CN104910026A - Alpha-(di-n-butylamine methyl)-2,7-dichloro-9-p-chlorobenzylidene-4-fluorenemethanol crystal form and preparation method thereof - Google Patents
Alpha-(di-n-butylamine methyl)-2,7-dichloro-9-p-chlorobenzylidene-4-fluorenemethanol crystal form and preparation method thereof Download PDFInfo
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Abstract
The invention discloses an alpha-(di-n-butylamine methyl)-2,7-dichloro-9-p-chlorobenzylidene-4-fluorenemethanol crystal form and its preparation method. A powder x-ray diffraction pattern of the alpha-(di-n-butylamine methyl)-2,7-dichloro-9-p-chlorobenzylidene-4-fluorenemethanol crystal form displays characteristic diffraction peaks at 2theta+/-0.1 degree reflection-angle of 39.4, 33.2, 29.3, 24.2, 23.9, 23.5, 22.3, 21.5, 20.8, 18.4, 16.0, 15.1, 14.8, 14.2, 13.1, 10.9, 9.1, 6.1 and 3.1. The preparation method comprises the following steps: adding an organic solvent which is 25-30 times larger by volume than a benflumetol crude product into the benflumetol crude product, stirring at the temperature of 60-70 DEG C until the benflumetol crude product is completely dissolved, carrying out reflux for 15-30 min, carrying out suction filtration, and crystallizing a filtrate to obtain the target object. Through a new solvent system and a new recrystallization method, a new crystal form of benflumetol is obtained, and impurities generated by a common method can be removed. Content, yield and quality of the product are all greatly enhanced, and production cost is low. The preparation method is suitable for industrial production.
Description
Technical field
The invention belongs to medical art, be specifically related to the chloro-9-of a kind of α-(Di-n-Butyl Amine methyl)-2,7-bis-to chlorobenzene methylene radical-4-Lumefantrine crystal formation and preparation method thereof.
Background technology
Benzfluorenol (Lumefantrine; Benflumetolum) be a kind new medicine of China's initiative, have gonosome and phorozoon to have obvious killing action to vivax malaria have vivax malaria and good prevent effect.Also have killing action to subtertian malaria phorozoon, but onset is slow.Gametophyte rate in blood can be reduced, suppress gametophyte to be grown in mosquito body.At anti-Chloroquine-resistant Falciparum Malaria Endemic Area probationary certificate, the curative ratio of the subtertian malaria of antagonism chloroquine or multi-medicine resistance is more than 95%.With Artemether compatibility, the two Antimalarial can be complementary, and benzfluorenol desinsection is thorough, persistent, but it is slow to control symptom.And Artemether is quick-acting, but recrudescence rate is high.Experimentation on animals proves, this product toxicity is very little, clinically has no untoward reaction.
Benzfluorenol is yellow crystalline powder, has Semen Armeniacae Amarum smelly, tasteless.This product is easily held in chloroform, slightly molten in acetone, almost insoluble in ethanol or water.Benzfluorenol CAS:82186-77-4, molecular formula: C
30h
32cl
3nO, molecular weight: 528.94018, fusing point 125-131 DEG C (Chinese Pharmacopoeia version in 2010 two annex VI C, annex 40), standard No.: WS-197 (X-165)-94.This material can by shown in formula I:
Ⅰ
At present, recrystallization many employings ethanol of benzfluorenol, dehydrated alcohol or ethyl acetate are carried out, the crystal formation of gained fine work is basically identical, ethanol, dehydrated alcohol recrystallization can obtain qualified product, but there will be 2 impurity, and yield is substantially at 76-89%, solvent load is larger, be generally 60-80 times amount, recovery is all cumbersome, causes high expensive.Feasible during re-crystallizing in ethyl acetate lab scale, yield at 80-85%, but has precipitation comparatively fast and the shortcoming such as not easily to drain during pilot scale, the product after this can cause recrystallization can produce the situation of content heterogeneity peritectoid, is difficult to realize industrialization and produces.Therefore, exploitation one can solve the problems of the technologies described above, and can remove crystal formation of the impurity produced in common method and preparation method thereof and be very important.
Summary of the invention
The first object of the present invention is to provide the chloro-9-of a kind of α-(Di-n-Butyl Amine methyl)-2,7-bis-to chlorobenzene methylene radical-4-Lumefantrine crystal formation; Second object is to provide the chloro-9-of described α-(Di-n-Butyl Amine methyl)-2,7-bis-to the preparation method of chlorobenzene methylene radical-4-Lumefantrine crystal formation.
The first object of the present invention is achieved in that the chloro-9-of described α-(Di-n-Butyl Amine methyl)-2,7-bis-to the powder x-ray diffraction collection of illustrative plates of the crystal formation of chlorobenzene methylene radical-4-Lumefantrine 39.4,33.2,29.3,24.2,23.9,23.5,22.3,21.5,20.8,18.4,16.0,15.1,14.8,14.2,13.1,10.9,2 θ ± 0.1 ° reflection angle place indicating characteristic the diffraction peak of 9.1,6.1,3.1.
The second object of the present invention is achieved in that and will adds in the organic solvent of weightmeasurement ratio 25 ~ 30 times in benzfluorenol crude product, is stirred to and dissolves completely at temperature 60 ~ 70 DEG C, and carry out suction filtration after backflow 15 ~ 30min, filtrate is carried out crystallization and obtained target compound.
The present invention obtains a kind of new crystal of benzfluorenol by new solvent systems and new means re-crystallization, and the impurity produced in common method can be removed, the content of product, yield and quality are all improved a lot, and production cost is low, is applicable to suitability for industrialized production.
Accompanying drawing explanation
Fig. 1 is the feature X-powder diffractogram of embodiment 1, and ordinate zou represents relative diffracted intensity (%), and X-coordinate represents angle of diffraction (2 θ);
Fig. 2 is the feature X-powder diffractogram of embodiment 2, and ordinate zou represents relative diffracted intensity (%), and X-coordinate represents angle of diffraction (2 θ);
Fig. 3 is the feature X-powder diffractogram of embodiment 3, and ordinate zou represents relative diffracted intensity (%), and X-coordinate represents angle of diffraction (2 θ);
Fig. 4 is the feature X-powder diffractogram of embodiment 4, and ordinate zou represents relative diffracted intensity (%), and X-coordinate represents angle of diffraction (2 θ);
Fig. 5 is the feature X-powder diffractogram of embodiment 5, and ordinate zou represents relative diffracted intensity (%), and X-coordinate represents angle of diffraction (2 θ);
Fig. 6 is the feature X-powder diffractogram of embodiment 6, and ordinate zou represents relative diffracted intensity (%), and X-coordinate represents angle of diffraction (2 θ);
Fig. 7 is the feature X-powder diffractogram of embodiment 7, and ordinate zou represents relative diffracted intensity (%), and X-coordinate represents angle of diffraction (2 θ);
Fig. 8 is the feature X-powder diffractogram of embodiment 8, and ordinate zou represents relative diffracted intensity (%), and X-coordinate represents angle of diffraction (2 θ);
Fig. 9 is the feature X-powder diffractogram of embodiment 9, and ordinate zou represents relative diffracted intensity (%), and X-coordinate represents angle of diffraction (2 θ);
Figure 10 is the feature X-powder diffractogram of embodiment 10, and ordinate zou represents relative diffracted intensity (%), and X-coordinate represents angle of diffraction (2 θ);
Figure 11 is the feature X-powder diffractogram of embodiment 11, and ordinate zou represents relative diffracted intensity (%), and X-coordinate represents angle of diffraction (2 θ);
Figure 12 is the feature X-powder diffractogram of embodiment 12, and ordinate zou represents relative diffracted intensity (%), and X-coordinate represents angle of diffraction (2 θ);
Figure 13 is the feature X-powder diffractogram of embodiment 13, and ordinate zou represents relative diffracted intensity (%), and X-coordinate represents angle of diffraction (2 θ);
Figure 14 is the feature X-powder diffractogram of embodiment 14, and ordinate zou represents relative diffracted intensity (%), and X-coordinate represents angle of diffraction (2 θ);
Figure 15 is the feature X-powder diffractogram of embodiment 15, and ordinate zou represents relative diffracted intensity (%), and X-coordinate represents angle of diffraction (2 θ);
Figure 16 is the feature X-powder diffractogram of embodiment 16, and ordinate zou represents relative diffracted intensity (%), and X-coordinate represents angle of diffraction (2 θ);
Figure 17 is the feature X-powder diffractogram of embodiment 17, and ordinate zou represents relative diffracted intensity (%), and X-coordinate represents angle of diffraction (2 θ);
Figure 18 is the feature X-powder diffractogram of embodiment 18, and ordinate zou represents relative diffracted intensity (%), and X-coordinate represents angle of diffraction (2 θ);
Figure 19 is the feature X-powder diffractogram of embodiment 19, and ordinate zou represents relative diffracted intensity (%), and X-coordinate represents angle of diffraction (2 θ);
Figure 20 is the feature X-powder diffractogram of embodiment 20, and ordinate zou represents relative diffracted intensity (%), and X-coordinate represents angle of diffraction (2 θ);
Figure 21 is the feature X-powder diffractogram of embodiment 21, and ordinate zou represents relative diffracted intensity (%), and X-coordinate represents angle of diffraction (2 θ).
Figure 22 is the feature X-powder diffractogram of the commercially available i.e. crystal form A of 2012-3, and ordinate zou represents relative diffracted intensity (%), and X-coordinate represents angle of diffraction (2 θ).
Figure 23 is the feature X-powder diffractogram of the commercially available i.e. crystal form B of 2012-8, and ordinate zou represents relative diffracted intensity (%), and X-coordinate represents angle of diffraction (2 θ).
Figure 24 is the DSC heat difference curve spectrogram of the commercially available i.e. crystal form A of 2012-3.
Figure 25 is the DSC heat difference curve spectrogram of the crystal form B of new crystal and 2012-8.
Figure 26 is the TGA thermogravimetric analysis spectrogram of the commercially available i.e. crystal form A of 2012-3.
Figure 27 is the TGA thermogravimetric analysis spectrogram of the commercially available i.e. crystal form B of 2012-8.
Figure 28 is the HPLC analysis of spectra of the commercially available i.e. crystal form A of 2012-3.
Figure 29 is the HPLC analysis of spectra of the commercially available i.e. crystal form B of 2012-8.
Embodiment
Below in conjunction with accompanying drawing, the present invention is further illustrated, but limited the present invention never in any form, and any conversion done based on training centre of the present invention or replacement, all belong to protection scope of the present invention.
The chloro-9-of α of the present invention-(Di-n-Butyl Amine methyl)-2,7-bis-to the powder x-ray diffraction collection of illustrative plates of chlorobenzene methylene radical-4-Lumefantrine crystal formation 39.4,33.2,29.3,24.2,23.9,23.5,22.3,21.5,20.8,18.4,16.0,15.1,14.8,14.2,13.1,10.9,2 θ ± 0.1 ° reflection angle place indicating characteristic the diffraction peak of 9.1,6.1,3.1.
Described α-(Di-n-Butyl Amine methyl)-2, the characteristic peak 39.4(w that the chloro-9-of 7-bis-is representing by d-value () chlorobenzene methylene radical-4-Lumefantrine crystal formation), 33.2(w), 29.3(vw), 24.2(m), 23.9 (m), 23.5(w), 22.3(m), 21.5(m), 20.8(vw), 18.4(w), 16.0(vw), 15.1(m), 14.8(w), 14.2(w), 13.1(w), 10.9(vm), 9.1(w), 6.1(s), 3.1(vs) place has α-(the Di-n-Butyl Amine methyl)-2 of feature X-powder diffraction spectrum, the crystal formation of the chloro-9-of 7-bis-to chlorobenzene methylene radical-4-Lumefantrine is called B crystal form.Abbreviation in bracket described herein represents: (vs)=extra-heavy peak; (s)=strong peak; (m)=in strong peak; (w)=weak peak; (vw)=very weak peak.
The crystal formation of the chloro-9-of described α-(Di-n-Butyl Amine methyl)-2,7-bis-to chlorobenzene methylene radical-4-Lumefantrine is needle-like crystal formation; And 2 impurity removings that A in ordinary method produces by this new crystal B.
α of the present invention-(Di-n-Butyl Amine methyl)-2, the preparation method of the chloro-9-of 7-bis-to chlorobenzene methylene radical-4-Lumefantrine crystal formation will add in the organic solvent of weightmeasurement ratio 25 ~ 30 times in benzfluorenol crude product, be stirred at temperature 60 ~ 70 DEG C and dissolve completely, carry out suction filtration after backflow 15 ~ 30min, filtrate is carried out crystallization and is obtained target compound.
Described organic solvent is one or more in ketone, aldehydes, ethers, ester class, acetone, butanone, diacetone alcohol, sym.-diisopropylideneacetone, isophorone, mesityl oxide, methyl iso-butyl ketone (MIBK), methyl phenyl ketone or cyclohexanone.
Described mixing speed is 200 ~ 250rpm.
Described preparation method is the acetone by adding weightmeasurement ratio 25 ~ 30 times in raw material benzfluorenol first product, being stirred to the mixing speed of 200 ~ 250rpm at 60 ~ 70 DEG C dissolves completely, after backflow 15 ~ 30min, carry out suction filtration, carry out stirring and crystallizing after filtrate is concentrated into 1/10 ~ 1/5, collection solid dries 4 ~ 6h and obtains target compound at 55 ~ 65 DEG C; The mixing speed of described stirring and crystallizing is 200 ~ 250rpm.
Described preparation method is the acetone by adding weightmeasurement ratio 25 ~ 30 times in raw material benzfluorenol first product, being stirred to the mixing speed of 200 ~ 250rpm at 60 ~ 70 DEG C dissolves completely, after backflow 15 ~ 30min, carry out suction filtration, add solvent stirring and crystallizing under the mixing speed of 200 ~ 250rpm of volume ratio 10 ~ 20 times in filtrate, collection solid dries 4 ~ 6h and obtains target compound at 55 ~ 65 DEG C; Described solvent is one or more in water, methyl alcohol, ethanol, butanols or propyl alcohol.
Described preparation method be by add weightmeasurement ratio 25 ~ 30 times in raw material benzfluorenol first product acetone,
one in butanone, diacetone alcohol, sym.-diisopropylideneacetone, isophorone, mesityl oxide, methyl iso-butyl ketone (MIBK), methyl phenyl ketone or cyclohexanone, then add the glacial acetic acid of raw material weight volume ratio 1 ~ 5 times, hydrochloric acid, sulfuric acid, phosphoric acid,
one in nitric acid, perchloric acid or Periodic acid, being stirred to the mixing speed of 200 ~ 250rpm at 60 ~ 70 DEG C dissolves completely, after backflow 15 ~ 30min, carry out suction filtration, add solvent stirring and crystallizing under the mixing speed of 200 ~ 250rpm of volume ratio 10 ~ 20 times in filtrate, collection solid dries 4 ~ 6h and obtains target compound at 55 ~ 65 DEG C; Described solvent is one or more in water, methyl alcohol, ethanol, butanols or propyl alcohol.
Described preparation method be by add weightmeasurement ratio 25 ~ 30 times in raw material benzfluorenol first product acetone, butanone, diacetone alcohol, sym.-diisopropylideneacetone, isophorone, mesityl oxide, methyl iso-butyl ketone (MIBK), methyl phenyl ketone or cyclohexanone in one, then add the glacial acetic acid of raw material weight volume ratio 1 ~ 5 times, hydrochloric acid, sulfuric acid, phosphoric acid,
one in nitric acid, perchloric acid or Periodic acid, being stirred to the mixing speed of 200 ~ 250rpm at 60 ~ 70 DEG C dissolves completely, after backflow 15 ~ 30min, filter, filtrate adds alkali lye adjustment filtrate pH value to 6.5 ~ 7.5 of volume ratio 1 ~ 5 times after being cooled to 0 ~ 30 DEG C, add non-polar solvent stirring and crystallizing under the mixing speed of 200 ~ 250rpm of 10 ~ 20 times, collection solid dries 4 ~ 6h and obtains target compound at 55 ~ 65 DEG C; Described non-polar solvent is one or more in water, methyl alcohol, ethanol, butanols or propyl alcohol; Described alkali lye is one or more in sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium hydroxide, calcium hydroxide, ammoniacal liquor, sodium alkoxide, sodium hydrogen, diethylamine or triethylamine solution.
Described preparation method to be the petroleum ether-ethyl acetate by adding weightmeasurement ratio 10 ~ 20 times in raw material benzfluorenol first product, dissolving is being stirred to completely with the mixing speed of 200 ~ 250rpm at 60 ~ 70 DEG C, after backflow 15 ~ 30min, carry out suction filtration, filtrate is stirring and crystallizing under the mixing speed of 100 ~ 150rpm, and collection solid dries 4 ~ 6h and obtains target compound at 55 ~ 65 DEG C.
Described petroleum ether-ethyl acetate volume ratio is 4:1.
Also comprise before described backflow and add 8 ~ 12g gac.
The object that the present invention refines benzfluorenol is to obtain a kind of new needle-like crystal formation by this solvent systems and the method, and the aspects such as the content of this product, yield are increased, and production cost can be reduced.New crystal product and commercially available crystal formation product move at medicine, and in medicine generation, the character of the aspects such as toxicity is consistent, and acts on identical.
This product refines the novel solvent of employing and new solution is achieved in that
1, the benzfluorenol crude product taking 1 times amount drops into, the acetone measuring 25-30 times amount is poured into wherein, opening mixing speed controls at 200-250rpm, and be heated to 60-70 DEG C make it dissolve, to be dissolved complete time, add the gac (visual content in crude product is selected to add or do not add) of 2%-5% times amount, backflow for some time, pour out suction filtration while hot, filtrate adds after concentrating the 5-10 times amount of input amount that whipping appts rotating speed controls in 100-150rpm stirring and crystallizing, stop stirring in time separating out complete taking out collected by suction solid, put into 60 DEG C of oven for drying, obtain a kind of new crystal product, mother liquor continues after can collecting to apply mechanically or recycling.
2, the benzfluorenol crude product taking 1 times amount drops into, measuring 25-30 acetone doubly pours into wherein, opening mixing speed controls at 200-250rpm, and be heated to 60-70 DEG C make it dissolve, to be dissolved complete time, add the gac (visual content in crude product is selected to add or do not add) of 2%-5% times amount, backflow for some time, pour out suction filtration while hot, filtrate adds that whipping appts mixing speed controls at 200-250rpm, now add water or other solvent compatible with solvent for use of 10-20 times amount, until separate out completely, agitation and filtration is stopped to collect solid, put into 60 DEG C of oven for drying, obtain a kind of needle-like crystal formation product, it is abandoned after filtrate process.
3, the benzfluorenol crude product taking 1 times amount drops into, the acetone measuring 5-10 times amount (or can be used as solvent, but the ketone of benzfluorenol can not be dissolved completely under normal temperature state, alcohols, ethers, ester class is as solvent, as acetone, butanone, methyl alcohol, ethanol, sherwood oil, ethyl acetate etc.) pour into wherein, the glacial acetic acid measuring again 1-5 times amount amount (maybe can make the acid of benzfluorenol salify, example hydrochloric acid, sulfuric acid, phosphoric acid etc.) pour into, opening mixing speed controls at 200-250rpm, add the gac (visual content in crude product is selected to add or do not add) of 2%-5% times amount, after heating 60-70 DEG C of backflow for some time, take out and filter, filtrate is opened mixing speed and is controlled after 200-250rpm is first cooled to room temperature after adding whipping appts, add the water of 10-20 times amount or other little polarity and the solvent compatible with solvent for use, after precipitation completely, stop agitation and filtration collecting solid, put into 60 DEG C of oven for drying, obtain a kind of needle-like crystal formation product, it is abandoned after filtrate process.
4, the benzfluorenol crude product taking 1 times amount drops into, and the acetone measuring 5-10 times amount (or can be used as solvent, but can not dissolve the ketone of benzfluorenol completely under normal temperature state, alcohols, ethers, ester class as solvent, as acetone, butanone, methyl alcohol, ethanol, sherwood oil, ethyl acetate etc.) to pour into wherein, the glacial acetic acid measuring again 1-5 times amount (maybe can make the acid of benzfluorenol salify, example hydrochloric acid, sulfuric acid, phosphoric acid etc.) pour into, opening mixing speed controls at 200-250rpm, add the gac (visual content in crude product is selected to add or do not add) of 2%-5% times amount, after heating 60-70 DEG C of backflow for some time, take out and filter, filtrate is opened mixing speed and is controlled first to be cooled to room temperature at 200-250rpm after adding whipping appts, the alkali lye of 1-5 times amount is slowly added in filtrate until filtrate is in neutral, period notes heating, be cooled to room temperature again, add the water of 10-20 times amount or other insoluble or indissoluble benzfluorenol and the solvent compatible with solvent for use, after precipitation completely, stop agitation and filtration collecting solid, put into 60 DEG C of oven for drying, obtain a kind of needle-like crystal formation product, after filtrate process, abandon it.
5, preparing ratio is the sherwood oil of 4:1: it is stand-by that ethyl acetate mixes rear placement, the benzfluorenol crude product taking 1 times amount drops into, the solvent (sherwood oil: ethyl acetate) measuring 10-20 times amount adds wherein, open mixing speed to control at 200-250rpm and be heated to 60-70 DEG C to make it to dissolve completely, add the gac (visual content in crude product is selected to add or do not add) of 2%-5% times amount, make it for some time of refluxing, suction filtration while hot, collect filtrate, filtrate is opened mixing speed and is controlled at 100-150rpm crystallization after adding whipping appts.After precipitation completely, stopping is stirred and is taken out collected by suction solid, puts into 60 DEG C of oven for drying, obtains a kind of needle-like crystal formation product, and after detecting, mother liquor can carry out applying mechanically or rectifying recovery.
With embodiment, the present invention will be further described below:
embodiment 1
100g benzfluorenol crude product is added in 5L there-necked flask, add 2.5L acetone, unlatching mixing speed controls at 250rpm and reflux makes it to dissolve, when temperature rises to 70 DEG C, dissolve completely, now add 10g gac, backflow 15min, reflux temperature 68 DEG C, take out suction filtration while hot, filtrate adds after concentrating 5L that whipping appts rotating speed controls in 100rpm stirring and crystallizing, stirs 2 hours, stops stirring taking out collected by suction solid, put into 60 DEG C of oven for drying, obtain a kind of needle-like crystal formation product B, filtrate collection is applied mechanically or is reclaimed, yield: 94%; This crystal is pulverized laggard row powder x-ray diffraction, and accompanying drawing 1 is shown in by collection of illustrative plates.
The α obtained-(Di-n-Butyl Amine methyl)-2, the characteristic peak 39.4(w that the chloro-9-of 7-bis-is representing by d-value () chlorobenzene methylene radical-4-Lumefantrine crystal formation), 33.2(w), 29.3(vw), 24.2(m), 23.9 (m), 23.5(w), 22.3(m), 21.5(m), 20.8(vw), 18.4(w), 16.0(vw), 15.1(m), 14.8(w), 14.2(w), 13.1(w), 10.9(vm), 9.1(w), 6.1(s), 3.1(vs) place has α-(the Di-n-Butyl Amine methyl)-2 of feature X-powder diffraction spectrum, the crystal formation of the chloro-9-of 7-bis-to chlorobenzene methylene radical-4-Lumefantrine is called B crystal form.Abbreviation in bracket described herein represents: (vs)=extra-heavy peak; (s)=strong peak; (m)=in strong peak; (w)=weak peak; (vw)=very weak peak.
Embodiment 2
100g benzfluorenol crude product is added in 5L there-necked flask, add 2.5L acetone, unlatching mixing speed controls at 250rpm and reflux makes it to dissolve, when temperature rises to 70 DEG C, dissolve completely, now add 10g gac, backflow 15min, reflux temperature 68 DEG C, take out suction filtration while hot, filtrate adds after concentrating 5L that whipping appts rotating speed controls in 150rpm stirring and crystallizing, stirs 4 hours, stops stirring taking out collected by suction solid, put into 60 DEG C of baking ovens and dry 6h, obtain a kind of needle-like crystal formation product B, filtrate collection is applied mechanically or is reclaimed, yield: 92%; This crystal is pulverized laggard row powder x-ray diffraction, and accompanying drawing 2 is shown in by collection of illustrative plates.
The α obtained-(Di-n-Butyl Amine methyl)-2, the characteristic peak 39.7(w that the chloro-9-of 7-bis-is representing by d-value () chlorobenzene methylene radical-4-Lumefantrine crystal formation), 33.4(w), 30.6(vw), 26.2(m), 24.2 (m), 23.5(w), 22.3(m), 21.5(m), 20.8(vw), 18.4(w), 16.0(vw), 15.1(m), 14.8(w), 14.2(w), 13.1(w), 10.9(vm), 9.1(w), 6.1(s), 3.1(vs) place has α-(the Di-n-Butyl Amine methyl)-2 of feature X-powder diffraction spectrum, the crystal formation of the chloro-9-of 7-bis-to chlorobenzene methylene radical-4-Lumefantrine is called B crystal form.Abbreviation in bracket described herein represents: (vs)=extra-heavy peak; (s)=strong peak; (m)=in strong peak; (w)=weak peak; (vw)=very weak peak.
embodiment 3
100g benzfluorenol crude product is added in 5L there-necked flask, add 2.5L acetone, unlatching mixing speed controls at 200rpm and reflux makes it to dissolve, when temperature rises to 70 DEG C, dissolve completely, backflow 15min, reflux temperature 68 DEG C, take out suction filtration while hot, filtrate adds that whipping appts rotating speed controls to start slowly to add water after 200rpm, make it slowly to separate out, add the water yield of 10:1, stir about 1 hour again, take out suction filtration, collect solid, put into 60 DEG C of baking ovens and dry 6h, obtain a kind of needle-like crystal formation product B, abandon after filtrate process or rectifying recovery, yield: 90-92%, this crystal is pulverized laggard row powder x-ray diffraction, accompanying drawing 3 is shown in by collection of illustrative plates.
The α obtained-(Di-n-Butyl Amine methyl)-2, the characteristic peak 36.5(w that the chloro-9-of 7-bis-is representing by d-value () chlorobenzene methylene radical-4-Lumefantrine crystal formation), 30.6(w), 29.3(vw), 24.2(m), 23.9 (m), 23.5(w), 22.3(m), 21.5(m), 20.8(vw), 18.4(w), 16.0(vw), 15.1(m), 14.8(w), 14.2(w), 13.1(w), 10.9(vm), 9.1(w), 6.1(s), 3.1(vs) place has α-(the Di-n-Butyl Amine methyl)-2 of feature X-powder diffraction spectrum, the crystal formation of the chloro-9-of 7-bis-to chlorobenzene methylene radical-4-Lumefantrine is called B crystal form.Abbreviation in bracket described herein represents: (vs)=extra-heavy peak; (s)=strong peak; (m)=in strong peak; (w)=weak peak; (vw)=very weak peak.
Embodiment 4
100g benzfluorenol crude product is added in 5L there-necked flask, add 2.5L acetone, unlatching mixing speed controls at 250rpm and reflux makes it to dissolve, when temperature rises to 70 DEG C, dissolve completely, backflow 15min, reflux temperature 68 DEG C, take out suction filtration while hot, filtrate adds that whipping appts rotating speed controls to start slowly to add water after 250rpm, make it slowly to separate out, add the water yield of 20:1, stir 1 hour again, take out suction filtration, collect solid, put into 60 DEG C of baking ovens and dry 6h, obtain a kind of needle-like crystal formation product B, abandon after filtrate process or rectifying recovery, yield: 90-92%, this crystal is pulverized laggard row powder x-ray diffraction, accompanying drawing 4 is shown in by collection of illustrative plates.
The α obtained-(Di-n-Butyl Amine methyl)-2, the characteristic peak 39.4(w that the chloro-9-of 7-bis-is representing by d-value () chlorobenzene methylene radical-4-Lumefantrine crystal formation), 30.6(w), 27.3(vw), 24.2(m), 23.9 (m), 23.5(w), 22.3(m), 21.5(m), 20.8(vw), 18.4(w), 16.0(vw), 15.1(m), 14.8(w), 14.2(w), 13.1(w), 10.9(vm), 9.1(w), 6.1(s), 3.1(vs) place has α-(the Di-n-Butyl Amine methyl)-2 of feature X-powder diffraction spectrum, the crystal formation of the chloro-9-of 7-bis-to chlorobenzene methylene radical-4-Lumefantrine is called B crystal form.Abbreviation in bracket described herein represents: (vs)=extra-heavy peak; (s)=strong peak; (m)=in strong peak; (w)=weak peak; (vw)=very weak peak.
embodiment 5
100g benzfluorenol crude product is added in 5L there-necked flask, add 2.5L acetone, unlatching mixing speed controls at 200-250rpm and reflux makes it to dissolve, when temperature rises to 70 DEG C, dissolve completely, now add 10g gac, backflow 15min, reflux temperature 68 DEG C, take out suction filtration while hot, filtrate adds that whipping appts rotating speed controls to start slowly to add sherwood oil after 200rpm, add-on is 2 times of amounts of acetone, continue stir about 2 hours, take out suction filtration, collect solid, put into 55 DEG C of baking ovens and dry 6h, obtain a kind of needle-like crystal formation product B, filtrate rectifying is reclaimed, yield: 90%.This crystal is pulverized laggard row powder x-ray diffraction, and accompanying drawing 5 is shown in by collection of illustrative plates.
The α obtained-(Di-n-Butyl Amine methyl)-2, the characteristic peak 39.4(w that the chloro-9-of 7-bis-is representing by d-value () chlorobenzene methylene radical-4-Lumefantrine crystal formation), 33.2(w), 29.3(vw), 24.2(m), 23.9 (m), 23.5(w), 22.3(m), 21.5(m), 20.8(vw), 18.4(w), 16.0(vw), 15.1(m), 14.8(w), 14.2(w), 13.1(w), 10.9(vm), 9.1(w), 6.1(s), 3.1(vs) place has α-(the Di-n-Butyl Amine methyl)-2 of feature X-powder diffraction spectrum, the crystal formation of the chloro-9-of 7-bis-to chlorobenzene methylene radical-4-Lumefantrine is called B crystal form.Abbreviation in bracket described herein represents: (vs)=extra-heavy peak; (s)=strong peak; (m)=in strong peak; (w)=weak peak; (vw)=very weak peak.
Embodiment 6
100g benzfluorenol crude product is added in 5L there-necked flask, add 2.5L acetone, unlatching mixing speed controls at 250rpm and reflux makes it to dissolve, when temperature rises to 70 DEG C, dissolve completely, backflow 15min, reflux temperature 68 DEG C, take out suction filtration while hot, filtrate adds that whipping appts rotating speed controls to start slowly to add No. 6 oil after 200-250rpm, and add-on is 3 times of amounts of acetone, continues stir about 3 hours, take out suction filtration, collect solid, put into 65 DEG C of baking ovens and dry 6h, obtain a kind of needle-like crystal formation product B, filtrate rectifying is reclaimed, yield: 92%.This crystal is pulverized laggard row powder x-ray diffraction, and accompanying drawing 6 is shown in by collection of illustrative plates.
The α obtained-(Di-n-Butyl Amine methyl)-2, the characteristic peak 39.7(w that the chloro-9-of 7-bis-is representing by d-value () chlorobenzene methylene radical-4-Lumefantrine crystal formation), 33.4(w), 30.6(vw), 26.2(m), 24.2 (m), 23.5(w), 22.3(m), 21.5(m), 20.8(vw), 18.4(w), 16.0(vw), 15.1(m), 14.8(w), 14.2(w), 13.1(w), 10.9(vm), 9.1(w), 6.1(s), 3.1(vs) place has α-(the Di-n-Butyl Amine methyl)-2 of feature X-powder diffraction spectrum, the crystal formation of the chloro-9-of 7-bis-to chlorobenzene methylene radical-4-Lumefantrine is called B crystal form.Abbreviation in bracket described herein represents: (vs)=extra-heavy peak; (s)=strong peak; (m)=in strong peak; (w)=weak peak; (vw)=very weak peak.
embodiment 7
100g benzfluorenol crude product is added in 5L there-necked flask, add 2.5L acetone, unlatching mixing speed controls at 200rpm and reflux makes it to dissolve, when temperature rises to 70 DEG C, dissolve completely, now add 10g gac, backflow 15min, reflux temperature 68 DEG C, take out suction filtration while hot, filtrate adds that whipping appts rotating speed controls to start slowly to add methyl alcohol or anhydrous methanol after 200rpm, add-on is 5 times of amounts of acetone, continue stirring 2 hours, take out suction filtration, collect solid, put into 55 DEG C of casees and dry 6h, obtain a kind of needle-like crystal formation product B, filtrate rectifying is reclaimed, yield: 90%.This crystal is pulverized laggard row powder x-ray diffraction, and accompanying drawing 7 is shown in by collection of illustrative plates.
The α obtained-(Di-n-Butyl Amine methyl)-2, the characteristic peak 36.5(w that the chloro-9-of 7-bis-is representing by d-value () chlorobenzene methylene radical-4-Lumefantrine crystal formation), 30.6(w), 29.3(vw), 24.2(m), 23.9 (m), 23.5(w), 22.3(m), 21.5(m), 20.8(vw), 18.4(w), 16.0(vw), 15.1(m), 14.8(w), 14.2(w), 13.1(w), 10.9(vm), 9.1(w), 6.1(s), 3.1(vs) place has α-(the Di-n-Butyl Amine methyl)-2 of feature X-powder diffraction spectrum, the crystal formation of the chloro-9-of 7-bis-to chlorobenzene methylene radical-4-Lumefantrine is called B crystal form.Abbreviation in bracket described herein represents: (vs)=extra-heavy peak; (s)=strong peak; (m)=in strong peak; (w)=weak peak; (vw)=very weak peak.
Embodiment 8
100g benzfluorenol crude product is added in 5L there-necked flask, add 2.5L acetone, unlatching mixing speed controls at 250rpm and reflux makes it to dissolve, when temperature rises to 70 DEG C, dissolve completely, backflow 15min, reflux temperature 68 DEG C, take out suction filtration while hot, filtrate adds that whipping appts rotating speed controls to start slowly to add methyl alcohol or anhydrous methanol after 250rpm, and add-on is 5 times of amounts of acetone, continues stir about 3 hours, take out suction filtration, collect solid, put into 65 DEG C of baking ovens and dry 6h, obtain a kind of needle-like crystal formation product B, filtrate rectifying is reclaimed, yield: 92%.This crystal is pulverized laggard row powder x-ray diffraction, and accompanying drawing 8 is shown in by collection of illustrative plates.
The α obtained-(Di-n-Butyl Amine methyl)-2, the characteristic peak 39.4(w that the chloro-9-of 7-bis-is representing by d-value () chlorobenzene methylene radical-4-Lumefantrine crystal formation), 30.6(w), 27.3(vw), 24.2(m), 23.9 (m), 23.5(w), 22.3(m), 21.5(m), 20.8(vw), 18.4(w), 16.0(vw), 15.1(m), 14.8(w), 14.2(w), 13.1(w), 10.9(vm), 9.1(w), 6.1(s), 3.1(vs) place has α-(the Di-n-Butyl Amine methyl)-2 of feature X-powder diffraction spectrum, the crystal formation of the chloro-9-of 7-bis-to chlorobenzene methylene radical-4-Lumefantrine is called B crystal form.Abbreviation in bracket described herein represents: (vs)=extra-heavy peak; (s)=strong peak; (m)=in strong peak; (w)=weak peak; (vw)=very weak peak.
embodiment 9
100g benzfluorenol crude product is added in 5L there-necked flask, add 2.5L acetone, unlatching mixing speed controls at 220rpm and reflux makes it to dissolve, when temperature rises to 70 DEG C, dissolve completely, now add 10g gac, backflow 15min, reflux temperature 68 DEG C, take out suction filtration while hot, filtrate adds that whipping appts rotating speed controls to start slowly to add ethanol or dehydrated alcohol after 200rpm, add-on is 5 times of amounts of acetone, continue stir about 2 hours, take out suction filtration, collect solid, put into 60 DEG C of baking ovens and dry 6h, obtain a kind of needle-like crystal formation product B, filtrate rectifying is reclaimed, yield: 90%.This crystal is pulverized laggard row powder x-ray diffraction, and accompanying drawing 9 is shown in by collection of illustrative plates.
The α obtained-(Di-n-Butyl Amine methyl)-2, the characteristic peak 39.7(w that the chloro-9-of 7-bis-is representing by d-value () chlorobenzene methylene radical-4-Lumefantrine crystal formation), 33.4(w), 30.6(vw), 26.2(m), 24.2 (m), 23.5(w), 22.3(m), 21.5(m), 20.8(vw), 18.4(w), 16.0(vw), 15.1(m), 14.8(w), 14.2(w), 13.1(w), 10.9(vm), 9.1(w), 6.1(s), 3.1(vs) place has α-(the Di-n-Butyl Amine methyl)-2 of feature X-powder diffraction spectrum, the crystal formation of the chloro-9-of 7-bis-to chlorobenzene methylene radical-4-Lumefantrine is called B crystal form.Abbreviation in bracket described herein represents: (vs)=extra-heavy peak; (s)=strong peak; (m)=in strong peak; (w)=weak peak; (vw)=very weak peak.
Embodiment 10
100g benzfluorenol crude product is added in 5L there-necked flask, add 2.5L acetone, unlatching mixing speed controls at 250rpm and reflux makes it to dissolve, when temperature rises to 70 DEG C, dissolve completely, backflow 15min, reflux temperature 68 DEG C, take out suction filtration while hot, filtrate adds that whipping appts rotating speed controls to start slowly to add ethanol or dehydrated alcohol after 250rpm, and add-on is 5 times of amounts of acetone, continues stir about 3 hours, take out suction filtration, collect solid, put into 60 DEG C of baking ovens and dry 6h, obtain a kind of needle-like crystal formation product B, filtrate rectifying is reclaimed, yield: 92%.This crystal is pulverized laggard row powder x-ray diffraction, and accompanying drawing 10 is shown in by collection of illustrative plates.
The α obtained-(Di-n-Butyl Amine methyl)-2, the characteristic peak 39.4(w that the chloro-9-of 7-bis-is representing by d-value () chlorobenzene methylene radical-4-Lumefantrine crystal formation), 33.2(w), 29.3(vw), 24.2(m), 23.9 (m), 23.5(w), 22.3(m), 21.5(m), 20.8(vw), 18.4(w), 16.0(vw), 15.1(m), 14.8(w), 14.2(w), 13.1(w), 10.9(vm), 9.1(w), 6.1(s), 3.1(vs) place has α-(the Di-n-Butyl Amine methyl)-2 of feature X-powder diffraction spectrum, the crystal formation of the chloro-9-of 7-bis-to chlorobenzene methylene radical-4-Lumefantrine is called B crystal form.Abbreviation in bracket described herein represents: (vs)=extra-heavy peak; (s)=strong peak; (m)=in strong peak; (w)=weak peak; (vw)=very weak peak.
embodiment 11
300g benzfluorenol crude product is added in 5L there-necked flask, add 1500ml acetone, opening mixing speed controls at 200-250rpm, after measure 300ml content more than 99% glacial acetic acid slowly add wherein, visible benzfluorenol dissolves, add 30g gac, open and heat and make it the 30min that refluxes, reflux temperature 68 DEG C.Take out suction filtration while hot, filtrate adds whipping appts and opens mixing speed and controls to cool the temperature to room temperature after 250rpm, now starts slowly to add 1800ml purified water, stop adding water, after stirring 1h, then add 5400ml purified water water, after continuing to stir 1h, take out suction filtration, collect solid, put into 60 DEG C of baking ovens and dry 6h, obtain a kind of needle-like crystal formation product B, abandon after filtrate process or rectifying recovery, yield: 94%.This crystal is pulverized laggard row powder x-ray diffraction, and accompanying drawing 11 is shown in by collection of illustrative plates.
The α obtained-(Di-n-Butyl Amine methyl)-2, the characteristic peak 36.5(w that the chloro-9-of 7-bis-is representing by d-value () chlorobenzene methylene radical-4-Lumefantrine crystal formation), 30.6(w), 29.3(vw), 24.2(m), 23.9 (m), 23.5(w), 22.3(m), 21.5(m), 20.8(vw), 18.4(w), 16.0(vw), 15.1(m), 14.8(w), 14.2(w), 13.1(w), 10.9(vm), 9.1(w), 6.1(s), 3.1(vs) place has α-(the Di-n-Butyl Amine methyl)-2 of feature X-powder diffraction spectrum, the crystal formation of the chloro-9-of 7-bis-to chlorobenzene methylene radical-4-Lumefantrine is called B crystal form.Abbreviation in bracket described herein represents: (vs)=extra-heavy peak; (s)=strong peak; (m)=in strong peak; (w)=weak peak; (vw)=very weak peak.
Embodiment 12
In 5L there-necked flask, add 300g benzfluorenol crude product, add 1500ml butanone, open mixing speed and control at 200-250rpm, after measure 300ml 36% ~ 38% hydrochloric acid slowly add wherein, visible benzfluorenol dissolves, and opens and heats and make it the 30min that refluxes, reflux temperature 68 DEG C.Take out suction filtration while hot, filtrate adds whipping appts and opens mixing speed and controls to cool the temperature to room temperature after 250rpm, now starts slowly to add 1800ml purified water, stop adding water, after stirring 1h, then add 5400ml purified water water, after continuing to stir 1h, take out suction filtration, collect solid, put into 60 DEG C of baking ovens and dry 6h, obtain a kind of needle-like crystal formation product B, abandon after filtrate process or rectifying recovery, yield: 98%.This crystal is pulverized laggard row powder x-ray diffraction, and accompanying drawing 12 is shown in by collection of illustrative plates.
The α obtained-(Di-n-Butyl Amine methyl)-2, the characteristic peak 39.4(w that the chloro-9-of 7-bis-is representing by d-value () chlorobenzene methylene radical-4-Lumefantrine crystal formation), 30.6(w), 27.3(vw), 24.2(m), 23.9 (m), 23.5(w), 22.3(m), 21.5(m), 20.8(vw), 18.4(w), 16.0(vw), 15.1(m), 14.8(w), 14.2(w), 13.1(w), 10.9(vm), 9.1(w), 6.1(s), 3.1(vs) place has α-(the Di-n-Butyl Amine methyl)-2 of feature X-powder diffraction spectrum, the crystal formation of the chloro-9-of 7-bis-to chlorobenzene methylene radical-4-Lumefantrine is called B crystal form.Abbreviation in bracket described herein represents: (vs)=extra-heavy peak; (s)=strong peak; (m)=in strong peak; (w)=weak peak; (vw)=very weak peak.
embodiment 13
In 5L there-necked flask, add 300g benzfluorenol crude product, add 1500ml methyl alcohol, open mixing speed and control at 200rpm, after measure 300ml 98% sulfuric acid slowly add wherein, visible benzfluorenol dissolves, and adds 30g gac, open and heat and make it the 30min that refluxes, reflux temperature 68 DEG C.Take out suction filtration while hot, filtrate adds whipping appts and opens mixing speed and controls to cool the temperature to room temperature after 230rpm, now starts slowly to add 1800ml purified water, stop adding water, after stirring 1h, then add 5400ml purified water water, after continuing to stir 1h, take out suction filtration, collect solid, put into 60 DEG C of baking ovens and dry 6h, obtain a kind of needle-like crystal formation product B, abandon after filtrate process or rectifying recovery, yield: 95%.This crystal is pulverized laggard row powder x-ray diffraction, and accompanying drawing 13 is shown in by collection of illustrative plates.
The α obtained-(Di-n-Butyl Amine methyl)-2, the characteristic peak 39.4(w that the chloro-9-of 7-bis-is representing by d-value () chlorobenzene methylene radical-4-Lumefantrine crystal formation), 30.6(w), 27.3(vw), 24.2(m), 23.9 (m), 23.5(w), 22.3(m), 21.5(m), 20.8(vw), 18.4(w), 16.0(vw), 15.1(m), 14.8(w), 14.2(w), 13.1(w), 10.9(vm), 9.1(w), 6.1(s), 3.1(vs) place has α-(the Di-n-Butyl Amine methyl)-2 of feature X-powder diffraction spectrum, the crystal formation of the chloro-9-of 7-bis-to chlorobenzene methylene radical-4-Lumefantrine is called B crystal form.Abbreviation in bracket described herein represents: (vs)=extra-heavy peak; (s)=strong peak; (m)=in strong peak; (w)=weak peak; (vw)=very weak peak.
embodiment 14
In 5L there-necked flask, add 300g benzfluorenol crude product, add 1500ml ethanol, open mixing speed and control at 240rpm, after measure 300ml 85% phosphoric acid slowly add wherein, visible benzfluorenol dissolves, open and heat and make it backflow 30min, reflux temperature 68 DEG C.Take out suction filtration while hot, filtrate adds whipping appts and opens mixing speed and controls to cool the temperature to room temperature after 250rpm, now starts slowly to add 1800ml purified water, stop adding water, after stirring 1h, then add 5400ml purified water water, after continuing to stir 1h, take out suction filtration, collect solid, put into 60 DEG C of baking ovens and dry 6h, obtain a kind of needle-like crystal formation product B, abandon after filtrate process or rectifying recovery, yield: 97%.This crystal is pulverized laggard row powder x-ray diffraction, and accompanying drawing 14 is shown in by collection of illustrative plates.
The α obtained-(Di-n-Butyl Amine methyl)-2, the characteristic peak 36.5(w that the chloro-9-of 7-bis-is representing by d-value () chlorobenzene methylene radical-4-Lumefantrine crystal formation), 30.6(w), 29.3(vw), 24.2(m), 23.9 (m), 23.5(w), 22.3(m), 21.5(m), 20.8(vw), 18.4(w), 16.0(vw), 15.1(m), 14.8(w), 14.2(w), 13.1(w), 10.9(vm), 9.1(w), 6.1(s), 3.1(vs) place has α-(the Di-n-Butyl Amine methyl)-2 of feature X-powder diffraction spectrum, the crystal formation of the chloro-9-of 7-bis-to chlorobenzene methylene radical-4-Lumefantrine is called B crystal form.Abbreviation in bracket described herein represents: (vs)=extra-heavy peak; (s)=strong peak; (m)=in strong peak; (w)=weak peak; (vw)=very weak peak.
embodiment 15
300g benzfluorenol crude product is added in 5L there-necked flask, add 1500ml sherwood oil, opening mixing speed controls at 200-250rpm, after measure 300ml content more than 99% glacial acetic acid slowly add wherein, visible benzfluorenol dissolves, add 30g gac, open and heat and make it the 30min that refluxes, reflux temperature 68 DEG C.Take out suction filtration while hot, filtrate adds whipping appts and opens mixing speed and controls to cool the temperature to room temperature after 200rpm, now starts slowly to add 1800ml purified water, stop adding water, after stirring 1h, then add 5400ml purified water water, after continuing to stir 1h, take out suction filtration, collect solid, put into 60 DEG C of baking ovens and dry 6h, obtain a kind of needle-like crystal formation product B, abandon after filtrate process or rectifying recovery, yield: 98%.This crystal is pulverized laggard row powder x-ray diffraction, and accompanying drawing 15 is shown in by collection of illustrative plates.
The α obtained-(Di-n-Butyl Amine methyl)-2, the characteristic peak 39.7(w that the chloro-9-of 7-bis-is representing by d-value () chlorobenzene methylene radical-4-Lumefantrine crystal formation), 33.4(w), 30.6(vw), 26.2(m), 24.2 (m), 23.5(w), 22.3(m), 21.5(m), 20.8(vw), 18.4(w), 16.0(vw), 15.1(m), 14.8(w), 14.2(w), 13.1(w), 10.9(vm), 9.1(w), 6.1(s), 3.1(vs) place has α-(the Di-n-Butyl Amine methyl)-2 of feature X-powder diffraction spectrum, the crystal formation of the chloro-9-of 7-bis-to chlorobenzene methylene radical-4-Lumefantrine is called B crystal form.Abbreviation in bracket described herein represents: (vs)=extra-heavy peak; (s)=strong peak; (m)=in strong peak; (w)=weak peak; (vw)=very weak peak.
embodiment 16
In 5L there-necked flask, add 300g benzfluorenol crude product, add 1500ml ethyl acetate, open mixing speed and control at 200rpm, after measure 300ml 98% sulfuric acid slowly add wherein, visible benzfluorenol dissolves, and opens and heats and make it the 30min that refluxes, reflux temperature 68 DEG C.Take out suction filtration while hot, filtrate adds whipping appts and opens mixing speed and controls to cool the temperature to room temperature after 200rpm, now starts slowly to add 1800ml purified water, stop adding water, after stirring 1h, then add 5400ml purified water water, after continuing to stir 1h, take out suction filtration, collect solid, put into 60 DEG C of baking ovens and dry 6h, obtain a kind of needle-like crystal formation product B, abandon after filtrate process or rectifying recovery, yield: 98%.This crystal is pulverized laggard row powder x-ray diffraction, and accompanying drawing 16 is shown in by collection of illustrative plates.
The α obtained-(Di-n-Butyl Amine methyl)-2, the characteristic peak 36.5(w that the chloro-9-of 7-bis-is representing by d-value () chlorobenzene methylene radical-4-Lumefantrine crystal formation), 30.6(w), 29.3(vw), 24.2(m), 23.9 (m), 23.5(w), 22.3(m), 21.5(m), 20.8(vw), 18.4(w), 16.0(vw), 15.1(m), 14.8(w), 14.2(w), 13.1(w), 10.9(vm), 9.1(w), 6.1(s), 3.1(vs) place has α-(the Di-n-Butyl Amine methyl)-2 of feature X-powder diffraction spectrum, the crystal formation of the chloro-9-of 7-bis-to chlorobenzene methylene radical-4-Lumefantrine is called B crystal form.Abbreviation in bracket described herein represents: (vs)=extra-heavy peak; (s)=strong peak; (m)=in strong peak; (w)=weak peak; (vw)=very weak peak.
embodiment 17
In 5L there-necked flask, add 300g benzfluorenol crude product, add 1500ml acetone, open mixing speed and control at 200rpm, after measure 300ml content 99% glacial acetic acid slowly add wherein, visible benzfluorenol dissolves, and adds 30g gac, open and heat and make it the 30min that refluxes, reflux temperature 68 DEG C.Take out suction filtration while hot, filtrate adds whipping appts and opens mixing speed and controls to cool the temperature to room temperature after 200rpm, the alkali lye configured slowly is joined wherein, now note heat condition, treat pH value arrive neutrality just can, treat that temperature is down to room temperature, can slowly add 1800ml purified water, stopping adds water, after stirring 1h, then add 5400ml purified water, after continuing to stir 1h, take out suction filtration, collect solid, put into 60 DEG C of baking ovens and dry 6h, obtain a kind of needle-like crystal formation product B, abandon after filtrate process or rectifying recovery, yield: 94%.This crystal is pulverized laggard row powder x-ray diffraction, and accompanying drawing 17 is shown in by collection of illustrative plates.
The α obtained-(Di-n-Butyl Amine methyl)-2, the characteristic peak 39.4(w that the chloro-9-of 7-bis-is representing by d-value () chlorobenzene methylene radical-4-Lumefantrine crystal formation), 30.6(w), 27.3(vw), 24.2(m), 23.9 (m), 23.5(w), 22.3(m), 21.5(m), 20.8(vw), 18.4(w), 16.0(vw), 15.1(m), 14.8(w), 14.2(w), 13.1(w), 10.9(vm), 9.1(w), 6.1(s), 3.1(vs) place has α-(the Di-n-Butyl Amine methyl)-2 of feature X-powder diffraction spectrum, the crystal formation of the chloro-9-of 7-bis-to chlorobenzene methylene radical-4-Lumefantrine is called B crystal form.Abbreviation in bracket described herein represents: (vs)=extra-heavy peak; (s)=strong peak; (m)=in strong peak; (w)=weak peak; (vw)=very weak peak.
Embodiment 18
In 5L there-necked flask, add 300g benzfluorenol crude product, add 1500ml methyl alcohol, open mixing speed and control at 250rpm, after measure 300ml 36% ~ 38% hydrochloric acid slowly add wherein, visible benzfluorenol dissolves, and adds 30g gac, open and heat and make it the 30min that refluxes, reflux temperature 68 DEG C.Take out suction filtration while hot, filtrate adds whipping appts and opens mixing speed and controls to cool the temperature to room temperature after 200rpm, the alkali lye configured slowly is joined wherein, now note heat condition, treat pH value arrive neutrality just can, treat that temperature is down to room temperature, can slowly add 1800ml purified water, stopping adds water, after stirring 1h, then add 5400ml purified water, after continuing to stir 1h, take out suction filtration, collect solid, put into 60 DEG C of baking ovens and dry 6h, obtain a kind of needle-like crystal formation product B, abandon after filtrate process or rectifying recovery, yield: 98%.This crystal is pulverized laggard row powder x-ray diffraction, and accompanying drawing 18 is shown in by collection of illustrative plates.
The α obtained-(Di-n-Butyl Amine methyl)-2, the characteristic peak 36.5(w that the chloro-9-of 7-bis-is representing by d-value () chlorobenzene methylene radical-4-Lumefantrine crystal formation), 30.6(w), 29.3(vw), 24.2(m), 23.9 (m), 23.5(w), 22.3(m), 21.5(m), 20.8(vw), 18.4(w), 16.0(vw), 15.1(m), 14.8(w), 14.2(w), 13.1(w), 10.9(vm), 9.1(w), 6.1(s), 3.1(vs) place has α-(the Di-n-Butyl Amine methyl)-2 of feature X-powder diffraction spectrum, the crystal formation of the chloro-9-of 7-bis-to chlorobenzene methylene radical-4-Lumefantrine is called B crystal form.Abbreviation in bracket described herein represents: (vs)=extra-heavy peak; (s)=strong peak; (m)=in strong peak; (w)=weak peak; (vw)=very weak peak.
embodiment 19
In 5L there-necked flask, add 300g benzfluorenol crude product, add 1500ml ethyl acetate, open mixing speed and control at 250rpm, after measure 300ml content 99% glacial acetic acid and slowly add wherein, visible benzfluorenol dissolves, and opens and heats and make it the 30min that refluxes, reflux temperature 68 DEG C.Take out suction filtration while hot, filtrate adds whipping appts and opens mixing speed and controls to cool the temperature to room temperature after 250rpm, the alkali lye configured slowly is joined wherein, now note heat condition, treat pH value arrive neutrality just can, treat that temperature is down to room temperature, can slowly add 1800ml purified water, stopping adds water, after stirring 1h, then add 5400ml purified water, after continuing to stir 1h, take out suction filtration, collect solid, put into 60 DEG C of baking ovens and dry 6h, obtain a kind of needle-like crystal formation product B, abandon after filtrate process or rectifying recovery, yield: 97%.This crystal is pulverized laggard row powder x-ray diffraction, and accompanying drawing 19 is shown in by collection of illustrative plates.
The α obtained-(Di-n-Butyl Amine methyl)-2, the characteristic peak 39.7(w that the chloro-9-of 7-bis-is representing by d-value () chlorobenzene methylene radical-4-Lumefantrine crystal formation), 33.4(w), 30.6(vw), 26.2(m), 24.2 (m), 23.5(w), 22.3(m), 21.5(m), 20.8(vw), 18.4(w), 16.0(vw), 15.1(m), 14.8(w), 14.2(w), 13.1(w), 10.9(vm), 9.1(w), 6.1(s), 3.1(vs) place has α-(the Di-n-Butyl Amine methyl)-2 of feature X-powder diffraction spectrum, the crystal formation of the chloro-9-of 7-bis-to chlorobenzene methylene radical-4-Lumefantrine is called B crystal form.Abbreviation in bracket described herein represents: (vs)=extra-heavy peak; (s)=strong peak; (m)=in strong peak; (w)=weak peak; (vw)=very weak peak.
embodiment 20
Preparation 200ml sherwood oil: the mixing solutions of ethyl acetate (4:1), open mixing speed to control evenly to place stand-by afterwards at 250rpm, taking 10g benzfluorenol crude product drops in 250ml there-necked flask, the solvent (sherwood oil: ethyl acetate=4:1) measuring 150ml adds wherein, open mixing speed to control at 250rpm and heat to make it to dissolve completely, add 1g gac, make it the 20min that refluxes, reflux temperature 60 DEG C, suction filtration while hot, collect filtrate, filtrate adds that whipping appts rotating speed controls to open stirring and crystallizing after 100rpm.After precipitation completely, stop stirring taking out collected by suction solid, put into 55 DEG C of baking ovens and dry 6h, obtain a kind of needle-like crystal formation product B, after detecting, mother liquor can carry out applying mechanically or rectifying recovery, yield: 65%.This crystal is pulverized laggard row powder x-ray diffraction, and accompanying drawing 20 is shown in by collection of illustrative plates.
The α obtained-(Di-n-Butyl Amine methyl)-2, the characteristic peak 39.4(w that the chloro-9-of 7-bis-is representing by d-value () chlorobenzene methylene radical-4-Lumefantrine crystal formation), 33.2(w), 29.3(vw), 24.2(m), 23.9 (m), 23.5(w), 22.3(m), 21.5(m), 20.8(vw), 18.4(w), 16.0(vw), 15.1(m), 14.8(w), 14.2(w), 13.1(w), 10.9(vm), 9.1(w), 6.1(s), 3.1(vs) place has α-(the Di-n-Butyl Amine methyl)-2 of feature X-powder diffraction spectrum, the crystal formation of the chloro-9-of 7-bis-to chlorobenzene methylene radical-4-Lumefantrine is called B crystal form.Abbreviation in bracket described herein represents: (vs)=extra-heavy peak; (s)=strong peak; (m)=in strong peak; (w)=weak peak; (vw)=very weak peak.
Embodiment 21
Preparation 200ml sherwood oil: the mixing solutions of ethyl acetate (4:1), open mixing speed to control evenly to place stand-by afterwards at 200rpm, taking 10g benzfluorenol crude product drops in 250ml there-necked flask, the solvent (sherwood oil: ethyl acetate=4:1) measuring 150ml adds wherein, open mixing speed to control at 200rpm and heat to make it to dissolve completely, make it the 20min that refluxes, reflux temperature 60 DEG C, suction filtration while hot, collect filtrate, filtrate adds that whipping appts rotating speed controls to open stirring and crystallizing after 150rpm.After precipitation completely, stop stirring taking out collected by suction solid, put into 65 DEG C of baking ovens and dry 6h, obtain a kind of needle-like crystal formation product B, after detecting, mother liquor can carry out applying mechanically or rectifying recovery, yield: 70%.This crystal is pulverized laggard row powder x-ray diffraction, and accompanying drawing 21 is shown in by collection of illustrative plates.
The α obtained-(Di-n-Butyl Amine methyl)-2, the characteristic peak 39.4(w that the chloro-9-of 7-bis-is representing by d-value () chlorobenzene methylene radical-4-Lumefantrine crystal formation), 33.2(w), 29.3(vw), 24.2(m), 23.9 (m), 23.5(w), 22.3(m), 21.5(m), 20.8(vw), 18.4(w), 16.0(vw), 15.1(m), 14.8(w), 14.2(w), 13.1(w), 10.9(vm), 9.1(w), 6.1(s), 3.1(vs) place has α-(the Di-n-Butyl Amine methyl)-2 of feature X-powder diffraction spectrum, the crystal formation of the chloro-9-of 7-bis-to chlorobenzene methylene radical-4-Lumefantrine is called B crystal form.Abbreviation in bracket described herein represents: (vs)=extra-heavy peak; (s)=strong peak; (m)=in strong peak; (w)=weak peak; (vw)=very weak peak.
Claims (10)
1. the chloro-9-of α-(Di-n-Butyl Amine methyl)-2,7-bis-is to chlorobenzene methylene radical-4-Lumefantrine crystal formation, it is characterized in that the chloro-9-of described α-(Di-n-Butyl Amine methyl)-2,7-bis-to the powder x-ray diffraction collection of illustrative plates of the crystal formation of chlorobenzene methylene radical-4-Lumefantrine 39.4,33.2,29.3,24.2,23.9,23.5,22.3,21.5,20.8,18.4,16.0,15.1,14.8,14.2,13.1,10.9,2 θ ± 0.1 ° reflection angle place indicating characteristic the diffraction peak of 9.1,6.1,3.1.
2. α according to claim 1-(Di-n-Butyl Amine methyl)-2, the chloro-9-of 7-bis-is to chlorobenzene methylene radical-4-Lumefantrine crystal formation, it is characterized in that the crystal formation of the chloro-9-of described α-(Di-n-Butyl Amine methyl)-2,7-bis-to chlorobenzene methylene radical-4-Lumefantrine is needle-like crystal formation.
3. the α described in a claim 1 or 2-(Di-n-Butyl Amine methyl)-2, the chloro-9-of 7-bis-is to the preparation method of chlorobenzene methylene radical-4-Lumefantrine crystal formation, it is characterized in that adding in the organic solvent of weightmeasurement ratio 25 ~ 30 times in benzfluorenol crude product, be stirred at temperature 60 ~ 70 DEG C and dissolve completely, carry out suction filtration after backflow 15 ~ 30min, filtrate is carried out crystallization and is obtained target compound.
4. preparation method according to claim 3, is characterized in that described organic solvent is one or more in acetone, butanone, diacetone alcohol, sym.-diisopropylideneacetone, isophorone, mesityl oxide, methyl iso-butyl ketone (MIBK), methyl phenyl ketone or cyclohexanone.
5. preparation method according to claim 3, is characterized in that described mixing speed is 200 ~ 250rpm.
6. preparation method according to claim 3, it is characterized in that the acetone by adding weightmeasurement ratio 25 ~ 30 times in raw material benzfluorenol first product, being stirred to the mixing speed of 200 ~ 250rpm at 60 ~ 70 DEG C dissolves completely, after backflow 15 ~ 30min, carry out suction filtration, carry out stirring and crystallizing after filtrate is concentrated into 1/10 ~ 1/5, collection solid dries 4 ~ 6h and obtains target compound at 55 ~ 65 DEG C; The mixing speed of described stirring and crystallizing is 200 ~ 250rpm.
7. preparation method according to claim 3, it is characterized in that the acetone by adding weightmeasurement ratio 25 ~ 30 times in raw material benzfluorenol first product, being stirred to the mixing speed of 200 ~ 250rpm at 60 ~ 70 DEG C dissolves completely, after backflow 15 ~ 30min, carry out suction filtration, add solvent stirring and crystallizing under the mixing speed of 200 ~ 250rpm of volume ratio 10 ~ 20 times in filtrate, collection solid dries 4 ~ 6h and obtains target compound at 55 ~ 65 DEG C; Described solvent is one or more in water, methyl alcohol, ethanol, butanols or propyl alcohol.
8. preparation method according to claim 3, it is characterized in that the acetone by adding weightmeasurement ratio 25 ~ 30 times in raw material benzfluorenol first product, butanone, diacetone alcohol, sym.-diisopropylideneacetone, isophorone, mesityl oxide, methyl iso-butyl ketone (MIBK), one in methyl phenyl ketone or cyclohexanone, add the glacial acetic acid of raw material weight volume ratio 1 ~ 5 times again, hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, one in perchloric acid or Periodic acid, being stirred to the mixing speed of 200 ~ 250rpm at 60 ~ 70 DEG C dissolves completely, after backflow 15 ~ 30min, carry out suction filtration, solvent stirring and crystallizing under the mixing speed of 200 ~ 250rpm of volume ratio 10 ~ 20 times is added in filtrate, collection solid dries 4 ~ 6h and obtains target compound at 55 ~ 65 DEG C, described solvent is one or more in water, methyl alcohol, ethanol, butanols or propyl alcohol.
9. preparation method according to claim 3, it is characterized in that the acetone by adding weightmeasurement ratio 25 ~ 30 times in raw material benzfluorenol first product, butanone, diacetone alcohol, sym.-diisopropylideneacetone, isophorone, mesityl oxide, methyl iso-butyl ketone (MIBK), one in methyl phenyl ketone or cyclohexanone, add the glacial acetic acid of raw material weight volume ratio 1 ~ 5 times again, hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, one in perchloric acid or Periodic acid, being stirred to the mixing speed of 200 ~ 250rpm at 60 ~ 70 DEG C dissolves completely, after backflow 15 ~ 30min, filter, filtrate adds alkali lye adjustment filtrate pH value to 6.5 ~ 7.5 of volume ratio 1 ~ 5 times after being cooled to 0 ~ 30 DEG C, add solvent stirring and crystallizing under the mixing speed of 200 ~ 250rpm of 10 ~ 20 times, collection solid dries 4 ~ 6h and obtains target compound at 55 ~ 65 DEG C, described solvent is one or more in water, methyl alcohol, ethanol, butanols or propyl alcohol, described alkali lye is one or more in sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium hydroxide, calcium hydroxide, ammoniacal liquor, sodium alkoxide, sodium hydrogen, diethylamine or triethylamine solution.
10. preparation method according to claim 3, it is characterized in that it will being the petroleum ether-ethyl acetate by adding weightmeasurement ratio 10 ~ 20 times in raw material benzfluorenol first product, dissolving is being stirred to completely with the mixing speed of 200 ~ 250rpm at 60 ~ 70 DEG C, after backflow 15 ~ 30min, carry out suction filtration, filtrate is stirring and crystallizing under the mixing speed of 100 ~ 150rpm, and collection solid dries 4 ~ 6h and obtains target compound at 55 ~ 65 DEG C.
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| 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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| CN103319356A (en) * | 2013-06-17 | 2013-09-25 | 张家港威胜生物医药有限公司 | One-step green synthesis process of antimalarial raw material benflumetol |
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| CN103319356A (en) * | 2013-06-17 | 2013-09-25 | 张家港威胜生物医药有限公司 | One-step green synthesis process of antimalarial raw material benflumetol |
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