its at room temperature 50 times of solubleness in ethyl acetate), 7 days crystallizatioies are stirred at 40 DEG C, filter, by the solid room temperature vacuum-drying that obtains 48 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } form IV of-3-azetidinecarboxylic acid.Output is 3.0mg; Productive rate is 81%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 6.
embodiment 35
Under room temperature, the fluoro-4-of 1.5mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 150mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 100mL isopropyl acetate (volume content of water is 0.0000%), within ultrasonic 15 minutes, obtain white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is its at room temperature 1.5 times of solubleness in isopropyl acetate), stirred at ambient temperature 7 days crystallizatioies, filter, by the solid room temperature vacuum-drying that obtains 24 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } form IV of-3-azetidinecarboxylic acid.Output is 0.7mg; Productive rate is 47%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 6.
embodiment 36
Under room temperature, the fluoro-4-of 6.1mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 1.0mL1, 4-dioxane (volume content of water is 0.0001%), within ultrasonic 15 minutes, obtain white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is that it is at room temperature 1, 10 times of solubleness in 4-dioxane), 7 days crystallizatioies are stirred at 60 DEG C, filter, by solid 40 DEG C of vacuum-dryings of obtaining 48 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } form IV of-3-azetidinecarboxylic acid.Output is 4.5mg; Productive rate is 74%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 6.
embodiment 37
Under room temperature, the fluoro-4-of 1.2mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 2.4mL acetonitrile (volume content of water is 0.00005%), within ultrasonic 15 minutes, obtain white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is its at room temperature 50 times of solubleness in acetonitrile), stirred at ambient temperature 7 days crystallizatioies, filter, by solid 60 DEG C of vacuum-dryings of obtaining 24 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } form IV of-3-azetidinecarboxylic acid.Output is 0.7mg; Productive rate is 58%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 6.
embodiment 38
Under room temperature, the fluoro-4-of 5.9mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl } (volume content of acetone is 50% for the ethanolic soln of-3-azetidinecarboxylic acid and 1.0mL acetone, the volume content of water is 0.00005%), within ultrasonic 15 minutes, obtain white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is its at room temperature 10 times of solubleness in the ethanolic soln of acetone), stirred at ambient temperature 14 days crystallizatioies, filter, by the solid room temperature vacuum-drying that obtains 24 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } form IV of-3-azetidinecarboxylic acid.Output is 3.3mg; Productive rate is 56%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 6.
embodiment 39
Under room temperature, the fluoro-4-of 10.1mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl } (volume content of tetrahydrofuran (THF) is 50% for the ethanolic soln of-3-azetidinecarboxylic acid and 0.5mL tetrahydrofuran (THF), the volume content of water is 0.0002%), within ultrasonic 15 minutes, obtain white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is its at room temperature 10 times of solubleness in the ethanolic soln of tetrahydrofuran (THF)), stirred at ambient temperature 3 days crystallizatioies, filter, by the solid room temperature vacuum-drying that obtains 24 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } form IV of-3-azetidinecarboxylic acid.Output is 8.1mg; Productive rate is 80%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 6.
embodiment 40
Under room temperature, the fluoro-4-of 1.9mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl } (volume content of acetonitrile is 50% for the ethanolic soln of-3-azetidinecarboxylic acid and 0.3mL acetonitrile, the volume content of water is 0.0002%), within ultrasonic 15 minutes, obtain white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is its at room temperature 10 times of solubleness in the ethanolic soln of acetonitrile), stirred at ambient temperature 7 days crystallizatioies, filter, by the solid room temperature vacuum-drying that obtains 24 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } form IV of-3-azetidinecarboxylic acid.Output is 1.0mg; Productive rate is 53%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 6.
embodiment 41
Under room temperature, the fluoro-4-of 10.1mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 1.0mL methyl alcohol (volume content of water is 0.0001%) heating in water bath to 60 DEG C, be stirred to sample and dissolve (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 completely, 2, 4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is 1.0 times of its solubleness in described methyl alcohol at 60 DEG C), close after water-bath naturally cools to room temperature and continue stirring 10 hours, obtain white solid, filter, 40 DEG C of vacuum-drying 24 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } form IV of-3-azetidinecarboxylic acid.Output is 8.7mg; Productive rate is 86%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 6.
embodiment 42
Under room temperature, the fluoro-4-of 9.7mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 2.0mL ethanol (volume content of water is 0.0002%) heating in water bath to 70 DEG C, be stirred to sample and dissolve (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 completely, 2, 4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is 0.5 times of its solubleness in described ethanol at 70 DEG C), close after water-bath naturally cools to room temperature and continue stirring 0.5 hour, obtain white solid, filter, 40 DEG C of vacuum-drying 48 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } form IV of-3-azetidinecarboxylic acid.Output is 8.1mg; Productive rate is 84%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 6.
embodiment 43
Under room temperature, the fluoro-4-of 9.1mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 2.0mL Virahol (volume content of water is 0.0005%) heating in water bath to 75 DEG C, be stirred to sample and dissolve (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 completely, 2, 4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is 1 times of its solubleness in described Virahol at 75 DEG C), close after water-bath naturally cools to room temperature and continue stirring 72 hours, obtain white solid, filter, 60 DEG C of vacuum-drying 24 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } form IV of-3-azetidinecarboxylic acid.Output is 6.4mg; Productive rate is 70%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 6.
embodiment 44
Under room temperature, the fluoro-4-of 9.0mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 4.0mL n-propyl alcohol (volume content of water is 0.001%) heating in water bath to 75 DEG C, be stirred to sample and dissolve (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 completely, 2, 4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is 0.5 times of its solubleness in described n-propyl alcohol at 75 DEG C), close after water-bath naturally cools to room temperature and continue stirring 72 hours, obtain white solid, filter, 60 DEG C of vacuum-drying 48 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } form IV of-3-azetidinecarboxylic acid.Output is 5.6mg; Productive rate is 62%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 6.
embodiment 45
Under room temperature, the fluoro-4-of 8.5mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 4.0mL propyl carbinol (volume content of water is 0.0001%) heating in water bath to 80 DEG C, be stirred to sample and dissolve (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 completely, 2, 4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is 1 times of its solubleness in described propyl carbinol at 80 DEG C), close after water-bath naturally cools to room temperature and continue stirring 10 hours, obtain white solid, filter, 60 DEG C of vacuum-drying 48 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } form IV of-3-azetidinecarboxylic acid.Output is 6.1mg; Productive rate is 72%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 6.
embodiment 46
Under room temperature, the fluoro-4-of 9.2mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 4.0mL sec-butyl alcohol (volume content of water is 0.0001%) heating in water bath to 70 DEG C, be stirred to sample and dissolve (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 completely, 2, 4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is 1 times of its solubleness in described sec-butyl alcohol at 70 DEG C), close after water-bath naturally cools to room temperature and continue stirring 72 hours, obtain white solid, filter, 60 DEG C of vacuum-drying 24 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } form IV of-3-azetidinecarboxylic acid.Output is 5.9mg; Productive rate is 64%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 6.
embodiment 47
Under room temperature, the fluoro-4-of 3.7mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 1.0mL acetone (volume content of water is 0.001%) heating in water bath to 50 DEG C, be stirred to sample and dissolve (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 completely, 2, 4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is 1 times of its solubleness in described acetone at 50 DEG C), close after water-bath naturally cools to room temperature and continue stirring 10 hours, obtain white solid, filter, dry 24 hours of room temperature in vacuo, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } form IV of-3-azetidinecarboxylic acid.Output is 1.8mg; Productive rate is 49%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 6.
embodiment 48
Under room temperature, the fluoro-4-of 4.0mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 3.0mL butanone (volume content of water is 0.0001%) heating in water bath to 40 DEG C, be stirred to sample and dissolve (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 completely, 2, 4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is 0.5 times of its solubleness in described butanone at 40 DEG C), close after water-bath naturally cools to room temperature and continue stirring 10 hours, obtain white solid, filter, dry 24 hours of room temperature in vacuo, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } form IV of-3-azetidinecarboxylic acid.Output is 1.7mg; Productive rate is 42%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 6.
embodiment 49
Under room temperature, the fluoro-4-of 10.9mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 1.5mL ethyl acetate (volume content of water is 0.0002%) heating in water bath to 60 DEG C, be stirred to sample and dissolve (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 completely, 2, 4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is 1 times of its solubleness in described ethyl acetate at 60 DEG C), close after water-bath naturally cools to room temperature and continue stirring 10 hours, obtain white solid, filter, 40 DEG C of vacuum-drying 24 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } form IV of-3-azetidinecarboxylic acid.Output is 9.7mg; Productive rate is 89%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 6.
embodiment 50
Under room temperature, the fluoro-4-of 8.7mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 1.5mL isopropyl acetate (volume content of water is 0.0001%) heating in water bath to 80 DEG C, be stirred to sample and dissolve (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 completely, 2, 4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is 0.8 times of its solubleness in described isopropyl acetate at 80 DEG C), close after water-bath naturally cools to room temperature and continue stirring 10 hours, obtain white solid, filter, 40 DEG C of vacuum-drying 48 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } form IV of-3-azetidinecarboxylic acid.Output is 6.5mg; Productive rate is 75%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 6.
embodiment 51
Under room temperature, the fluoro-4-of 10.3mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 1.0mL1, 4-dioxane (volume content of water is 0.0005%) heating in water bath to 60 DEG C, be stirred to sample and dissolve (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 completely, 2, 4-oxadiazole-3-base]-benzyl the amount of-3-azetidinecarboxylic acid be at 60 DEG C its described 1, 1 times of solubleness in 4-dioxane), close after water-bath naturally cools to room temperature and continue stirring 10 hours, obtain white solid, filter, dry 48 hours of room temperature in vacuo, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } form IV of-3-azetidinecarboxylic acid.Output is 9.5mg; Productive rate is 92%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 6.
embodiment 52
Under room temperature, the fluoro-4-of 6.7mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 2.0mL toluene (volume content of water is 0.0005%) heating in water bath to 85 DEG C, be stirred to sample and dissolve (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 completely, 2, 4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is 0.8 times of its solubleness in described toluene at 85 DEG C), close after water-bath naturally cools to room temperature and continue stirring 10 hours, obtain white solid, filter, 60 DEG C of vacuum-drying 48 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } form IV of-3-azetidinecarboxylic acid.Output is 5.9mg; Productive rate is 88%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 6.
embodiment 53
Under room temperature, the fluoro-4-of 6.1mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl } (volume content of ethanol is 25% for the acetonitrile solution of-3-azetidinecarboxylic acid and 1.0mL ethanol, the volume content of water is 0.0005%) and heating in water bath to 70 DEG C, be stirred to sample and dissolve (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 completely, 2, 4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is 1 times of its solubleness in the acetonitrile solution of described ethanol at 70 DEG C), close after water-bath naturally cools to room temperature and continue stirring 10 hours, obtain white solid, filter, 40 DEG C of vacuum-drying 48 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } form IV of-3-azetidinecarboxylic acid.Output is 5.1mg; Productive rate is 76%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 6.
embodiment 54
Under room temperature, the fluoro-4-of 1.9mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 1.9mL methyl-sulphoxide (volume content of water is 0.001%), after ultrasonic 5min, sample dissolves (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 completely, 2, 4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is 1 times of its solubleness in methyl-sulphoxide under room temperature), dimethyl sulfoxide solution is dropped to and is equipped with in the 5mL vial of 1.9mL sec-butyl alcohol, stirred at ambient temperature 72 hours, centrifugal, 40 DEG C of vacuum-drying 24 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } form IV of-3-azetidinecarboxylic acid.Output is 0.5mg; Productive rate is 26%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 6.
embodiment 55
Under room temperature, the fluoro-4-of 1.5mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 1.0mL trifluoroethanol (volume content of water is 0.0005%), after ultrasonic 5min, sample dissolves (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 completely, 2, 4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is 0.5 times of its solubleness in trifluoroethanol under room temperature), being dropped to by trifluoroethanol solution is equipped with in the 20mL vial of 10.0mL propyl carbinol, stirred at ambient temperature 10 hours, centrifugal, 60 DEG C of vacuum-drying 24 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } form IV of-3-azetidinecarboxylic acid.Output is 0.3mg; Productive rate is 20%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 6.
embodiment 56
Under room temperature, the fluoro-4-of 3.2mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 20mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 20.0mL tetrahydrofuran (THF) (volume content of water is 0.001%), after ultrasonic 5min, sample dissolves (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 completely, 2, 4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is 0.1 times of its solubleness in tetrahydrofuran (THF) under room temperature), tetrahydrofuran solution is dropped to and is equipped with in the 150mL single port bottle of 100.0mL ethyl acetate, stirred at ambient temperature 48 hours, centrifugal, dry 48 hours of room temperature in vacuo, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } form IV of-3-azetidinecarboxylic acid.Output is 0.6mg; Productive rate is 19%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 6.
embodiment 57
Under room temperature, the fluoro-4-of 1.5mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 1.5mL methyl-sulphoxide (volume content of water is 0.0005%), after ultrasonic 5min, sample dissolves (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 completely, 2, 4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is 1 times of its solubleness in methyl-sulphoxide under room temperature), dimethyl sulfoxide solution is dropped to and is equipped with in the 100mL single port bottle of 50.0mL isopropyl acetate, , stirred at ambient temperature 10 hours, centrifugal, 60 DEG C of vacuum-drying 48 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } form IV of-3-azetidinecarboxylic acid.Output is 0.5mg; Productive rate is 33%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 6.
embodiment 58
Under room temperature, the fluoro-4-of 1.2mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 2.0mL1, 4-dioxane (volume content of water is 0.0005%), after ultrasonic 5min, sample dissolves (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 completely, 2, 4-oxadiazole-3-base]-benzyl the amount of-3-azetidinecarboxylic acid be under room temperature its 1, 1 times of solubleness in 4-dioxane), by 1, 4-dioxane solution drops to and is equipped with in the 20mL vial of 10.0mL normal heptane, stirred at ambient temperature 0.5 hour, filter, 40 DEG C of vacuum-drying 24 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } form IV of-3-azetidinecarboxylic acid.Output is 0.7mg; Productive rate is 58%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 6.
embodiment 59
Under room temperature, the fluoro-4-of 1.8mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 20mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 6.0mL1, 4-dioxane (volume content of water is 0.0008%), after ultrasonic 5min, sample dissolves (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 completely, 2, 4-oxadiazole-3-base]-benzyl the amount of-3-azetidinecarboxylic acid be under room temperature its 1, 0.5 times of solubleness in 4-dioxane), in wherein dripping 6.0mL isopropyl ether, stirred at ambient temperature 10 hours, filter, 40 DEG C of vacuum-drying 24 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } form IV of-3-azetidinecarboxylic acid.Output is 1.0mg; Productive rate is 56%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 6.
embodiment 60
Under room temperature, the fluoro-4-of 1.8mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 20mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 6.0mL1, 4-dioxane (volume content of water is 0.0005%), after ultrasonic 5min, sample dissolves (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 completely, 2, 4-oxadiazole-3-base]-benzyl the amount of-3-azetidinecarboxylic acid be under room temperature its 1, 0.5 times of solubleness in 4-dioxane), in wherein dripping 12.0mL n-propyl alcohol, stirred at ambient temperature 10 hours, centrifugal, 40 DEG C of vacuum-drying 24 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } form IV of-3-azetidinecarboxylic acid.Output is 0.3mg; Productive rate is 17%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 6.
embodiment 61
Under room temperature, the fluoro-4-of 1.8mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 3.0mL methyl alcohol (volume content of water is 0.0001%), within ultrasonic 15 minutes, obtain colorless cleared solution (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this solution, 2, 4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is its 1 times of solubleness in methyl alcohol at such a temperature), with 0.45 μm of organic filter membrane filtration, filtrate is placed in 5mL vial room temperature lower open mouth volatilization crystallization, by the solid room temperature vacuum-drying that obtains 1 hour, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } form IV of-3-azetidinecarboxylic acid.Output is 1.4mg; Productive rate is 78%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 6.
embodiment 62
Under room temperature, the fluoro-4-of 1.6mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 4.0mL ethanol (volume content of water is 0.0005%), within ultrasonic 15 minutes, obtain colorless cleared solution (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this solution, 2, 4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is 0.5 times of its solubleness in ethanol at such a temperature), with 0.45 μm of organic filter membrane filtration, filtrate is placed in 5mL vial 60 DEG C of lower open mouth volatilization crystallizatioies, by solid 40 DEG C of vacuum-dryings of obtaining 24 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } form IV of-3-azetidinecarboxylic acid.Output is 1.0mg; Productive rate is 62%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 6.
embodiment 63
Under room temperature, the fluoro-4-of 1.2mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 5.0mL Virahol (volume content of water is 0.0005%), within ultrasonic 15 minutes, obtain colorless cleared solution (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this solution, 2, 4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is its 0.8 times of solubleness in Virahol at such a temperature), with 0.45 μm of organic filter membrane filtration, filtrate is placed in 5mL vial 60 DEG C of lower open mouth volatilization crystallizatioies, by solid 60 DEG C of vacuum-dryings of obtaining 24 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } form IV of-3-azetidinecarboxylic acid.Output is 0.5mg; Productive rate is 42%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 6.
embodiment 64
Under room temperature, the fluoro-4-of 1.3mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 4.0mL n-propyl alcohol (volume content of water is 0.0005%), within ultrasonic 15 minutes, obtain colorless cleared solution (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this solution, 2, 4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is its 1 times of solubleness in n-propyl alcohol at such a temperature), with 0.45 μm of organic filter membrane filtration, filtrate is placed in 5mL vial room temperature lower open mouth volatilization crystallization, by solid 40 DEG C of vacuum-dryings of obtaining 48 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } form IV of-3-azetidinecarboxylic acid.Output is 0.6mg; Productive rate is 46%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 6.
embodiment 65
Under room temperature, the fluoro-4-of 1.0mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 5.0mL propyl carbinol (volume content of water is 0.0001%), within ultrasonic 15 minutes, obtain colorless cleared solution (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this solution, 2, 4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is its 1 times of solubleness in propyl carbinol at such a temperature), with 0.45 μm of organic filter membrane filtration, filtrate is placed in 5mL vial 60 DEG C of lower open mouth volatilization crystallizatioies, by solid 60 DEG C of vacuum-dryings of obtaining 48 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } form IV of-3-azetidinecarboxylic acid.Output is 0.5mg; Productive rate is 50%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 6.
embodiment 66
Under room temperature, the fluoro-4-of 0.8mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 5.0mL sec-butyl alcohol (volume content of water is 0.0001%), within ultrasonic 15 minutes, obtain colorless cleared solution (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this solution, 2, 4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is its 0.8 times of solubleness in sec-butyl alcohol at such a temperature), with 0.45 μm of organic filter membrane filtration, filtrate is placed in 5mL vial 60 DEG C of lower open mouth volatilization crystallizatioies, by solid 60 DEG C of vacuum-dryings of obtaining 24 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } form IV of-3-azetidinecarboxylic acid.Output is 0.6mg; Productive rate is 75%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 6.
embodiment 67
Under room temperature, the fluoro-4-of 1..0mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 5.0mL butanone (volume content of water is 0.0001%), within ultrasonic 15 minutes, obtain colorless cleared solution (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this solution, 2, 4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is its 1 times of solubleness in butanone at such a temperature), with 0.45 μm of organic filter membrane filtration, filtrate is placed in 5mL vial room temperature lower open mouth volatilization crystallization, by the solid room temperature vacuum-drying that obtains 1 hour, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } form IV of-3-azetidinecarboxylic acid.Output is 0.6mg; Productive rate is 60%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 6.
embodiment 68
Under room temperature, the fluoro-4-of 2.1mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 4.0mL methyl-sulphoxide (volume content of water is 0.0005%), within ultrasonic 15 minutes, obtain colorless cleared solution (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this solution, 2, 4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is its 0.5 times of solubleness in methyl-sulphoxide at such a temperature), with 0.45 μm of organic filter membrane filtration, filtrate is placed in 5mL vial 60 DEG C of lower open mouth volatilization crystallizatioies, by solid 60 DEG C of vacuum-dryings of obtaining 48 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } form IV of-3-azetidinecarboxylic acid.Output is 1.0mg; Productive rate is 48%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 6.
embodiment 69
Under room temperature, the fluoro-4-of 0.5mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 5.0mL ethyl acetate (volume content of water is 0.0001%), within ultrasonic 15 minutes, obtain colorless cleared solution (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this solution, 2, 4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is its 1 times of solubleness in ethyl acetate at such a temperature), with 0.45 μm of organic filter membrane filtration, filtrate is placed in 5mL vial 60 DEG C of lower open mouth volatilization crystallizatioies, by solid 60 DEG C of vacuum-dryings of obtaining 1 hour, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } form IV of-3-azetidinecarboxylic acid.Output is 0.1mg; Productive rate is 20%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 6.
embodiment 70
Under room temperature, the fluoro-4-of 0.4mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 4.0mL isopropyl acetate (volume content of water is 0.0002%), within ultrasonic 15 minutes, obtain colorless cleared solution (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this solution, 2, 4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is its 1 times of solubleness in isopropyl acetate at such a temperature), with 0.45 μm of organic filter membrane filtration, filtrate is placed in 5mL vial 40 DEG C of lower open mouth volatilization crystallizatioies, by solid 40 DEG C of vacuum-dryings of obtaining 24 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } form IV of-3-azetidinecarboxylic acid.Output is 0.2mg; Productive rate is 50%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 6.
embodiment 71
Under room temperature, the fluoro-4-of 3.2mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 2.0mL tetrahydrofuran (THF) (volume content of water is 0.0005%), within ultrasonic 15 minutes, obtain colorless cleared solution (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this solution, 2, 4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is its 1 times of solubleness in tetrahydrofuran (THF) at such a temperature), with 0.45 μm of organic filter membrane filtration, filtrate is placed in 5mL vial room temperature lower open mouth volatilization crystallization, by the solid room temperature vacuum-drying that obtains 24 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } form IV of-3-azetidinecarboxylic acid.Output is 2.0mg; Productive rate is 62%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 6.
embodiment 72
Get 5.9mg crystal formation I, directly be placed in the thermal station crystallization upper 1 hour being warming up to 125 DEG C, be directly cooled to room temperature and detect, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } crystal form II of-3-azetidinecarboxylic acid.Output is 5.9mg; Productive rate is 100%.
X-ray powder diffraction pattern as shown in figure 16, is crystal form II.
FT-IR collection of illustrative plates as shown in figure 17.
embodiment 73
Get 2.7mg crystal formation I, be warming up to 150 DEG C with DSC with 10 DEG C/min and be incubated 0.5 hour crystallization, being directly cooled to room temperature and detecting, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } crystal form II of-3-azetidinecarboxylic acid.Output is 2.7mg; Productive rate is 100%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Figure 16.
embodiment 74
Get 3.2mg crystal formation I, be warming up to 110 DEG C with TGA with 10 DEG C/min and be incubated 0.5 hour crystallization, being directly cooled to room temperature and detecting, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } crystal form II of-3-azetidinecarboxylic acid.Output is 3.2mg; Productive rate is 100%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Figure 16.
embodiment 75
Get 5.3mg crystal formation I, 24 hours crystallizatioies in the baking oven being directly placed in 100 DEG C, are directly cooled to room temperature and detect, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } crystal form II of-3-azetidinecarboxylic acid.Output is 5.3mg; Productive rate is 100%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Figure 16.
embodiment 76
Under room temperature, the fluoro-4-of 4.5mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 20mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 3.0mL trifluoroethanol, after ultrasonic 5min, sample dissolves (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 completely, 2, 4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is 0.5 times of its solubleness in trifluoroethanol under room temperature), in wherein dripping water 3.0mL, obtain white solid at once, stirred at ambient temperature 0.5 hour, filter, not drying, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal form II I of-3-azetidinecarboxylic acid.Output is 3.1mg; Productive rate is 69%.
X-ray powder diffraction pattern as shown in figure 18, is crystal form II I.
FT-IR collection of illustrative plates as shown in figure 19.
embodiment 77
Under room temperature, the fluoro-4-of 4.2mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 1.4mL trifluoroethanol, after ultrasonic 5min, sample dissolves (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 completely, 2, 4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is 1 times of its solubleness in trifluoroethanol under room temperature), being dropped to by trifluoroethanol solution is equipped with in the 20mL vial of 14mL acetone, obtain white solid at once, stirred at ambient temperature 10 hours, filter, not drying, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal form II I of-3-azetidinecarboxylic acid.Output is 2.4mg; Productive rate is 57%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Figure 18.
embodiment 78
Under room temperature, the fluoro-4-of 6.0mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 2.0mL trifluoroethanol, after ultrasonic 5min, sample dissolves (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 completely, 2, 4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is 1 times of its solubleness in trifluoroethanol under room temperature), trifluoroethanol solution is dropped to and is equipped with in the 100mL single port bottle of 100mL ethyl acetate, obtain white solid at once, stirred at ambient temperature 72 hours, filter, not drying, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal form II I of-3-azetidinecarboxylic acid.Output is 1.3mg; Productive rate is 22%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Figure 18.
embodiment 79
Under room temperature, the fluoro-4-of 3.9mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 200mL single port bottle, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 13mL trifluoroethanol, after ultrasonic 5min, sample dissolves (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 completely, 2, 4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is 0.1 times of its solubleness in trifluoroethanol under room temperature), in wherein dripping isopropyl ether 130mL, obtain white solid at once, stirred at ambient temperature 10 hours, filter, not drying, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal form II I of-3-azetidinecarboxylic acid.Output is 0.8mg; Productive rate is 21%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Figure 18.
embodiment 80
Under room temperature, the fluoro-4-of 4.8mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 20mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 1.6mL trifluoroethanol, after ultrasonic 5min, sample dissolves (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 completely, 2, 4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is 1 times of its solubleness in trifluoroethanol under room temperature), in wherein dripping acetonitrile 16mL, obtain white solid at once, stirred at ambient temperature 0.5 hour, filter, not drying, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal form II I of-3-azetidinecarboxylic acid.Output is 1.3mg; Productive rate is 27%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Figure 18.
embodiment 81
Under room temperature, the fluoro-4-of 5.9mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 2.0mL trifluoroethanol, after ultrasonic 5min, sample dissolves (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 completely, 2, 4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is 1 times of its solubleness in trifluoroethanol under room temperature), trifluoroethanol solution is dropped to and is equipped with in the 50mL single port bottle of 20mL methyl tertiary butyl ether, obtain white solid at once, stirred at ambient temperature 10 hours, filter, not drying, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal form II I of-3-azetidinecarboxylic acid.Output is 2.0mg; Productive rate is 34%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Figure 18.
embodiment 82
Under room temperature, the fluoro-4-of 4.5mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 20mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 15mL trifluoroethanol, after ultrasonic 5min, sample dissolves (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 completely, 2, 4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is 0.1 times of its solubleness in trifluoroethanol under room temperature), with 0.45 μm of organic filter membrane filtration, filtrate is placed in 20mL vial room temperature lower open mouth volatilization crystallization 7 days, not drying, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal form II I of-3-azetidinecarboxylic acid.Output is 0.3mg; Productive rate is 7%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Figure 18.
embodiment 83
Under room temperature, the fluoro-4-of 5.2mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 3.4mL trifluoroethanol, after ultrasonic 5min, sample dissolves (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 completely, 2, 4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is 0.5 times of its solubleness in trifluoroethanol under room temperature), with 0.45 μm of organic filter membrane filtration, filtrate is placed in 5mL vial room temperature lower open mouth volatilization crystallization 3 days, not drying, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal form II I of-3-azetidinecarboxylic acid.Output is 2.1mg; Productive rate is 40%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Figure 18.
embodiment 84
Under room temperature, the fluoro-4-of 6.1mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 2.0mL trifluoroethanol, after ultrasonic 5min, sample dissolves (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 completely, 2, 4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is 1 times of its solubleness in trifluoroethanol under room temperature), with 0.45 μm of organic filter membrane filtration, filtrate is placed in 5mL vial room temperature lower open mouth volatilization crystallization 1 day, not drying, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal form II I of-3-azetidinecarboxylic acid.Output is 3.8mg; Productive rate is 62%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Figure 18.
embodiment 85
Under room temperature, the fluoro-4-of 8.0mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 4.0mL propyl carbinol, ultrasonic 15min obtains white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is 10 times of its solubleness in propyl carbinol under room temperature), 7 days crystallizatioies are stirred at 60 DEG C, filter, by the solid room temperature vacuum-drying that obtains 48 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } crystal form V of-3-azetidinecarboxylic acid.Output is 6.1mg; Productive rate is 76%.
X-ray powder diffraction pattern as shown in figure 20, is crystal form V.
FT-IR collection of illustrative plates as shown in figure 21.
embodiment 86
Under room temperature, the fluoro-4-of 9.3mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 50mL single port bottle, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 31.0mL propyl carbinol, ultrasonic 15min obtains white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is 1.5 times of its solubleness in propyl carbinol under room temperature), stirred at ambient temperature 3 days crystallizatioies, filter, by solid 40 DEG C of vacuum-dryings of obtaining 48 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } crystal form V of-3-azetidinecarboxylic acid.Output is 4.0mg; Productive rate is 43%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Figure 20.
embodiment 87
Under room temperature, the fluoro-4-of 10.1mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 1.0mL propyl carbinol, ultrasonic 15min obtains white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is 50 times of its solubleness in propyl carbinol under room temperature), 14 days crystallizatioies are stirred at 60 DEG C, filter, by solid 60 DEG C of vacuum-dryings of obtaining 1 hour, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } crystal form V of-3-azetidinecarboxylic acid.Output is 8.3mg; Productive rate is 82%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Figure 20.
embodiment 88
Under room temperature, the fluoro-4-of 4.4mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 20mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 20.0mL propyl carbinol, ultrasonic 15min obtains white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is 1.1 times of its solubleness in propyl carbinol under room temperature), stirred at ambient temperature 7 days crystallizatioies, filter, by solid 40 DEG C of vacuum-dryings of obtaining 24 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } crystal form V of-3-azetidinecarboxylic acid.Output is 1.9mg; Productive rate is 43%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Figure 20.
embodiment 89
Under room temperature, the fluoro-4-of 7.9mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 1.0mL ethanol, ultrasonic 15min obtains white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is 10 times of its solubleness in ethanol under room temperature), stirred at ambient temperature 7 days crystallizatioies, filter, by the solid room temperature vacuum-drying that obtains 48 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal form V I of-3-azetidinecarboxylic acid.Output is 6.3mg; Productive rate is 80%.
X-ray powder diffraction pattern as shown in figure 22, is crystal form V I.
embodiment 90
Under room temperature, the fluoro-4-of 2.4mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 2.0mL ethanol, ultrasonic 15min obtains white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is 1.5 times of its solubleness in ethanol under room temperature), stirred at ambient temperature 3 days crystallizatioies, filter, by solid 40 DEG C of vacuum-dryings of obtaining 1 hour, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal form V I of-3-azetidinecarboxylic acid.Output is 1.5mg; Productive rate is 63%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Figure 22.
embodiment 91
Under room temperature, the fluoro-4-of 80.2mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 2.0mL ethanol, ultrasonic 15min obtains white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is 50 times of its solubleness in ethanol under room temperature), 14 days crystallizatioies are stirred at 60 DEG C, filter, by solid 60 DEG C of vacuum-dryings of obtaining 48 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal form V I of-3-azetidinecarboxylic acid.Output is 75.8mg; Productive rate is 95%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Figure 22.
embodiment 92
Under room temperature, the fluoro-4-of 1.8mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 2.0mL ethanol, ultrasonic 15min obtains white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is 1.1 times of its solubleness in ethanol under room temperature), stirred at ambient temperature 3 days crystallizatioies, filter, by the solid room temperature vacuum-drying that obtains 24 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal form V I of-3-azetidinecarboxylic acid.Output is 0.5mg; Productive rate is 28%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Figure 22.
embodiment 93
Under room temperature, the fluoro-4-of 4.1mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 20mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 4.0mL methyl-sulphoxide, after ultrasonic 5min, sample dissolves (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 completely, 2, 4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is 1 times of its solubleness in methyl-sulphoxide under room temperature), with 0.45 μm of organic membrane filtration, the vial that filtrate is housed is placed in lower 14 days of the closed atmosphere in 50mL water-100mL space, treat that 40.0mL water diffuses in dimethyl sulfoxide solution, filter after there is a large amount of solid, by solid 60 DEG C of vacuum-dryings of obtaining 24 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal form V II of-3-azetidinecarboxylic acid.Output is 2.4mg; Productive rate is 59%.
X-ray powder diffraction pattern as shown in figure 23, is crystal form V II.
FT-IR collection of illustrative plates as shown in figure 24.
embodiment 94
Under room temperature, the fluoro-4-of 2.0mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 20mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 4.0mL methyl-sulphoxide, after ultrasonic 5min, sample dissolves (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 completely, 2, 4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is 0.5 times of its solubleness in methyl-sulphoxide under room temperature), with 0.45 μm of organic membrane filtration, the vial that filtrate is housed is placed in lower 7 days of the closed atmosphere in 20mL water-100mL space, treat that 4.0mL water diffuses in dimethyl sulfoxide solution, filter after there is a large amount of solid, by solid 40 DEG C of vacuum-dryings of obtaining 24 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal form V II of-3-azetidinecarboxylic acid.Output is 0.4mg; Productive rate is 20%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Figure 23.
embodiment 95
Under room temperature, 6.4mg crystal form V I and 0.8mL ethanol is added in 5mL vial, ultrasonic 15min obtains white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is 10 times of its solubleness in ethanol under room temperature), stirred at ambient temperature 7 days crystallizatioies, filter, by the solid room temperature vacuum-drying that obtains 48 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal form V III of-3-azetidinecarboxylic acid.Output is 5.8mg; Productive rate is 91%.
X-ray powder diffraction pattern as shown in figure 25, is crystal form V III.
FT-IR collection of illustrative plates as shown in figure 26.
embodiment 96
Under room temperature, 2.8mg crystal form V I and 2.3mL ethanol is added in 5mL vial, ultrasonic 15min obtains white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is 1.5 times of its solubleness in ethanol under room temperature), stirred at ambient temperature 3 days crystallizatioies, filter, by solid 40 DEG C of vacuum-dryings of obtaining 1 hour, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal form V III of-3-azetidinecarboxylic acid.Output is 1.5mg; Productive rate is 54%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Figure 25.
embodiment 97
Under room temperature, 39.8mg crystal form V I and 1.0mL ethanol is added in 5mL vial, ultrasonic 15min obtains white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is 50 times of its solubleness in ethanol under room temperature), 14 days crystallizatioies are stirred at 60 DEG C, filter, by solid 60 DEG C of vacuum-dryings of obtaining 48 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal form V III of-3-azetidinecarboxylic acid.Output is 37.6mg; Productive rate is 94%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Figure 25.
embodiment 98
Under room temperature, 1.8mg crystal form V I and 2.1mL ethanol is added in 5mL vial, ultrasonic 15min obtains white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is 1.1 times of its solubleness in ethanol under room temperature), stirred at ambient temperature 3 days crystallizatioies, filter, by the solid room temperature vacuum-drying that obtains 24 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal form V III of-3-azetidinecarboxylic acid.Output is 0.3mg; Productive rate is 17%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Figure 25.
embodiment 99
Under room temperature, the fluoro-4-of 2.9mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 1.0mL Virahol, ultrasonic 15min obtains white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is 10 times of its solubleness in Virahol under room temperature), stirred at ambient temperature 7 days crystallizatioies, filter, by the solid room temperature vacuum-drying that obtains 48 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal formation IX of-3-azetidinecarboxylic acid.Output is 2.4mg; Productive rate is 83%.
X-ray powder diffraction pattern as shown in figure 27, is crystal formation IX.
FT-IR collection of illustrative plates as shown in figure 28.
embodiment 100
Under room temperature, the fluoro-4-of 4.5mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 20mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 10.0mL Virahol, ultrasonic 15min obtains white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is 1.5 times of its solubleness in Virahol under room temperature), stirred at ambient temperature 3 days crystallizatioies, filter, by solid 40 DEG C of vacuum-dryings of obtaining 1 hour, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal formation IX of-3-azetidinecarboxylic acid.Output is 1.5mg; Productive rate is 33%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Figure 27.
embodiment 101
Under room temperature, the fluoro-4-of 15.2mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 1.0mL Virahol, ultrasonic 15min obtains white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is 50 times of its solubleness in Virahol under room temperature), 14 days crystallizatioies are stirred at 60 DEG C, filter, by solid 60 DEG C of vacuum-dryings of obtaining 48 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal formation IX of-3-azetidinecarboxylic acid.Output is 11.9mg; Productive rate is 78%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Figure 27.
embodiment 102
Under room temperature, the fluoro-4-of 3.3mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 20mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 10.0mL Virahol, ultrasonic 15min obtains white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is 1.1 times of its solubleness in Virahol under room temperature), stirred at ambient temperature 3 days crystallizatioies, filter, by the solid room temperature vacuum-drying that obtains 24 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal formation IX of-3-azetidinecarboxylic acid.Output is 1.2mg; Productive rate is 36%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Figure 27.
embodiment 103
Under room temperature, the fluoro-4-of 6.1mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 20mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 10.0mL1, 4-dioxane, after ultrasonic 5min, sample dissolves (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 completely, 2, 4-oxadiazole-3-base]-benzyl the amount of-3-azetidinecarboxylic acid be under room temperature its 1, 1 times of solubleness in 4-dioxane), with 0.45 μm of organic filter membrane filtration, filtrate is placed in 20mL vial room temperature lower open mouth volatilization crystallization 7 days, by the solid room temperature vacuum-drying that obtains 48 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } crystal form X of-3-azetidinecarboxylic acid.Output is 5.7mg; Productive rate is 93%.
X-ray powder diffraction pattern as shown in figure 29, is crystal form X.
FT-IR collection of illustrative plates as shown in figure 30.
embodiment 104
Under room temperature, the fluoro-4-of 1.5mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 20mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 5.0mL1, 4-dioxane, after ultrasonic 5min, sample dissolves (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 completely, 2, 4-oxadiazole-3-base]-benzyl the amount of-3-azetidinecarboxylic acid be under room temperature its 1, 0.5 times of solubleness in 4-dioxane), with 0.45 μm of organic filter membrane filtration, filtrate is placed in 20mL vial room temperature lower open mouth volatilization crystallization 1 day, by solid 40 DEG C of vacuum-dryings of obtaining 24 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } crystal form X of-3-azetidinecarboxylic acid.Output is 0.5mg; Productive rate is 33%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Figure 29.
embodiment 105
Under room temperature, the fluoro-4-of 5.9mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 100mL single port bottle, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 100.0mL1, 4-dioxane, after ultrasonic 5min, sample dissolves (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 completely, 2, 4-oxadiazole-3-base]-benzyl the amount of-3-azetidinecarboxylic acid be under room temperature its 1, 0.1 times of solubleness in 4-dioxane), with 0.45 μm of organic filter membrane filtration, filtrate is placed in 100mL single port bottle 60 DEG C of lower open mouth volatilization crystallizatioies 3 days, by solid 60 DEG C of vacuum-dryings of obtaining 1 hour, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } crystal form X of-3-azetidinecarboxylic acid.Output is 2.1mg; Productive rate is 36%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Figure 29.
embodiment 106
Under room temperature, the fluoro-4-of 10.2mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 150mL single port bottle, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 100.0mL toluene, ultrasonic 15min obtains white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is 10 times of its solubleness in toluene under room temperature), stirred at ambient temperature 7 days crystallizatioies, filter, by the solid room temperature vacuum-drying that obtains 48 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal form X I of-3-azetidinecarboxylic acid.Output is 7.4mg; Productive rate is 73%.
X-ray powder diffraction pattern as shown in figure 31, is crystal form X I.
FT-IR collection of illustrative plates as shown in figure 32.
embodiment 107
Under room temperature, the fluoro-4-of 1.5mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 150mL single port bottle, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 100.0mL toluene, ultrasonic 15min obtains white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is 1.5 times of its solubleness in toluene under room temperature), stirred at ambient temperature 3 days crystallizatioies, filter, by solid 40 DEG C of vacuum-dryings of obtaining 1 hour, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal form X I of-3-azetidinecarboxylic acid.Output is 0.5mg; Productive rate is 33%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Figure 31.
embodiment 108
Under room temperature, the fluoro-4-of 2.5mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 5.0mL toluene, ultrasonic 15min obtains white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is 50 times of its solubleness in toluene under room temperature), 14 days crystallizatioies are stirred at 60 DEG C, filter, by solid 60 DEG C of vacuum-dryings of obtaining 48 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal form X I of-3-azetidinecarboxylic acid.Output is 1.9mg; Productive rate is 76%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Figure 31.
embodiment 109
Under room temperature, the fluoro-4-of 1.1mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 150mL single port bottle, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 100.0mL toluene, ultrasonic 15min obtains white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is 1.1 times of its solubleness in toluene under room temperature), stirred at ambient temperature 3 days crystallizatioies, filter, by the solid room temperature vacuum-drying that obtains 24 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal form X I of-3-azetidinecarboxylic acid.Output is 0.2mg; Productive rate is 22%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Figure 31.
embodiment 110
Under room temperature, the fluoro-4-of 12.1mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 2.0mL anhydrous methanol, ultrasonic 15min obtains white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is 10 times of its solubleness in anhydrous methanol under room temperature), stirred at ambient temperature 7 days crystallizatioies, filter, by the solid room temperature vacuum-drying that obtains 48 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal form X II of-3-azetidinecarboxylic acid.Output is 9.4mg; Productive rate is 78%.
X-ray powder diffraction pattern as shown in figure 11, is crystal form X II.
PLM collection of illustrative plates as shown in figure 12.Display: fine crystals.
DSC and TGA collection of illustrative plates as shown in figure 13.Display: crystal form X II has a roomy endotherm(ic)peak (solvent peak) at 25 ~ 90 DEG C, sloughs the sample after water 148 DEG C of fusion and decomposition; Crystal form X II is at 100 DEG C of slip surface solvents 1.7%, and decomposition temperature is 142 DEG C.Decomposition temperature is 142 DEG C.
DVS collection of illustrative plates as shown in figure 14.Display: 20%RH ~ 80%RH changes in weight is 1.3%.
FT-IR collection of illustrative plates as shown in figure 15.
Above-mentioned detected result shows: described crystal form X II is anhydride, not easily moisture absorption.
embodiment 111
Under room temperature, the fluoro-4-of 1.4mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 1.5mL anhydrous methanol, ultrasonic 15min obtains white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is 1.5 times of its solubleness in anhydrous methanol under room temperature), stirred at ambient temperature 3 days crystallizatioies, filter, by solid 40 DEG C of vacuum-dryings of obtaining 1 hour, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal form X II of-3-azetidinecarboxylic acid.Output is 0.6mg; Productive rate is 43%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Figure 11.
embodiment 112
Under room temperature, the fluoro-4-of 29.8mg1-{2-[5-(4-isobutyl phenenyl)-1 is added in 5mL vial, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid and 1.0mL anhydrous methanol, ultrasonic 15min obtains white suspension (the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1 in this suspension, 2, 4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is 50 times of its solubleness in anhydrous methanol under room temperature), 14 days crystallizatioies are stirred at 60 DEG C, filter, by solid 60 DEG C of vacuum-dryings of obtaining 24 hours, obtain the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl } the crystal form X II of-3-azetidinecarboxylic acid.Output is 25.1mg; Productive rate is 84%.XRPD detects and obtains the X-ray powder diffraction pattern substantially identical with Figure 11.
comparative example 1
Get the fluoro-4-of 1-{2-of the present invention [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl the crystal formation I of-3-azetidinecarboxylic acid, form IV, crystal form X II, crystal form II, crystal form II I, crystal form V, crystal form V I, crystal form V II, crystal form V III, crystal formation IX, crystal form X, crystal form X I and by preparation example 1 prepare unformed, the magma that is at war with is tested.
Concrete operations are as follows:
(1) 2mg crystal formation I, form IV, crystal form X II, crystal form II, crystal form II I, crystal form V, crystal form V I, crystal form V II, crystal form V III, crystal formation IX, crystal form X, crystal form X I and unformed is respectively got, form suspension respectively in Virahol, water, aqueous ethanolic solution (volume ratio of second alcohol and water is respectively 1:1,1:5,1:10 and 1:100), ethanol, aqueous acetone solution (volume ratio of acetone and water is respectively 1:1,1:5,1:10 and 1:100) and acetone, stirring at room temperature is carried out XRPD sign and is compared after 3 days.
(2) respectively get 5mg form IV and crystal form X II, form suspension respectively in water and acetone, stirring at room temperature is carried out XRPD sign and is compared after 3 days.
(3) respectively get 5mg crystal formation I and crystal form X II, form suspension respectively in ethanol, stirring at room temperature is carried out XRPD sign and is compared after 3 days.
The results detailed in Table 1, find:
(1), under room temperature, in Aquo System, crystal formation I is most stable crystal form, and in pure organic solvent, form IV is the most stable crystal formation.
(2) under room temperature, it is that crystal form X II is more stable that crystal form X II and form IV compete magma in water, and it is that form IV is more stable that crystal form X II and form IV compete magma in acetone.
Table 1: competition magma experimental data statistics
comparative example 2
Get crystal formation I of the present invention, form IV and crystal form X II, carry out stability and place test.
Concrete operations are as follows:
Respectively get 5mg crystal formation I, form IV and crystal form X II, respectively uncovered be placed on drying at room temperature device, room temperature, room temperature-97%RH, room temperature-75%RH or room temperature-44%RH under, carry out after 1 month XRPD characterize compare.
The results detailed in Table 2, find:
Place after one month under, room temperature-97%RH, room temperature-75%RH uncovered in drying at room temperature device, room temperature or room temperature-44%RH, crystal formation I, form IV and crystal form X II all remain unchanged.
Table 2: shelf-stability experimental data is added up
comparative example 3
The amorphous article got crystal formation I of the present invention, form IV, crystal form X II, crystal form II, crystal form II I, crystal form V, crystal form V I, crystal form V II, crystal form V III, crystal formation IX, crystal form X, crystal form X I and prepare by preparation example 1, adopt the conventional pharmaceutically acceptable auxiliary material used in this area, according to the ordinary method for the preparation of capsule, the capsule of obtained each crystal formation or amorphous article, then carries out the crystal formation that capsule places 0 day and 6 months and changes and dissolution rate simultaneous test.
Concrete operations are as follows:
Adopt paddle method, using water as dissolution medium, temperature 37 DEG C, rotating speed of agitator is 50 revs/min, capsule (remove photoresist softgel shell) is stirred into suspension liquid with 900mL pure water, littlely sample 20mL constantly respectively at 2 minutes, 10 minutes, 20 minutes, 40 minutes, 60 minutes, 120 minutes and 24, supply with water after every sub-sampling, HPLC measures the concentration of each time point sample.
Experimental result shows:
(1) each capsule is in placement after 6 months, in the capsule of amorphous article and crystal form II of the present invention, crystal form II I, crystal form V, crystal form V I, crystal form V II, crystal form V III, crystal formation IX, crystal form X and crystal form X I, its crystal formation partly or entirely there occurs change, and in the capsule of crystal formation I of the present invention, form IV and crystal form X II, its crystal formation remains unchanged, and illustrates that crystal formation I of the present invention, form IV and crystal form X II have good stability of crystal form;
(2) capsule of amorphous article and crystal form II of the present invention, crystal form II I, crystal form V, crystal form V I, crystal form V II, crystal form V III, crystal formation IX, crystal form X and crystal form X I there occurs change at the dissolution rate of 0 day and 6 months because of the transformation of its crystal formation, therefore can cause the instability of quality product, and then affect drug effect.And the capsule of crystal formation I of the present invention, form IV and crystal form X II is substantially constant at the dissolution rate of 0 day and 6 months, therefore crystal formation I of the present invention, form IV and crystal form X II are more suitable for the application of formulation products.
The all patent documentations quoted in this specification sheets and non-patent publications, be incorporated herein in full with it all by reference.
The above; be only the specific embodiment of the present invention; but protection scope of the present invention is not limited thereto; any those of ordinary skill in the art are in the technical scope disclosed by the present invention; the change can expected without creative work or replacement, all should be encompassed within protection scope of the present invention.

Claims (15)

1. the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-the base]-benzyl that structural formula is as follows } the crystal formation I of-3-azetidinecarboxylic acid,
It is characterized in that, use Cu-K α radiation, the X-ray powder diffraction pattern of described crystal formation I is that 4.8 ± 0.2 °, 5.5 ± 0.2 °, 8.2 ± 0.2 °, 15.0 ± 0.2 °, 17.0 ± 0.2 ° and 18.6 ± 0.2 ° of places have characteristic peak at diffraction angle 2 θ.
2. crystal formation I according to claim 1, it is characterized in that, the X-ray powder diffraction pattern of described crystal formation I is that 4.8 ± 0.2 °, 5.5 ± 0.2 °, 8.2 ± 0.2 °, 10.1 ± 0.2 °, 11.1 ± 0.2 °, 12.1 ± 0.2 °, 15.0 ± 0.2 °, 17.0 ± 0.2 °, 18.6 ± 0.2 °, 24.0 ± 0.2 °, 24.9 ± 0.2 ° and 27.0 ± 0.2 ° of places have characteristic peak at diffraction angle 2 θ.
3. crystal formation I according to claim 2, is characterized in that, the X-ray powder diffraction pattern of described crystal formation I is that following position has characteristic peak and relative intensity thereof at diffraction angle 2 θ:
Preferably, the X-ray powder diffraction pattern of described crystal formation I as shown in Figure 1.
4. the preparation method of the crystal formation I according to any one of claim 1-3, is characterized in that, described preparation method adopt in following method any one:
(1) by fluoro-for 1-{2-4-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid forms suspension in following solvent system, stirring and crystallizing, by the crystal separation of precipitation, drying, obtain the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the crystal formation I of-3-azetidinecarboxylic acid, wherein said solvent system is selected from the mixture of water or water and organic solvent, and described organic solvent is selected from C 1~ C 4alcohol, C 5~ C 6ether, C 3~ C 4ketone, ethyl acetate, Nitromethane 99Min., methylene dichloride, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, acetonitrile, chloroform, toluene, methyl-sulphoxide, C 7alkane and composition thereof;
Preferably, described organic solvent is selected from methyl alcohol, ethanol, propyl alcohol, butanols, methyl tertiary butyl ether, isopropyl ether, acetone, butanone, ethyl acetate, Nitromethane 99Min., methylene dichloride, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, acetonitrile, chloroform, toluene, methyl-sulphoxide, methylcyclohexane or normal heptane;
Preferably, in the mixture of described water and organic solvent, the volume content of water is at least 0.01%, is more preferably at least 0.1%;
Preferably, the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is 1.1 ~ 50 times of its solubleness in described solvent system under service temperature, is more preferably 1.5 ~ 10 times;
Preferably, described recrystallization temperature is room temperature to 60 DEG C, is more preferably room temperature;
Preferably, described service temperature is room temperature;
Preferably, the described crystallization time is 3-14 days, is more preferably 3-7 days;
(2) under certain temperature, by fluoro-for 1-{2-4-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid forms solution in the mixed system of water and tetrahydrofuran (THF), cooling is stirring and crystallizing also, by the crystal separation of precipitation, drying, obtains the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the crystal formation I of-3-azetidinecarboxylic acid;
Preferably, in the mixed system of described water and tetrahydrofuran (THF), the volume content of water is 0.01% ~ 50%, is more preferably 0.1% ~ 50%;
Preferably, in described solution, the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is 0.1 ~ 1 times of its solubleness in described mixed system under certain temperature, is more preferably 0.5 ~ 1 times;
Preferably, described certain temperature is 40 DEG C ~ 50 DEG C;
Preferably, described cooled temperature is room temperature;
Preferably, the described crystallization time is 0.5 ~ 72 hour, is more preferably 0.5 ~ 10 hour;
(3) to the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } add water in the solution that formed in organic solvent of-3-azetidinecarboxylic acid, stirring and crystallizing, by the crystal separation of precipitation, drying, obtain the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the crystal formation I of-3-azetidinecarboxylic acid, wherein said organic solvent is selected from ethanol and trifluoroethanol mixture, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, methyl-sulphoxide or its mixture;
Preferably, described organic solvent is selected from trifluoroethanol solution (volume content of ethanol is 66%), tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane or the methyl-sulphoxide of ethanol;
Preferably, the volume ratio of described water and organic solvent is 1:1 ~ 50:1, is more preferably 1:1 ~ 10:1;
Preferably, in described solution, the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is 0.1 ~ 1 times of its solubleness in described organic solvent under service temperature; Be more preferably 0.5 ~ 1 times;
Preferably, described service temperature is room temperature;
Preferably, described recrystallization temperature is room temperature to 60 DEG C, is more preferably room temperature;
Preferably, the described crystallization time is 0.5 ~ 72 hour, is more preferably 0.5 ~ 10 hour;
(4) by fluoro-for 1-{2-4-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the solution evaporation crystallization of-3-azetidinecarboxylic acid in the mixed system of water and organic solvent, by the crystal separation of precipitation, drying, obtain the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the crystal formation I of-3-azetidinecarboxylic acid; Wherein said organic solvent is selected from propyl alcohol, acetone, tetrahydrofuran (THF) or its mixture;
Preferably, described organic solvent is selected from Virahol, acetone or tetrahydrofuran (THF);
Preferably, in the mixture of described water and organic solvent, the volume content of water is 0.01% ~ 50%, is more preferably at least 0.1% ~ 50%;
Preferably, the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is 0.1 ~ 1 times of its solubleness in described solvent system under service temperature, is more preferably 0.5 ~ 1 times;
Preferably, described service temperature is room temperature;
Preferably, described recrystallization temperature is room temperature to 60 DEG C, is more preferably room temperature;
Preferably, the described crystallization time is 1 ~ 7 day, is more preferably 3 ~ 7 days;
In the preparation method of above-mentioned (1) ~ (4) crystal formation I, described drying temperature is room temperature ~ 60 DEG C, is preferably 40 DEG C; Described time of drying is 1 ~ 48 hour, is preferably 1 ~ 24 hour.
5. the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-the base]-benzyl that structural formula is as follows } form IV of-3-azetidinecarboxylic acid,
It is characterized in that, use Cu-K α radiation, the X-ray powder diffraction pattern of described form IV is that 4.8 ± 0.2 °, 9.0 ± 0.2 °, 15.1 ± 0.2 °, 15.9 ± 0.2 °, 17.5 ± 0.2 ° and 17.7 ± 0.2 ° of places have characteristic peak at diffraction angle 2 θ.
6. form IV according to claim 5, it is characterized in that, the X-ray powder diffraction pattern of described form IV is that 4.8 ± 0.2 °, 9.0 ± 0.2 °, 9.8 ± 0.2 °, 12.4 ± 0.2 °, 13.7 ± 0.2 °, 14.8 ± 0.2 °, 15.1 ± 0.2 °, 15.9 ± 0.2 °, 17.5 ± 0.2 °, 17.7 ± 0.2 °, 18.2 ± 0.2 ° and 19.8 ± 0.2 ° of places have characteristic peak at diffraction angle 2 θ.
7. form IV according to claim 6, is characterized in that, the X-ray powder diffraction pattern of described form IV is that following position has characteristic peak and relative intensity thereof at diffraction angle 2 θ:
Preferably, the X-ray powder diffraction pattern of described form IV as shown in Figure 6.
8. the preparation method of the form IV according to any one of claim 5-7, is characterized in that, described preparation method adopt in following method any one:
(1) by fluoro-for 1-{2-4-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid forms suspension in following organic solvent system, stirring and crystallizing, by the crystal separation of precipitation, drying, obtain the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } form IV of-3-azetidinecarboxylic acid, wherein said organic solvent is selected from C 2~ C 3alcohol, acetone, C 4~ C 5ester, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, acetonitrile and composition thereof;
Preferably, described organic solvent is selected from acetone, ethyl acetate, isopropyl acetate, 1, the ethanolic soln (volume content of acetonitrile is 50%) of the ethanolic soln (volume content of acetone is 50%) of 4-dioxane, acetonitrile, acetone, the ethanolic soln (volume content of tetrahydrofuran (THF) is 50%) of tetrahydrofuran (THF) and acetonitrile, be more preferably acetone, ethyl acetate, isopropyl acetate, Isosorbide-5-Nitrae-dioxane and acetonitrile;
Preferably, the process of described organic solvent drying, the volume content of Water in Organic Solvents is less than 0.001%;
Preferably, the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is 1.1 ~ 50 times of its solubleness in described solvent system under service temperature, is more preferably 1.5 ~ 10 times;
Preferably, described service temperature is room temperature;
Preferably, described recrystallization temperature is room temperature to 60 DEG C, is more preferably room temperature;
Preferably, the described crystallization time is 3-14 days, is more preferably 3-7 days;
(2) under certain temperature, by fluoro-for 1-{2-4-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl-3-azetidinecarboxylic acid forms solution in organic solvent, cooling stirring and crystallizing, by separate out crystal separation, drying, obtain the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } form IV of-3-azetidinecarboxylic acid, wherein said organic solvent is selected from C 1~ C 4alcohol, C 3~ C 4ketone, C 4~ C 5ester, Isosorbide-5-Nitrae-dioxane, acetonitrile, toluene and composition thereof;
Preferably, described organic solvent is selected from methyl alcohol, ethanol, Virahol, n-propyl alcohol, sec-butyl alcohol, propyl carbinol, acetone, butanone, ethyl acetate, isopropyl acetate, 1, the acetonitrile solution (volume content of ethanol is 25%) of 4-dioxane, toluene and ethanol, be more preferably methyl alcohol, ethanol, Virahol, propyl carbinol, acetone, butanone, ethyl acetate, isopropyl acetate, Isosorbide-5-Nitrae-dioxane, toluene;
Preferably, the process of described organic solvent drying, the volume content of Water in Organic Solvents is less than 0.001%;
Preferably, in described solution, the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is its 0.1 ~ 1 times of solubleness in described organic solvent under certain temperature, is more preferably 0.5 ~ 1 times;
Preferably, described certain temperature is 40 DEG C ~ 80 DEG C, is more preferably 50 DEG C ~ 80 DEG C;
Preferably, described cooled temperature is room temperature;
Preferably, the described crystallization time is 0.5 ~ 72 hour, is more preferably 0.5 ~ 10 hour;
(3) to the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } add slightly soluble or insoluble solvent in the solution that formed in soluble solvent of-3-azetidinecarboxylic acid, stirring and crystallizing, by the crystal separation of precipitation, drying, obtain the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } form IV of-3-azetidinecarboxylic acid, wherein said soluble solvent is selected from trifluoroethanol, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, methyl-sulphoxide or its mixture; Described slightly soluble or insoluble solvent are selected from C 3~ C 4alcohol, C 4~ C 5ester, isopropyl ether, normal heptane or its mixture;
Preferably, described soluble solvent is selected from trifluoroethanol, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane or methyl-sulphoxide;
Preferably, described slightly soluble or insoluble solvent are selected from n-propyl alcohol, propyl carbinol, sec-butyl alcohol, ethyl acetate, isopropyl acetate, isopropyl ether or normal heptane;
Preferably, the equal drying process of described solvent, the volume content of Water in Organic Solvents is less than 0.001%;
Preferably, the volume ratio of described slightly soluble or insoluble solvent and soluble solvent is 1:1 ~ 50:1, is more preferably 1:1 ~ 10:1;
Preferably, in described solution, the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is 0.1 ~ 1 times of its solubleness in described soluble solvent under service temperature; Be more preferably 0.5 ~ 1 times;
Preferably, described service temperature is room temperature;
Preferably, described recrystallization temperature is room temperature to 60 DEG C, is more preferably room temperature;
Preferably, the described crystallization time is 0.5 ~ 72 hour, is more preferably 0.5 ~ 10 hour;
(4) by fluoro-for 1-{2-4-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid solution evaporation crystallization in organic solvent, by the crystal separation of precipitation, drying, obtain the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } form IV of-3-azetidinecarboxylic acid; Wherein said organic solvent is selected from C 1~ C 4alcohol, C 4~ C 5ester, butanone, tetrahydrofuran (THF), methyl-sulphoxide or its mixture;
Preferably, described organic solvent is selected from methyl alcohol, ethanol, Virahol, n-propyl alcohol, sec-butyl alcohol, propyl carbinol, butanone, ethyl acetate, isopropyl acetate, tetrahydrofuran (THF) or methyl-sulphoxide;
Preferably, the process of described organic solvent drying, the volume content of Water in Organic Solvents is less than 0.001%;
Preferably, the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } amount of-3-azetidinecarboxylic acid is 0.1 ~ 1 times of its solubleness in described solvent system under service temperature, is more preferably 0.5 ~ 1 times;
Preferably, described service temperature is room temperature;
Preferably, described recrystallization temperature is room temperature to 60 DEG C, is more preferably room temperature;
Preferably, the described crystallization time is 1 ~ 7 day, is more preferably 3 ~ 7 days;
In the preparation method of above-mentioned (1) ~ (4) form IV, described drying temperature is room temperature ~ 60 DEG C, is preferably 40 DEG C; Described time of drying is 1 ~ 48 hour, is preferably 1 ~ 24 hour.
9. the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-the base]-benzyl that structural formula is as follows } the crystal form X II of-3-azetidinecarboxylic acid,
It is characterized in that, use Cu-K α radiation, the X-ray powder diffraction pattern of described crystal form X II is that 6.3 ± 0.2 °, 9.5 ± 0.2 °, 12.7 ± 0.2 °, 18.0 ± 0.2 ° and 19.3 ± 0.2 ° of places have characteristic peak at diffraction angle 2 θ.
10. crystal form X II according to claim 9, it is characterized in that, the X-ray powder diffraction pattern of described crystal form X II is that 6.3 ± 0.2 °, 9.5 ± 0.2 °, 12.7 ± 0.2 °, 18.0 ± 0.2 °, 19.3 ± 0.2 °, 21.8 ± 0.2 °, 22.1 ± 0.2 °, 22.4 ± 0.2 °, 24.2 ± 0.2 °, 24.6 ± 0.2 ° and 25.7 ± 0.2 ° of places have characteristic peak at diffraction angle 2 θ.
11. crystal form X II according to claim 10, is characterized in that, the X-ray powder diffraction pattern of described crystal form X II is that following position has characteristic peak and relative intensity thereof at diffraction angle 2 θ:
Preferably, the X-ray powder diffraction pattern of described crystal form X II as shown in figure 11.
The preparation method of the crystal form X II according to any one of 12. claim 9-11, is characterized in that, described preparation method adopts following method to prepare:
By fluoro-for 1-{2-4-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid forms suspension in anhydrous methanol, stirring and crystallizing, by the crystal separation of precipitation, drying, obtain the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } the crystal form X II of-3-azetidinecarboxylic acid;
Preferably, the fluoro-4-of described 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } consumption of-3-azetidinecarboxylic acid is 1.1 ~ 50 times of its solubleness in anhydrous methanol under service temperature, is more preferably 1.5 ~ 10 times;
Preferably, described recrystallization temperature is room temperature to 60 DEG C, is more preferably room temperature;
Preferably, described service temperature is room temperature;
Preferably, the described crystallization time is 3-14 days, is more preferably 3-7 days;
In the preparation method of above-mentioned crystal form X II, described drying temperature is room temperature ~ 60 DEG C, is preferably 40 DEG C; Described time of drying is 1 ~ 48 hour, is preferably 1 ~ 24 hour.
13. 1 kinds of pharmaceutical compositions, its comprise treat and/or prevent significant quantity one or more be selected from the form IV according to any one of crystal formation I, claim 5-7 according to any one of claim 1-3, form IV that crystal formation I, according to claim 8 preparation method that crystal form X II, the according to claim 4 preparation method according to any one of claim 9-11 obtains obtain, or according to the crystal form X II that preparation method described in claim 12 obtains, and the pharmaceutically acceptable carrier of at least one.
The form IV that crystal formation I, according to claim 8 preparation method that the form IV according to any one of crystal formation I, claim 5-7 according to any one of 14. claim 1-3, crystal form X II, according to claim 4 preparation method according to any one of claim 9-11 obtain obtain or the crystal form X II that obtains according to preparation method described in claim 12 treat and/or prevent by the purposes in the medicine of the receptor-mediated disease of S1P1 or illness in preparation.
15. 1 kinds of methods treated and/or prevented by the receptor-mediated disease of S1P1 or illness, described method comprises one or more the crystal formation I be selected from according to any one of claim 1-3 of patient treatment and/or the prevention significant quantity giving needs, form IV according to any one of claim 5-7, crystal form X II according to any one of claim 9-11, the crystal formation I that obtains of preparation method according to claim 4, the form IV that obtains of preparation method or the crystal form X II obtained according to preparation method described in claim 12 or pharmaceutical composition according to claim 13 according to claim 8.
CN201410376027.0A 2014-08-01 2014-08-01 The crystal form of 1- { the fluoro- 4- of 2- [5- (4- isobutyl phenenyl) -1,2,4- oxadiazoles -3- base]-benzyl } -3- azetidinecarboxylic acid Active CN105315266B (en)

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CN108299412A (en) * 2017-01-11 2018-07-20 苏州康乃德生物医药有限公司 The addition salts and its crystal form and pharmaceutical composition of a kind of S1P1 receptor stimulating agents
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