CN103304432A - Polymorphic substances of E-type lumefantrine and preparation methods thereof - Google Patents
Polymorphic substances of E-type lumefantrine and preparation methods thereof Download PDFInfo
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Abstract
The invention relates to polymorphic substances of E-type lumefantrine and preparation methods thereof. Specifically, the invention discloses two polymorphic substances of (9E)-2,7-dichloro-9-[(4-chlorophenyl) methylene)-alpha-[(di-n-butylamino) methyl]-9H-fluorene-4- methanol, namely, a polymorphic substance with a crystal form I and a polymorphic substance with a crystal form II. Furthermore, the invention also discloses preparation methods of the two polymorphic substances and usage of the polymorphic substances in preparation of antimalarial medicaments.
Description
Technical field
The invention belongs to the pharmaceutical chemistry technical field, be specifically related to (9E)-2,7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-polymorphic form of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol and preparation method thereof.
Background technology
Benzfluorenol (also claiming phenyl fluorenol) is that 20 century 70s are developed by China Microbiology and Epidemic Disease Inst., Academy of Military-Medical Sciences (C, is used for the treatment of subtertian malaria.The compound preparation that itself and Artemether are made for treatment heavy malaria, hybrid malaria and subtertian malaria, comprises that the curative effect of disease such as brain malaria is remarkable.
Benzfluorenol chemistry α by name-(two n-butylaminomethyls)-2,7-two chloro-9H-9-(rubigan methylene radical)-4-Lumefantrine, its structural formula is suc as formula shown in (I):
Benzfluorenol has E formula and two kinds of isomer of Z formula, and its Z formula isomer chemical name is (9Z)-2,7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol; E formula isomer chemical name is (9E)-2,7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol.
The document of reporting the earliest at present the benzfluorenol crystal formation be by clock scape magnitude at Acta Pharmaceutica Sinica 1997,32 (11): the crystal of the Lumefantrine of reporting among the 824-829 and molecular structure.The document discloses the single crystal structure of Z formula benzfluorenol, but not to this crystal formation name.The patent WO2006117616 of India Ranbaxy company application in 2005 has reported a kind of new crystal of benzfluorenol, and called after I type crystallization, confirm by experiment that by the inventor this I type crystallization is not new crystal, its crystal formation with aforementioned clock scape magnitude report is consistent.
Being used for the treatment of clinically malaria employed is the Z formula isomer of benzfluorenol.In the prior art, also only reported the preparation method of raceme benzfluorenol and Z formula isomer.The synthetic method of raceme benzfluorenol is mainly CN1042535 and Acta Pharmaceutica Sinica, and 2000,35(1), the disclosed method of 22-25.The preparation method of Z formula isomer, such as Ulrich Beutler etc. at Organic Process Research﹠amp; Development, 2007,11,341-5 have reported that the rising temperature can improve the productive rate of Z formula isomer, have correspondingly just reduced the productive rate of E formula isomer.
Produce benzfluorenol in batches according to existing preparation method, the product fusing point that obtains is on the low side, melting range is longer, and product purity is not high.Aforesaid method also has many defectives, and such as long reaction time, perhaps temperature of reaction raises and causes E formula productive rate to descend.Also cross the highly purified E formula of any preparation isomer without any bibliographical information at present.
Summary of the invention
An object of the present invention is to provide a kind of (9E)-2,7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-polymorphic form of the crystal formation I of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol and preparation method thereof.
Another object of the present invention provides a kind of (9E)-2,7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-polymorphic form of the crystal form II of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol and preparation method thereof.
First aspect present invention provides a kind of (9E)-2,7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-polymorphic form of the crystal formation I of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol.
In another preference, the powder diffraction spectrum of described polymorphic form comprises and is selected from lower group 2 θ values more than 3 or 3: 3.0 ° ± 0.2 °, 6.0 ° ± 0.2 °, 13.2 ° ± 0.2 °, 18.5 ± 0.2 °, 21.9 ± 0.2 °, 22.4 ± 0.2 ° and 23.7 ° ± 0.2 °.
In another preference, the powder diffraction spectrum of described polymorphic form comprises 4,5,6 or 72 θ values that are selected from lower group: 3.0 ° ± 0.2 °, 6.0 ° ± 0.2 °, 13.2 ° ± 0.2 °, 18.5 ± 0.2 °, 21.9 ± 0.2 °, 22.4 ± 0.2 ° and 23.7 ° ± 0.2 °.
In another preference, the powder diffraction spectrum of described polymorphic form comprises and is selected from lower group 2 θ values: 3.0 ° ± 0.1 °, 6.0 ° ± 0.1 °, 13.2 ° ± 0.1 °, 18.5 ± 0.1 °, 21.9 ± 0.1 °, 22.4 ± 0.1 ° and 23.7 ° ± 0.1 °.
In another preference, the dsc of described polymorphic form is analyzed collection of illustrative plates has the feature endotherm(ic)peak at 70 ~ 120 ℃.
In another preference, the infrared absorption spectra of described polymorphic form 1640 ± 2,1426 ± 2,1356 ± 2,1232 ± 2,999 ± 2,839 ± 2,558 ± 2cm
-1There is absorption peak at the place.
In another preference, the powder diffraction spectrum of described polymorphic form substantially as shown in Figure 1.
In another preference, the dsc of described polymorphic form is analyzed collection of illustrative plates as shown in Figure 2.
In another preference, the infrared absorption spectra of described polymorphic form as shown in Figure 3.
It is a kind of such as described (9E)-2 of first aspect present invention that second aspect present invention provides, 7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-preparation method of the polymorphic form of the crystal formation I of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol, it is characterized in that, comprise step:
(1) provides (9E)-2 that are dissolved in the inert solvent, 7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-solution of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol, described (9E)-2,7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-chemical purity of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol 〉=95%;
(2) the described solution with step (1) is cooled to-15 ~ 10 ℃, crystallize out, thereby obtain described (9E)-2 of first aspect present invention, 7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-polymorphic form of the crystal formation I of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol.
In another preference, in the described step (2), mixture is cooled to-10-5 ℃.
In another preference, described step (2) also comprises step: after crystal is filtered, and drying.
In another preference, described inert solvent is organic solvent.
In another preference, described inert solvent is selected from lower group: ketones solvent, esters solvent, aromatic hydrocarbon solvent, ether solvent or its combination;
Wherein, described ketones solvent is selected from lower group: acetone, butanone, pentanone or its combination;
Described esters solvent is selected from lower group: ethyl acetate, methyl acetate, methyl-formiate, isopropyl acetate or its combination;
Described aromatic hydrocarbon solvent is selected from lower group: benzene,toluene,xylene or its combination;
Described ether solvent is selected from lower group: ether, isopropyl ether, methyl tertiary butyl ether, glycol dimethyl ether, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane or its combination.
In another preference, described inert solvent is selected from lower group: acetone, ethyl acetate, isopropyl ether, tetrahydrofuran (THF) or toluene.
In another preference, the weight-volume ratio of benzfluorenol and inert solvent is 1g:3 ~ 300ml; Preferably be 1g:3 ~ 30ml.
Third aspect present invention provides a kind of (9E)-2,7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-polymorphic form of the crystal form II of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol.
In another preference, described polymorphic form is oblique system, and spacer is P-1, and unit cell parameters is
α=76.064 (1) °, β=79.713 (1) °, γ=86.532 (1) °.
In another preference, the powder diffraction spectrum of described polymorphic form comprise be selected from more than 3 or 3 lower group 2 θ values: 5.9 ° ± 0.2 °, 9.8 ° ± 0.2 °, 13.8 ° ± 0.2 °, 16.0 ± 0.2 °, 18.7 ° ± 0.2 °, 20.7 ± 0.2 ° and 23.7 ° ± 0.2 °.
In another preference, the powder diffraction spectrum of described polymorphic form comprises 4,5,6 or 72 θ values that are selected from lower group: 5.9 ° ± 0.2 °, 9.8 ° ± 0.2 °, 13.8 ° ± 0.2 °, 16.0 ± 0.2 °, 18.7 ° ± 0.2 °, 20.7 ± 0.2 ° and 23.7 ° ± 0.2 °.
In another preference, the powder diffraction spectrum of described polymorphic form comprises and is selected from lower group 2 θ values: 5.9 ° ± 0.1 °, 9.8 ° ± 0.1 °, 13.8 ° ± 0.1 °, 16.0 ± 0.1 °, 18.7 ° ± 0.1 °, 20.7 ± 0.1 ° and 23.7 ° ± 0.1 °.
In another preference, the dsc of described polymorphic form is analyzed collection of illustrative plates has the feature endotherm(ic)peak at 80 ~ 110 ℃.
In another preference, the infrared absorption spectra of described polymorphic form 2814 ± 2,1149 ± 2,1094 ± 2,1084 ± 2,1049 ± 2,993 ± 2,896 ± 2,828 ± 2,703 ± 2, there is absorption peak at 519 ± 2cm-1 place.
In another preference, the monocrystalline three-dimensional structure diagram of described polymorphic form as shown in Figure 4.
In another preference, the powder diffraction spectrum of described polymorphic form substantially as shown in Figure 5.
In another preference, the dsc of described polymorphic form is analyzed collection of illustrative plates as shown in Figure 6.
In another preference, the infrared absorption spectra of described polymorphic form as shown in Figure 7.
It is a kind of such as described (9E)-2 of third aspect present invention that fourth aspect present invention provides, 7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-preparation method of the polymorphic form of the crystal form II of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol, comprise step:
(i) provide (9E)-2 that are dissolved in the inert solvent, 7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-solution of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol, described (9E)-2,7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-chemical purity of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol 〉=95%;
(ii) the described solution with step (i) is cooled to 25-28 ℃, partial solvent is volatilized, crystallize out, thereby obtain described (9E)-2 of third aspect present invention, 7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-polymorphic form of the crystal form II of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol.
In another preference, described step (ii) also comprises step: after crystal is filtered, and drying.
In another preference, described inert solvent is organic solvent.
In another preference, described inert solvent is selected from lower group: alcoholic solvent, dimethyl sulfoxide (DMSO), water or its mixture; Wherein, described alcoholic solvent is the alcohol of the straight or branched of C1～C5.
In another preference, described alcoholic solvent is methyl alcohol or ethanol.
Fifth aspect present invention provides a kind of highly purified E formula phenyl fluorenol isomer, described isomer is (9E)-2,7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol, and described isomer is selected from lower group:
(9E)-2,7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-polymorphic form of the crystal formation I of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol; And/or
(9E)-2,7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-polymorphic form of the crystal form II of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol.
Sixth aspect present invention provides a kind of pharmaceutical composition, and described composition comprises:
(a) the described polymorphic form of first aspect present invention or third aspect present invention or the described E formula of fifth aspect present invention phenyl fluorenol isomer;
(b) pharmaceutically acceptable carrier or vehicle.
In another preference, said composition for the preparation of the treatment malaria medicine in purposes.
In should be understood that within the scope of the present invention, above-mentioned each technical characterictic of the present invention and can making up mutually between specifically described each technical characterictic in below (eg embodiment), thus consist of new or preferred technical scheme.As space is limited, this tired stating no longer one by one.
Description of drawings
Fig. 1 has shown the X-ray powder diffraction of the polymorphic form of E formula phenyl fluorenol crystal formation I.
Fig. 2 has shown the DSC collection of illustrative plates of the polymorphic form of E formula phenyl fluorenol crystal formation I.
Fig. 3 has shown the FTIR collection of illustrative plates of the polymorphic form of E formula phenyl fluorenol crystal formation I.
Fig. 4 has shown the X-monocrystalline three-dimensional structure diagram of the polymorphic form of E formula phenyl fluorenol crystal form II.
Fig. 5 has shown the X-ray powder diffraction of the polymorphic form of E formula phenyl fluorenol crystal form II.
Fig. 6 has shown the DSC collection of illustrative plates of the polymorphic form of E formula phenyl fluorenol crystal form II.
Fig. 7 has shown the FTIR collection of illustrative plates of the polymorphic form of E formula phenyl fluorenol crystal form II.
Fig. 8 has shown the monocrystalline three-dimensional structure diagram of Z formula phenyl fluorenol crystal formation.
Fig. 9 has shown the X-ray powder diffraction of Z formula phenyl fluorenol crystal formation.
Fig. 10 has shown the DSC collection of illustrative plates of Z formula phenyl fluorenol crystal formation.
Figure 11 has shown the FTIR collection of illustrative plates of Z formula phenyl fluorenol crystal formation.
Embodiment
The inventor is by long-term and deep research, (9E)-2 have been surprised to find that, 7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-polymorphic form of two kinds of crystal formations of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol, described two kinds of crystal formations are respectively crystal formation I and crystal form II.And provide the preparation method of above-mentioned two kinds of crystal formations, described method is by changing the employed solvent of crystallization and selecting suitable Tc, can obtain respectively highly purified (9E)-2,7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-crystal formation I and the crystal form II of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol.On this basis, the contriver has finished the present invention.
Term
The present invention's used " Z formula isomer of benzfluorenol " or " Z formula phenyl fluorenol " or " Z formula isomer " all refer to (9Z)-2,7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol, can Alternate.
The present invention's used " E formula isomer of benzfluorenol ", " E formula phenyl fluorenol " or " E formula isomer " all refer to (9E)-2,7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol, can Alternate.
The present invention's used " alcohol of the straight or branched of C1～C5 " refers to contain the alcohol of the straight or branched of 1-5 carbon atom, similar compounds such as methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol or isopropylcarbinol.
Term used herein Z formula and cis (cis) are suitable; E formula and trans (trans) are suitable.When using the E/Z mark, at first to determine that each two key atom connects the priority of two groups according to Cahn-Ingold-Prelog sequence rule.If two two more preferential groups of key atom connected are in two key homonymies, then be referred to as " Z formula isomer "; Otherwise then be called " E formula isomer ".
Chemical purity of the present invention all calculates by the HPLC area normalization method.
The preparation method
Now in conjunction with the specific embodiment of the invention described preparation method is described further:
One, (9E)-2,7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-preparation method of the polymorphic form of the crystal formation I of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol, comprise step:
(1) provides (9E)-2 that are dissolved in the inert solvent, 7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-solution of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol, described (9E)-2,7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-chemical purity of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol 〉=95%;
Described solution is to be dissolved in inert solvent by the benzfluorenol that will contain E formula benzfluorenol to make; Weight-the volume ratio that preferably makes benzfluorenol and inert solvent is 1g:3 ~ 300ml; Preferably be 1g:3 ~ 30ml.
Wherein, described inert solvent is selected from lower group: ketones solvent, esters solvent, aromatic hydrocarbon solvent, ether solvent or its mixture;
Described ketones solvent is selected from lower group: acetone, butanone, pentanone or its combination;
Described esters solvent is selected from lower group: ethyl acetate, methyl acetate, methyl-formiate, isopropyl acetate or its combination;
Described aromatic hydrocarbon solvent is selected from lower group: benzene,toluene,xylene or its combination;
Described ether solvent is selected from lower group: ether, isopropyl ether, methyl tertiary butyl ether, glycol dimethyl ether, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane or its combination.
Preferably, described inert solvent is selected from lower group: acetone, ethyl acetate, isopropyl ether, tetrahydrofuran (THF) or toluene.
(2) the described solution with step (1) is cooled to-15 ~ 10 ℃ (preferred-10 ~ 5 ℃), behind the crystallize out, mixture is filtered, with filtration cakes torrefaction, thereby obtain (9E)-2,7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-polymorphic form of the crystal formation I of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol.
Two, (9E)-2,7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-preparation method of the polymorphic form of the crystal form II of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol, comprise step:
(i) provide (9E)-2 that are dissolved in the inert solvent, 7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-solution of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol, described (9E)-2,7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-chemical purity of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol 〉=95%;
Described solution is to be dissolved in inert solvent by the benzfluorenol that will contain E formula benzfluorenol to make; Weight-the volume ratio that preferably makes benzfluorenol and inert solvent is 1g:20 ~ 200ml; Preferably be 1g:50 ~ 100ml.
Described inert solvent is selected from lower group: alcoholic solvent, dimethyl sulfoxide (DMSO), water or its mixture; Wherein, described alcoholic solvent is the alcohol of the straight or branched of C1～C5; Particular methanol or ethanol.
(ii) the described solution with step (i) is cooled to room temperature (such as 25-28 ℃), partial solvent is volatilized naturally, crystallize out, thereby obtain (9E)-2,7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-polymorphic form of the crystal form II of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol.
The evaluation of polymorphic form and character
The present invention is at preparation (9E)-2,7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-polymorphic form of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol after, adopt following various ways and instrument that its character is studied.For example adopt X single crystal diffraction, X-ray powder diffraction, differential scanning calorimetry or infrared spectrophotometry (FTIR) analytical procedure (employing pellet technique).
The method of the X single crystal diffraction of mensuration crystal formation of the present invention is well known in the art.For example, adopt the Smart apex II type single crystal diffractometer of Bruker company.Light source is monochromatic MoK α 1 target X ray.Intensity data is collected by ω-2 θ scanning; Probe temperature: 296K; Modification method: Multi-Scan; R=0.0445 (3333); ω R2=0.1430 (3993); Theta (max)=25.010.
The method of the X-ray powder diffraction of mensuration crystal formation of the present invention is well known in the art.For example, adopt X-ray powder diffraction instrument: Brucker D8 advance X-ray powder diffraction instrument, with the copper target
At ambient temperature scanning, Generator kv:40kv, Generator mA:40mA, 2-Theta Start:2.000 °, sweep limit: 2.0000 ~ 50.000 °, StepSize:0.020 °, StepTime:0.100s.
(9E)-2 of the present invention, 7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-polymorphic form of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol, have specific crystal formation form, in X-ray powder diffraction (XRPD) figure, have specific characteristic peak.
Preferably, (9E)-2 of the present invention, 7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-polymorphic form of the crystal formation I of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol has X-ray powder diffraction figure as shown in Figure 1.
(9E)-2 of the present invention, 7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-polymorphic form of the crystal form II of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol has X-ray powder diffraction figure as shown in Figure 5.
DSC measuring method of the present invention is well known in the art.For example can use dsc (DSC) instrument: the Q2000 type DSC of TA company, in room temperature to 160 ℃ scope, 10 ℃/min of heating rate analyzes sample under the nitrogen flow rate 50ml/min condition.
(9E)-2 of the present invention, 7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-polymorphic form of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol, in differential scanning calorimetry (DSC) figure, have specific characteristic peak.
Preferably, (9E)-2 of the present invention, 7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-polymorphic form of the crystal formation I of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol has differential scanning calorimetric thermogram as shown in Figure 2.
(9E)-2 of the present invention, 7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-polymorphic form of the crystal form II of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol has differential scanning calorimetric thermogram as shown in Figure 6.
Pharmaceutical composition
As used herein, term " the compounds of this invention " refers to the polymorphic form of E formula phenyl fluorenol, comprises crystal formation I and crystal form II.
Because it is active that the compounds of this invention has excellent anti-malarial, therefore the compounds of this invention and to contain the compounds of this invention be that the pharmaceutical composition of main active ingredient can be used for treating malaria especially has an excellent inhibition to the red blood cell phase growth of malaria parasites active.
The compounds of this invention that pharmaceutical composition of the present invention comprises in the safe and effective weight range reaches pharmaceutically acceptable vehicle or carrier.
Wherein, " safe and effective amount " refers to: the amount of compound is enough to obviously improve the state of an illness, and is unlikely to produce severe side effect.Usually, pharmaceutical composition contains 1-2000mg the compounds of this invention/agent, more preferably, contains 10-200mg the compounds of this invention/agent.Preferably, described " potion " is a capsule or tablet.
" pharmaceutically acceptable carrier " refers to: one or more consistency solids or liquid filler or gelatinous mass, they are fit to the people uses, and sufficiently high purity and enough low toxicity must be arranged." consistency " referred to herein as each component energy and compound of the present invention and mutually blending between them in the composition, and the drug effect of not obvious reduction compound.Pharmaceutically acceptable carrier part example has Mierocrystalline cellulose and derivative (such as Xylo-Mucine, ethyl cellulose sodium, cellulose ethanoate etc.) thereof, gelatin, talcum, solid lubricant (such as stearic acid, Magnesium Stearate), calcium sulfate, vegetables oil (such as soya-bean oil, sesame oil, peanut oil, olive wet goods), polyvalent alcohol (such as propylene glycol, glycerine, N.F,USP MANNITOL, sorbyl alcohol etc.), emulsifying agent (such as tween
Wetting agent (such as sodium lauryl sulphate), tinting material, seasonings, stablizer, antioxidant, sanitas, apirogen water etc.
Application process
The method of application of the compounds of this invention or pharmaceutical composition is not particularly limited, and representational method of application comprises (but being not limited to): oral, snuffing enters, rectum and parenteral (intravenously, intramuscular or subcutaneous).
The solid dosage that is used for oral administration comprises capsule, tablet, pill, powder and granule.In these solid dosages, active compound mixes with at least a conventional inert excipient (or carrier), such as Trisodium Citrate or Si Liaodengji dicalcium phosphate feed grade, or mixes with following compositions: (a) filler or expanding material, for example, starch, lactose, sucrose, glucose, N.F,USP MANNITOL and silicic acid; (b) tackiness agent, for example, Walocel MT 20.000PV, alginate, gelatin, Polyvinylpyrolidone (PVP), sucrose and gum arabic; (c) wetting Agent for Printing Inks, for example, glycerine; (d) disintegrating agent, for example, agar, calcium carbonate, yam starch or tapioca (flour), alginic acid, some composition silicate and yellow soda ash; (e) retarding solvent, for example paraffin; (f) absorb accelerator, for example, quaternary ammonium compound; (g) wetting agent, for example hexadecanol and glyceryl monostearate; (h) sorbent material, for example, kaolin; (i) lubricant, for example, talcum, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium lauryl sulphate, or its mixture.In capsule, tablet and the pill, formulation also can comprise buffer reagent.
Solid dosage such as tablet, sugar-pill, capsule, pill and granule can adopt dressing and the preparation of shell material, such as casing and other material well known in the art.They can comprise opacifying agent, and, discharge in the mode that the release of active compound or compound can postpone in this composition certain part in digestive tube.The example of adoptable embedding component is polymeric material and Wax.In case of necessity, active compound also can with above-mentioned vehicle in one or more form microencapsulation form.
The liquid dosage form that is used for oral administration comprises pharmaceutically acceptable emulsion, solution, suspension, syrup or tincture.Except the active ingredient beyond the region of objective existence, liquid dosage form can comprise the conventional inert diluent that adopts in this area, such as water or other solvent, solubilizing agent and emulsifying agent, example is known, the mixture of ethanol, Virahol, ethyl-carbonate, ethyl acetate, propylene glycol, 1,3 butylene glycol, dimethyl formamide and oil, particularly Oleum Gossypii semen, peanut oil, maize germ, sweet oil, Viscotrol C and sesame oil or these materials etc.
Except these inert diluents, composition also can comprise auxiliary agent, such as wetting agent, emulsifying agent and suspension agent, sweeting agent, correctives and spices.
Except the active ingredient beyond the region of objective existence, suspension can comprise suspension agent, for example, and the mixture of ethoxylation isooctadecane alcohol, polyoxyethylene sorbitol and Isosorbide Dinitrate, Microcrystalline Cellulose, aluminum methylate and agar or these materials etc.
The composition that is used for parenteral injection can comprise physiologically acceptable aseptic moisture or anhydrous solution, dispersion liquid, suspension or emulsion, and is used for again being dissolved into aseptic Injectable solution or the sterilized powder of dispersion liquid.Suitable moisture and nonaqueous carrier, thinner, solvent or vehicle comprise water, ethanol, polyvalent alcohol and suitable mixture thereof.
The compounds of this invention can be individually dosed, perhaps with other pharmaceutically acceptable compound (such as Artemether) Combined Preparation.
When making pharmaceutical composition, it is the Mammals (such as the people) that the compounds of this invention of safe and effective amount need to be applicable to treatment, the effective dosage of dosage for pharmaceutically thinking when wherein using, for the people of 60kg body weight, day dosage is generally 1～2000mg, preferred 20～500mg.Certainly, concrete dosage also should be considered the factors such as route of administration, patient health situation, and these all are within the skilled practitioners skill.
Major advantage of the present invention is:
1. the invention provides a kind of new (9E)-2,7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-polymorphic form of the crystal formation I of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol.
2. the present invention also provides a kind of new (9E)-2,7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-polymorphic form of the crystal form II of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol.
3. the present invention also provides the preparation method of described two kinds of polymorphic forms, and described method condition is easy, percent crystallization in massecuite is high.
4. a kind of pharmaceutical composition also is provided, and described composition comprises the polymorphic form of crystal formation I and/or the polymorphic form of crystal form II.
Below in conjunction with implementation, further set forth the present invention.Should be understood that these embodiment only to be used for explanation the present invention and be not used in and limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, usually according to normal condition, the condition of for example advising according to manufacturer.Unless otherwise indicated, otherwise per-cent and umber calculate by weight.
Under nitrogen protection; in reaction flask, add NaOH(7.0g; 0.18mol), dehydrated alcohol 200ml, toluene 40ml, stir molten clearly in 25 ℃, add α-(two n-butylaminomethyls)-2; 7-two chloro-4-Lumefantrine (20.0g; 0.049mol), add 4-chloro-benzaldehyde (8.0g, 0.057mol) g; keep reaction in nitrogen atmosphere, stirred 3 hours in 25 ℃.After the TLC detection reaction was complete, the ethanolic soln that adds with 1N hydrochloric acid transferred to reaction solution pH7.Reaction mixture is evaporated to dried.Enriched material is heated to 65 ℃ of stirring and dissolving with 200ml toluene, and the washing organic phase is isolated organic phase to aqueous pH values 6.5, is concentrated into dried.Enriched material is analyzed through HPLC and obtained the raceme benzfluorenol: E formula isomer and Z formula benzfluorenol content ratio are about 1.2:1.
Refining for the first time: that raceme benzfluorenol crude product is heated to 60 ℃ of dissolvings with ethyl acetate 200ml, then slow cooling (cooling rate is per hour 15 ℃), be down to 28 ℃ of interior temperature, there is yellow solid to separate out, suction filtration, oven dry, the purity that HPLC detects the E formula isomer in this yellow solid is 2.4%.
Refining for the second time: as filtrate decompression to be concentrated into dried, add the 100ml ethyl acetate, add thermosol clear, slow cooling in oil bath (per hour 15 ℃ of cooling rates), be down to 12 ℃ of interior temperature, have yellow solid to separate out, suction filtration, oven dry, the purity that HPLC detects the E formula isomer in this yellow solid is 2.6%.
Refining for the third time: filtrate is concentrated into dried, by for the second time again crystallization of process for purification, obtains a small amount of yellow solid, the E formula isomer purity that HPLC detects in this yellow solid is 9.5%
The 4th time refining: filtrate is concentrated into dried, by for the second time again crystallization of process for purification, obtains a small amount of yellow solid of 0.5 gram, the E formula isomer purity that HPLC detects in this yellow solid is 92.1%.
The 5th time refining: filtrate is concentrated into dried, by for the second time again crystallization of process for purification, obtains 6.5 gram yellow solids, the E formula isomer purity that HPLC detects in this yellow solid is 95.6%.
With 5.0g (9E)-2,7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol, 20ml ethyl acetate joins in the reaction flask, under nitrogen atmosphere, stirs molten clear under the room temperature.Be cooled to 0 ℃ of crystallization.Filter, filter cake gets the 3.2g needle-like crystal in 50 ℃ of lower drying under reduced pressure to doing.
Embodiment 3 preparation (9E)-2,7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-the crystal formation I of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol
With 2.0g (9E)-2,7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol, 10ml toluene joins in the reaction flask, under nitrogen atmosphere, is heated to 50 ℃, stirs molten clear.Be cooled to 5 ℃ of crystallizatioies.Filter, filter cake gets the 1.0g needle-like crystal in 50 ℃ of lower drying under reduced pressure to doing.
C: with 2.0g (9E)-2,7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol, 10ml acetone joins in the reaction flask, under nitrogen atmosphere, stirs molten clear under the room temperature.Be cooled to-10 ℃ of crystallizatioies.Filter, filter cake gets the 1.3g needle-like crystal in 50 ℃ of lower drying under reduced pressure to doing.
Embodiment 5 preparation (9E)-2,7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-the crystal formation I of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol
With 2.0g (9E)-2,7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol, 15ml isopropyl ether joins in the reaction flask, under nitrogen atmosphere, is heated to 40 ℃, stirs molten clear.Be cooled to 0 ℃ of crystallization.Filter, filter cake gets the 1.3g needle-like crystal in 50 ℃ of lower drying under reduced pressure to doing.
(9E)-2 for embodiment 2-5 preparation, 7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-crystal of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol, confirm that through X-ray powder diffraction and dsc analysis the gained crystal is I type polymorphic form.Its x-ray diffractogram of powder as shown in Figure 1, the differential scanning spectrogram as shown in Figure 2, infared spectrum is as shown in Figure 3.
Embodiment 6 preparation (9E)-2,7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-crystal form II of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol
Under the room temperature with 1.0g (9E)-2,7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol joins in the 100ml dehydrated alcohol, stir molten clear, slowly be filled in the clean beaker, place under the room temperature (25-28 ℃) partial solvent is slowly volatilized, obtain the 0.5g bulk crystals.
Embodiment 7 preparation (9E)-2,7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-crystal form II of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol
Under the room temperature with 1.0g (9E)-2,7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol joins in the 50ml anhydrous methanol, be heated to 35 ℃, stir molten clear, slowly be filled in the clean beaker, place under the room temperature (25-28 ℃) partial solvent is slowly volatilized, obtain the 0.6g bulk crystals.
(9E)-2 for embodiment 6-7 preparation, 7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-crystal of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol, confirm that through X-ray single crystal diffraction, X-ray powder diffraction and dsc analysis the gained crystal is II type polymorphic form.Its X-ray monocrystalline three-dimensional structure diagram as shown in Figure 4, x-ray diffractogram of powder as shown in Figure 5, the differential scanning spectrogram as shown in Figure 6, infared spectrum is as shown in Figure 7.
Comparative Examples 1 Z formula phenyl fluorenol crystal formation
Z formula phenyl fluorenol crystal can be with reference to Organic Process Research﹠amp; Development, the method for 2007,11,341-5 report is prepared.
This Z formula phenyl fluorenol is carried out through X-ray single crystal diffraction, X-ray powder diffraction, dsc and infrared analysis, its X-ray monocrystalline three-dimensional structure diagram as shown in Figure 8, x-ray diffractogram of powder as shown in Figure 9, the differential scanning spectrogram as shown in figure 10, infared spectrum is as shown in figure 11.
The antimalarial active test of embodiment 8 E formula phenyl fluorenol crystal formation I
Experiment material:
1.E formula phenyl fluorenol crystal formation I: embodiment 2 preparations;
Z formula phenyl fluorenol (contrast): by Comparative Examples 1 described method preparation, powder, 4 degree are preserved.
2. experiment mice: the BALB/c strain, male, 8-10 age in week is available from Beijing dimension tonneau China, SPF rank.Raising is at Party B's Experimental Animal Center (cleaning level Animal Lab.).
3. plasmodium: Xia Shi plasmodium (Plasmodium chabaudi), liquid nitrogen is preserved.
4. solvent: 7%Tween80/3% ethanol, 4 ℃ of preservations.
5. experiment consumptive material: the gavage pin, syringe, scalpel carries thin slice, Giemsa stain, methyl alcohol, staining jar, blower, microscope.
Experimental design:
Prepare the E formula phenyl fluorenol crystal formation I:2mg of four dosage, 0.6mg, 0.2mg, 0.06mg; Mouse Weight is pressed 20g and is calculated, and is equivalent to: 100mg/Kg Mouse Weight, 30mg/Kg Mouse Weight, 10mg/Kg Mouse Weight, 3mg/Kg Mouse Weight (with reference to experimental standard program in the antimalarial drug body).
Infected front 14 days, the mouse of purchase enters Animal House and observes, and the observation period is 7 days.
Infected front 7 days, recovery Xia Shi plasmodium comprises step: be used for experiment after (1) mouse observation period finishes; (2) from liquid nitrogen container, take out the not to be resuscitated Xia Shi plasmodium of three pipes, infect respectively three mouse in the mode of abdominal injection; (3) plasmodium that recovery obtains in these three mouse will be for the infection experiment treated animal.
Infect the same day (0 day) and infect rear administration in the 1st, 2,3 days, the medicine dissolution with solvents throws something and feeds to guarantee the medication consistence with stomach tube.
Infected afterbody blood sampling preparation blood smear, chromoscopy Tubifex level (the Tubifex level represents with the pRBC number with having infected plasmodial red corpuscle in each hundred red corpuscle) rear the 4th, 14,21 days.
Concrete experimental procedure:
Infected the 0th day, and to three mouse heart blood samplings, after the merging, did blood smear and detect the Tubifex level, counting plasmodium concentration; Adjust plasmodium concentration to 4 * 10
7PRBC/ml, altogether 50ml.
With the mode infecting mouse of abdominal injection, 0.5ml/ mouse, totally 14 groups of mouse, 6/group.
Behind the infecting mouse 2 hours, according to experimental design:
12 groups of mouse administrations are with the mode administration 0.2ml/ mouse of gavage.
1 group of mouse gives solvent (solvent control), gives solvent 0.2ml/ mouse in the mode of gavage;
Remain 1 group of not administration, as blank.
Infected the 1st day, for the second time to 12 groups of mouse administrations, the solvent control mouse gives solvent; Administering mode is with for the first time.
Infected the 2nd day, to 12 groups of mouse administrations, the solvent control mouse gives solvent for the third time; Administering mode is with for the first time.
Infected the 3rd day, the 4th time the solvent control mouse gives solvent to 12 groups of mouse administrations; Administering mode is with for the first time.
Infected the 4th day, 14 groups of mouse that infect are cooked blood smear, dyeing, microscopy are observed the Tubifex level, the results are shown in Table 2; And the statistics phenyl fluorenol is to the survival rate of Xia Shi growth of malaria parasites inhibiting rate and mouse, the results are shown in Table 1 and table 3.
After stopping administration, after infection the 7th day, 10 days, 14 days, 17 days, 19 days, 21 days, 23 days and 26 days, 14 groups of mouse that infect are cooked blood smear, dyeing, microscopy are observed the Tubifex level.
Infected the 27th day, mouse Tubifex level is 0, puts to death mouse.
Table 1 E formula phenyl fluorenol crystal formation I is to the inhibiting rate of Xia Shi growth of malaria parasites
Table 2 E formula phenyl fluorenol crystal formation I is on the impact (infecting the 4th day Tubifex level) of Xia Shi growth of malaria parasites
The survival rate of mouse behind table 3 Infected With Plasmodium
The antimalarial active test of embodiment 9 E formula phenyl fluorenol crystal form IIs
Method is with embodiment 8, and difference is to replace E formula phenyl fluorenol crystal formation I with E formula phenyl fluorenol crystal form II.
The result shows: the anti-cruel activity of crystal form II and crystal formation I is basic identical.
The toxicity test of embodiment 10 E formula phenyl fluorenol crystal formation I and crystal form II
During this period, get the mouse (6 every group) that does not infect among two groups of embodiment 8, detect two batches of E formula phenyl fluorenols and (be respectively the E formula phenyl fluorenol crystal formation I of embodiment 2 preparations; The E formula phenyl fluorenol crystal form II of embodiment 6 preparations) to the potential toxic action of mouse possibility: two groups of the mouse that does not infect, every group 6, difference gastric infusion E formula phenyl fluorenol crystal formation I and E formula phenyl fluorenol crystal form II, dosage is maximum dose level (100mg/kg body weight), and successive administration is four times altogether.Observation subsequently (survival rate, observe animal behavior variation etc.) does not find that E formula phenyl fluorenol crystal formation I and crystal form II have undesirable action to normal mouse.
Comparative Examples 2
The sixties in last century, Karen.J.ott conducts in-depth research (seeing Experimetnal parasitology.1969,24:194-204) to common CF1 Strains of Mouse for the rejection of the plasmodial tolerance of Xia Shi and several frequently seen medicine.Use common CF
1Strains of Mouse is as test mice, and 20g is heavy, and male and female are mixed.In the situation that do not have medication, when dosage of inoculation is 1 * 10
7The red corpuscle of Xia Shi Infected With Plasmodium, abdominal injection, the average Tubifex level in the time of the 4th day is (14.4 ± 5.5) %; When dosage of inoculation is 1 * 10
6The red corpuscle of Xia Shi Infected With Plasmodium, abdominal injection, the average Tubifex level in the time of the 4th day is (0.8 ± 0.2) %.
Required dosage and common CF when table 4 reaches 90% inhibiting rate for several frequently seen medicine
1(dosage of inoculation is 1 * 10 to the per-cent that the Strains of Mouse survival rate increases
6The red corpuscle of Xia Shi Infected With Plasmodium, dose unit are mg/kg Mouse Weight/sky).
Table 4
Such as the result of embodiment 8-10 and Comparative Examples 2 as can be known: the polymorphic form of E formula phenyl fluorenol (crystal formation I or crystal form II) has very high anti-cruel activity, even under low-down dosage, plasmodium to higher infective dose also can be realized 100% inhibition, and subject (intact animal or through the animal of Infected With Plasmodium) is had no side effect, therefore, be a kind of good anti-malaria medicaments, further enriched the selectivity of anti-malaria medicaments.
Embodiment 11 pharmaceutical preparations
E formula phenyl fluorenol, Microcrystalline Cellulose, croscarmellose sodium are crossed 60 mesh sieve pre-treatment, accurately mix after the weighing by recipe quantity (seeing Table 5), take the 2wt%HPMC aqueous solution as the tackiness agent wet granulation, 50 ℃ of dryings, whole grain, add Magnesium Stearate and mix rear compressing tablet, carry out at last film coating.After quality test is qualified, can use.
Table 5
Embodiment 12 pharmaceutical preparations
E formula phenyl fluorenol, lactose, pregelatinized Starch, calcium carboxymethylcellulose, Magnesium Stearate are crossed 60 mesh sieve pre-treatment, accurately mix after the weighing by recipe quantity (seeing Table 6), carry out capsule charge.After quality test is qualified, can use.
Table 6
All quote in this application as a reference at all documents that the present invention mentions, just as each piece document is quoted separately as a reference.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims limited range equally.
Claims (24)
1. (9E)-2,7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-polymorphic form of the crystal formation I of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol.
2. polymorphic form as claimed in claim 1, it is characterized in that, the powder diffraction spectrum of described polymorphic form comprises and is selected from lower group 2 θ values more than 3 or 3: 3.0 ° ± 0.2 °, 6.0 ° ± 0.2 °, 13.2 ° ± 0.2 °, 18.5 ± 0.2 °, 21.9 ± 0.2 °, 22.4 ± 0.2 ° and 23.7 ° ± 0.2 °.
3. polymorphic form as claimed in claim 1 is characterized in that, the dsc of described polymorphic form is analyzed collection of illustrative plates has the feature endotherm(ic)peak at 70 ~ 120 ℃.
4. polymorphic form as claimed in claim 2 is characterized in that, the infrared absorption spectra of described polymorphic form 1640 ± 2,1426 ± 2,1356 ± 2,1232 ± 2,999 ± 2,839 ± 2,558 ± 2cm
-1There is absorption peak at the place.
5. polymorphic form as claimed in claim 2 is characterized in that, the powder diffraction spectrum of described polymorphic form substantially as shown in Figure 1.
6. polymorphic form as claimed in claim 3 is characterized in that, the dsc of described polymorphic form is analyzed collection of illustrative plates as shown in Figure 2.
7. polymorphic form as claimed in claim 4 is characterized in that, the infrared absorption spectra of described polymorphic form as shown in Figure 3.
8. such as each described (9E)-2 of claim 1 ~ 7,7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-preparation method of the polymorphic form of the crystal formation I of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol, it is characterized in that, comprise step:
(1) provides (9E)-2 that are dissolved in the inert solvent, 7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-solution of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol, described (9E)-2,7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-chemical purity of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol 〉=95%;
(2) the described solution with step (1) is cooled to-15 ~ 10 ℃, crystallize out, thereby obtain each described (9E)-2 of claim 1 ~ 7,7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-polymorphic form of the crystal formation I of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol.
9. method as claimed in claim 8 is characterized in that, described inert solvent is selected from lower group: ketones solvent, esters solvent, aromatic hydrocarbon solvent, ether solvent or its combination;
Wherein, described ketones solvent is selected from lower group: acetone, butanone, pentanone or its combination;
Described esters solvent is selected from lower group: ethyl acetate, methyl acetate, methyl-formiate, isopropyl acetate or its combination;
Described aromatic hydrocarbon solvent is selected from lower group: benzene,toluene,xylene or its combination;
Described ether solvent is selected from lower group: ether, isopropyl ether, methyl tertiary butyl ether, glycol dimethyl ether, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane or its combination.
10. method as claimed in claim 8 is characterized in that, the weight-volume ratio of benzfluorenol and inert solvent is 1g:3 ~ 300ml; Preferably be 1g:3 ~ 30ml.
11. (9E)-2,7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-polymorphic form of the crystal form II of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol.
12. polymorphic form as claimed in claim 11 is characterized in that, described polymorphic form is oblique system, and spacer is P-1, and unit cell parameters is
α=76.064 (1) °, β=79.713 (1) °, γ=86.532 (1) °.
13. polymorphic form as claimed in claim 11, it is characterized in that, the powder diffraction spectrum of described polymorphic form comprise be selected from more than 3 or 3 lower group 2 θ values: 5.9 ° ± 0.2 °, 9.8 ° ± 0.2 °, 13.8 ° ± 0.2 °, 16.0 ± 0.2 °, 18.7 ° ± 0.2 °, 20.7 ± 0.2 ° and 23.7 ° ± 0.2 °.
14. polymorphic form as claimed in claim 11 is characterized in that, the dsc of described polymorphic form is analyzed collection of illustrative plates has the feature endotherm(ic)peak at 80 ~ 110 ℃.
15. polymorphic form as claimed in claim 12, it is characterized in that, the infrared absorption spectra of described polymorphic form 2814 ± 2,1149 ± 2,1094 ± 2,1084 ± 2,1049 ± 2,993 ± 2,896 ± 2,828 ± 2,703 ± 2, there is absorption peak at 519 ± 2cm-1 place.
16. polymorphic form as claimed in claim 12 is characterized in that, the monocrystalline three-dimensional structure diagram of described polymorphic form as shown in Figure 4.
17. polymorphic form as claimed in claim 13 is characterized in that, the powder diffraction spectrum of described polymorphic form substantially as shown in Figure 5.
18. polymorphic form as claimed in claim 14 is characterized in that, the dsc of described polymorphic form is analyzed collection of illustrative plates as shown in Figure 6.
19. polymorphic form as claimed in claim 15 is characterized in that, the infrared absorption spectra of described polymorphic form as shown in Figure 7.
20. such as each described (9E)-2 of claim 11 ~ 19,7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-preparation method of the polymorphic form of the crystal form II of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol, it is characterized in that, comprise step:
(i) provide (9E)-2 that are dissolved in the inert solvent, 7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-solution of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol, described (9E)-2,7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-chemical purity of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol 〉=95%;
(ii) the described solution with step (i) is cooled to 25-28 ℃, partial solvent is volatilized, crystallize out, thereby obtain each described (9E)-2 of claim 11 ~ 19,7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-polymorphic form of the crystal form II of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol.
21. method as claimed in claim 20 is characterized in that, described inert solvent is selected from lower group: alcoholic solvent, dimethyl sulfoxide (DMSO), water or its mixture; Wherein, described alcoholic solvent is the alcohol of the straight or branched of C1～C5.
22. highly purified E formula phenyl fluorenol isomer, it is characterized in that, described isomer is (9E)-2,7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol, and described isomer is selected from lower group:
(9E)-2,7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-polymorphic form of the crystal formation I of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol; And/or
(9E)-2,7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-polymorphic form of the crystal form II of α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol.
23. a pharmaceutical composition is characterized in that, described composition comprises:
(a) claim 1～7 or 11～19 each described polymorphic forms or the described E formula of claim 22 phenyl fluorenol isomer;
(b) pharmaceutically acceptable carrier or vehicle.
24. the purposes of composition as claimed in claim 23 is characterized in that, said composition for the preparation of the treatment malaria medicine in purposes.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104910026A (en) * | 2014-03-13 | 2015-09-16 | 昆明制药集团股份有限公司 | Alpha-(di-n-butylamine methyl)-2,7-dichloro-9-p-chlorobenzylidene-4-fluorenemethanol crystal form and preparation method thereof |
| CN114436866A (en) * | 2022-01-19 | 2022-05-06 | 舞阳威森生物医药有限公司 | Refining process of benflumetol crude product |
-
2012
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104910026A (en) * | 2014-03-13 | 2015-09-16 | 昆明制药集团股份有限公司 | Alpha-(di-n-butylamine methyl)-2,7-dichloro-9-p-chlorobenzylidene-4-fluorenemethanol crystal form and preparation method thereof |
| CN114436866A (en) * | 2022-01-19 | 2022-05-06 | 舞阳威森生物医药有限公司 | Refining process of benflumetol crude product |
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Application publication date: 20130918 |