CN108440498A - Halofuginone hydrobromide lactate crystal form and preparation method thereof - Google Patents
Halofuginone hydrobromide lactate crystal form and preparation method thereof Download PDFInfo
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- CN108440498A CN108440498A CN201810492141.8A CN201810492141A CN108440498A CN 108440498 A CN108440498 A CN 108440498A CN 201810492141 A CN201810492141 A CN 201810492141A CN 108440498 A CN108440498 A CN 108440498A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The invention discloses a kind of new crystal forms of halofuginone hydrobromide lactate, indicate that ray powder diffraction has characteristic peak at 14.5 ± 0.2 ° (6.1), 18.0 ± 0.2 ° (4.9), 20.4 ± 0.2 ° (4.4) and 25.5 ± 0.2 ° (3.5) with 2 θ angles and interplanar distance d values.Preparation method：One is dissolve by heating 5~50 times of solvent I of halofuginone hydrobromide lactate, heating temperature is 60~75 DEG C, it filters while hot, gradient cooling, crystallization, filtering, 35~50 DEG C are dried in vacuo 5~7 hours, and the solvent I is the mixed solvent of water either organic solvent or water and organic solvent 0~10 ﹕ 50 by volume；Another preparation method is to dissolve by heating 5~30 times of water of halofuginone hydrobromide lactate, gradient cooling, crystallization, filtering, and 35~50 DEG C are dried in vacuo 5~7 hours.The novel crystal forms stability is good, is suitble to large-scale production.
Description
Technical field
The invention belongs to pharmaceutical chemistry synthesis technical field, it is related to crystal form and its preparation side of a kind of halofuginone hydrobromide lactate
Method.
Background technology
The chemical name of halofuginone hydrobromide lactate (Halofuginone lactate) is the chloro- 3- of the bromo- 6- of 7- [3- (3- hydroxyls -2-
Piperidyl) -2- oxygen propyl groups (acetonyl)] -4 (3H)-quinazolinone lactates, chemical structural formula is：
Halofuginone hydrobromide (Halofuginone) also known as bromine chlorine halofuginone hydrobromide, halogen quinoline ketone, Halofuginone.It is a kind of from the medicinal plant in China
The quinazoline ketones alkaloid separated in object Changshan (Dichroa febrifuga) --- orixine (Febrifugine)
Halo derivatives.Halofuginone hydrobromide hydrobromate has strong insecticidal activity, has stronger inhibitory or killing effect to a variety of Eimeria species, can have
Effect 6 breeder Eimerias of control are mainly used for chicken/coccidiosis of rabbit prevention, and can treat babesia taylor disease.It can be apparent after medication
Globidiosis clinical symptoms are controlled, and completely inhibit egg capsule discharge, keep environment no longer contaminated, to reduce the possibility infected again
(refer to document J.Johnson et al.；Exp.Parasitol.,1970,28:30；J.Grant et al.；
Parasitology Research,1991,77:595).Halofuginone hydrobromide lactate is for coming into being caused by ox/sheep Cryptosporidiosis
Diarrhea.Have many advantages, such as broad-spectrum high efficacy, it is irreversible, be discontinued after without recurrence, without cross-resistance, small toxicity, it is safe.
With going deep into halofuginone hydrobromide drug effect and pharmacological research, Israel Agricultural Research in 1991
The researcher of Organization and Hadasit Medical Research＆Development has found hydrobromic acid antifebrile dichroanone
Fibroblast synthesis Type I collagen synthetic inhibitor can be specifically inhibited (to refer to literature G.Spira et al.；
J.Hepatol.2002,37:331).Hereafter the Collgard Biopharmaceutieals Inc. of Israel, in 1996
Using halofuginone hydrobromide as the seldom used medicine for the treatment of scleroderma, the approval for obtaining U.S. FDA carries out preclinical study, hereafter halofuginone hydrobromide is developed
As treatment anti-fibrosis new drugHalofuginone hydrobromide be alternatively arranged as drug for bladder, prostate, mammary gland,
The Therapy study of the cancers such as skin, lung and scar (refers to document 1.Z.Garish et al.；Prostate,2002,51:73；
2.T.A.Guise et al.；Cancer Research,2012,72:6247).
Relevant information is disclosed：United States Patent (USP) US3320124, US6028075, US6090814, US6420371；It is Chinese special
Sharp CN101987843, CN103275063, CN1651428.It is well known that solid chemical material can be divided into crystalline state, unformed
State and eutectic state form, without the open report in relation to halofuginone hydrobromide lactate crystal form in existing literature.
The research of polymorph in pharmaceuticals is for the safety in the stability and Clinical practice during ensureing pharmaceutical production storage
Validity has extremely important meaning.And the polymorphic of drug is related with the structure of drug molecule, while being crystallized with when preparing
Method is related.
Invention content
It is an object of the invention to be directed to the above technical problem, a kind of crystal form for the halofuginone hydrobromide lactate that stability is good is provided
And preparation method thereof.
Technical scheme is as follows：
The object of the present invention is to provide a kind of new crystal habits (crystal form) of halofuginone hydrobromide lactate, with 2 θ angles and crystal face
Spacing (d values) indicate X-ray powder diffraction 14.5 ± 0.2 ° (6.1), 18.0 ± 0.2 ° (4.9), 20.4 ± 0.2 °
(4.4) and at 25.5 ± 0.2 ° (3.5) there is characteristic peak.
The crystal form of halofuginone hydrobromide lactate, the X-ray powder diffraction indicated with 2 θ angles and interplanar distance (d values) 8.9 ±
0.2°(9.8)、11.1±0.2°(7.9)、13.1±0.2°(6.7)、14.5±0.2°(6.1)、18.0±0.2°(4.9)、
There is characteristic peak at 20.4 ± 0.2 ° (4.4), 23.4 ± 0.2 ° (3.8) and 25.5 ± 0.2 ° (3.5).
The infrared absorption pattern of the halofuginone hydrobromide lactate of the crystal form 3280,3062,2956,1742,1684,1633,
1447,1381 and 1272cm-1There is characteristic absorption peak at place.
Thermogravimetric analysis-differential thermal analysis testing result shows halofuginone hydrobromide lactate novel crystal forms at 20~177 DEG C substantially without mistake
Weight is free of free water and solvent, there is sharp absorption peak at 182 ± 1 DEG C；177~210 DEG C of weightlessness about 11.99%, 210~
300 DEG C of weightlessness about 20.85%.
It is a further object of the present invention to provide the methods for the crystal form for preparing halofuginone hydrobromide lactate：
A kind of preparation method of halofuginone hydrobromide lactate crystal form, by halofuginone hydrobromide lactate, (5~50 times refer to 5~50 times
The mass ratio of solvent I volumes and halofuginone hydrobromide lactate) solvent I heating for dissolving, heating temperature is 60~75 DEG C, gradient cooling, analysis
Crystalline substance, filtering, 35~50 DEG C are dried in vacuo 5~7 hours, and the solvent I is water either organic solvent or water and organic solvent
The mixed solvent of 0~10 ﹕ 50 by volume：The organic solvent is methanol, ethyl alcohol, propyl alcohol, isopropanol, propylene glycol, butanol, different
One kind in butanol, butanediol, dimethyl sulfoxide, acetonitrile, n,N-Dimethylformamide, tetrahydrofuran, acetone and dioxane or
The a variety of mixtures of person.
The present invention also provides the preparation method of another halofuginone hydrobromide lactate crystal form, by halofuginone hydrobromide lactate with 5~30
Times water dissolves by heating, and organic solvent to halofuginone hydrobromide lactic acid salt crystal is slowly added dropwise and is just precipitated, gradient cooling, crystallization, filtering, and 35
~50 DEG C are dried in vacuo 5~7 hours, or are not added with organic solvent and 35~50 DEG C of vacuum directly after gradient cooling, crystallization, filtering
Dry 5~7 hours, the organic solvent be methanol, ethyl alcohol, propyl alcohol, isopropanol, propylene glycol, butanol, isobutanol, butanediol,
Any one in dimethyl sulfoxide, acetonitrile, n,N-Dimethylformamide, tetrahydrofuran, acetone and dioxane.
The beneficial effects of the invention are as follows：The present invention provides a kind of novel crystal forms of halofuginone hydrobromide lactate and preparation method thereof,
It can be distinguished by X-ray diffraction spectra, infrared spectrum and other methods such as thermogravimetric analysis-differential thermal analysis (TG-DTA).This
The halofuginone hydrobromide lactate of the crystal habit (crystal form) of invention is compared with amorphous state and the halofuginone hydrobromide lactate of other forms, tool
There is the advantages that stability is good, and suitable large-scale production is conducive to the operation in production process, and product quality is controllable.
Description of the drawings
Fig. 1 is the X-ray powder diffraction collection (P-XRD figures) of halofuginone hydrobromide lactate novel crystal forms.
Fig. 2 is the X-ray powder diffraction collection result of halofuginone hydrobromide lactate novel crystal forms.
Fig. 3 is the infrared absorption spectrum (FT-IR figures) of halofuginone hydrobromide lactate novel crystal forms.
Fig. 4 is halofuginone hydrobromide lactate thermogravimetric analysis-differential thermal analysis measurement chart (TG-DTA figures).
Specific implementation mode
Embodiment 1 prepares halofuginone hydrobromide lactate novel crystal forms
One, sample 1 is prepared：10 grams of halofuginone hydrobromide lactates are added in 500ml flasks, 150ml ethyl alcohol and 50ml water is added,
It is heated to 65~70 DEG C to be allowed to dissolve, gradient cooling, is cooled to 0 DEG C of crystallization, stands overnight, filter, ethyl alcohol washing, 40 DEG C of vacuum
Dry 5 hours to get halofuginone hydrobromide lactate novel crystal forms.
Two, sample 2 is prepared：10 grams of halofuginone hydrobromide lactates are added in 500ml flasks, 200ml acetonitriles and 100ml is added
Water is heated to 70~75 DEG C and is allowed to dissolve.Gradient cooling is cooled to 0 DEG C of crystallization, stands overnight, filtering, acetonitrile washing, 50 DEG C
7 hours are dried in vacuo to get halofuginone hydrobromide lactate novel crystal forms.
Three, sample 3 is prepared：10 grams of halofuginone hydrobromide lactates are added in 500ml flasks, 100mlN, N- dimethyl methyls is added
Amide, 50ml ethyl alcohol and 50ml water are heated to 60~65 DEG C and are allowed to dissolve.Gradient cooling is cooled to 0 DEG C of crystallization, stands overnight,
Filtering, ethyl alcohol washing, 40 DEG C are dried in vacuo 6 hours to get halofuginone hydrobromide lactate novel crystal forms.
Four, sample 4 is prepared：10 grams of halofuginone hydrobromide lactates are added in 100ml flasks, 50ml water is added, it is heated to 70~
75 DEG C are allowed to dissolve.Gradient cooling is cooled to 0 DEG C of crystallization, stands overnight, filtering, water washing, 35 DEG C be dried in vacuo 6 hours, i.e.,
Obtain halofuginone hydrobromide lactate novel crystal forms.
Five, sample 5 is prepared：10 grams of halofuginone hydrobromide lactates are added in 1000ml flasks, 500ml water is added, is heated to 70
~75 DEG C are allowed to dissolve.Gradient cooling is cooled to 0 DEG C of crystallization, stands overnight, filtering, water washing, 50 DEG C of dryings 6.5 hours, i.e.,
Obtain halofuginone hydrobromide lactate novel crystal forms.
Six, sample 6 is prepared：In 500ml flasks be added 10 grams of halofuginone hydrobromide lactates, be added 200ml tetrahydrofurans and
50ml water is heated to 60~65 DEG C and is allowed to dissolve.Gradient cooling is cooled to 0 DEG C of crystallization, stands overnight, and filtering, tetrahydrofuran is washed
It washs, 50 DEG C are dried in vacuo 5 hours to get halofuginone hydrobromide lactate novel crystal forms.
Seven, sample 7 is prepared：In 500ml flasks be added 10 grams of halofuginone hydrobromide lactates, be added 100ml dimethyl sulfoxides and
20ml water is heated to 60~65 DEG C and is allowed to dissolve.Gradient cooling is cooled to 0 DEG C of crystallization, stands overnight, and filtering, dimethyl sulfoxide is washed
It washs, 40 DEG C are dried in vacuo 6 hours to get halofuginone hydrobromide lactate novel crystal forms.
Eight, sample 8 is prepared：In 1000ml flasks be added 10 grams of halofuginone hydrobromide lactates, be added 250ml butanediols and
250ml ethyl alcohol is heated to 60~65 DEG C and is allowed to dissolve.Gradient cooling is cooled to 0 DEG C of crystallization, stands overnight, and filtering, ethyl alcohol is washed
It washs, 40 DEG C are dried in vacuo 7 hours, i.e. halofuginone hydrobromide lactate novel crystal forms.
Nine, sample 9 is prepared：10 grams of halofuginone hydrobromide lactates are added in 500ml flasks, 200ml butanol and 100ml bis- is added
Six ring of oxygen is heated to 70~75 DEG C DEG C and is allowed to dissolve.Gradient cooling is cooled to 0 DEG C of crystallization, stands overnight, and filtering, butanol is washed
It washs, 50 DEG C are dried in vacuo 5 hours, i.e. halofuginone hydrobromide lactate novel crystal forms.
Ten, sample 10 is prepared：10 grams of halofuginone hydrobromide lactates are added in 250ml flasks, 50ml dimethyl sulfoxides, heating is added
It is allowed to dissolve to 70~75 DEG C DEG C.Gradient cooling is cooled to 0 DEG C of crystallization, stands overnight, filtering, and dimethyl sulfoxide washing, 35 DEG C true
Sky is 6 hours dry, i.e. halofuginone hydrobromide lactate novel crystal forms.
Applicant changes the organic solvent that the present embodiment uses into methanol, propyl alcohol, isopropanol, propylene glycol, acetone and isobutyl
Any one or more of alcohol has also all been prepared the halofuginone hydrobromide lactate novel crystal forms as the present embodiment, has been penetrated through powder X-ray
Line diffractometer, infrared spectrometer, thermogravimetric analysis-differential thermal analysis detection, using the present embodiment method and aforementioned organic solvents system
The crystal form of standby obtained halofuginone hydrobromide lactate is identical.
Embodiment 2 prepares halofuginone hydrobromide lactate novel crystal forms
One, sample 11 is prepared：10 grams of halofuginone hydrobromide lactates are added in 500ml flasks, be added 100ml water be heated to 50~
55 DEG C are allowed to dissolve, and 200ml isopropanols are slowly added dropwise, and solution just becomes muddy, and gradient cooling, crystallization are stood overnight, and are filtered,
Isopropanol washs, and 40 DEG C are dried in vacuo 6 hours to get halofuginone hydrobromide lactate novel crystal forms.
Two, sample 12 is prepared：10 grams of halofuginone hydrobromide lactates are added in 250ml flasks, be added 50ml water be heated to 50~
55 DEG C are allowed to dissolve, and gradient cooling, crystallization are stood overnight, filtering, the washing of a small amount of cold water, 35 DEG C of vacuum drying 7 hours to get
Halofuginone hydrobromide lactate novel crystal forms.
Three, sample 13 is prepared：10 grams of halofuginone hydrobromide lactates are added in 500ml flasks, be added 300ml water be heated to 50~
55 DEG C are allowed to dissolve, and propylene glycol to halofuginone hydrobromide lactic acid salt crystal is slowly added dropwise and is just precipitated, and gradient cooling, crystallization are stood overnight,
Filtering, propylene glycol washing, 50 DEG C are dried in vacuo 5 hours to get halofuginone hydrobromide lactate novel crystal forms.
Four, sample 14 is prepared：10 grams of halofuginone hydrobromide lactates are added in 500ml flasks, be added 100ml water be heated to 50~
55 DEG C are allowed to dissolve, and acetonitrile to halofuginone hydrobromide lactic acid salt crystal is slowly added dropwise and is just precipitated, gradient cooling, crystallization are stood overnight, mistake
Filter, acetonitrile washing, 40 DEG C are dried in vacuo 6 hours to get halofuginone hydrobromide lactate novel crystal forms.
Five, sample 15 is prepared：10 grams of halofuginone hydrobromide lactates are added in 500ml flasks, be added 200ml water be heated to 50~
55 DEG C are allowed to dissolve, and acetone to halofuginone hydrobromide lactic acid salt crystal is slowly added dropwise and is just precipitated, gradient cooling, crystallization are stood overnight, mistake
Filter, acetone washing, 40 DEG C are dried in vacuo 6 hours to get halofuginone hydrobromide lactate novel crystal forms.
Applicant by the organic solvent that the present embodiment uses change into methanol, ethyl alcohol, propyl alcohol, butanol, isobutanol, butanediol,
Any one in dimethyl sulfoxide, n,N-Dimethylformamide, tetrahydrofuran and dioxane, has also all been prepared and this reality
The halofuginone hydrobromide lactate novel crystal forms as example are applied, through powder x-ray diffraction, infrared spectrometer, thermogravimetric analysis-differential thermal analysis
The crystal form of detection, the halofuginone hydrobromide lactate being prepared using the present embodiment method and aforementioned organic solvents is identical.
Analysis detection
By all samples powder x-ray diffraction made from embodiment 1 and embodiment 2, infrared spectrometer, thermogravimetric point
Analysis-differential thermal analysis is detected respectively.Used analytical instrument and testing conditions are：
Powder x-ray diffraction (Japan Shimadzu, XRD-6000), condition：Cu-Ka, 40KV, 30mA.
Infrared spectrometer (380 FT-IR spectrophotometer of Thermo Fisher Nicolet), condition：
KBr tablettings.
Thermogravimetric analysis-differential thermal analysis (Japan Shimadzu, DTG-60H), condition：10 DEG C/min of heating rate is surveyed
30~300 DEG C of amount temperature range；Nitrogen atmosphere.
The crystal form of all samples is identical after testing, and testing result is as shown in figures 1-4.
As shown in Figure 1, 2, crystal form of the invention is radiated using Cu-Ka, the X- indicated with 2 θ angles and interplanar distance (d values)
Ray powder diffraction about 8.9 ± 0.2 ° (9.8), 11.1 ± 0.2 ° (7.9), 13.1 ± 0.2 ° (6.7), 14.5 ± 0.2 °
(6.1), 18.0 ± 0.2 ° (4.9), 20.4 ± 0.2 ° (4.4), 23.4 ± 0.2 ° (3.8) and 25.5 ± 0.2 ° (3.5) have feature
Peak.
As shown in figure 3, the crystal form of the present invention is through infrared spectrum analysis (IR), infrared absorption pattern 3280,3062,
2956,1742,1684,1633,1447,1381 and 1272 (cm-1) at have characteristic absorption peak.
As shown in figure 4, the present invention crystal form through thermogravimetric analysis-differential thermal analysis (TG-DTA), testing result show its
20~177 DEG C, substantially without weightlessness, there is sharp absorption peak at 182 ± 1 DEG C；177~210 DEG C of weightlessness 11.99%, 210~300
DEG C weightlessness 20.85%.As a result it shows and is free of free water and solvent in halofuginone hydrobromide lactate novel crystal forms.
4 halofuginone hydrobromide lactate novel crystal forms study on the stability of embodiment is tested
The sample 3 for taking aforementioned preparation takes in right amount loaded in plate, is respectively placed in following conditions (4500lx ± 500lx light
According to, 45 DEG C of high temperature, 92.5% high humility of relative humidity) under investigate its stability of crystal form, 3 repetitions are done in each experiment, measure knot
Fruit is as shown in table 1-3.
Result is investigated in 1 strong illumination stability test of table
2 hot test study on the stability result (45 ± 2 DEG C) of table
3 high humidity test study on the stability result (RH90 ± 5%) of table
Above-mentioned table 1,2,3 the result shows that, crystal form of the invention is through under strong illumination, high temperature, super-humid conditions, in relation to object
Matter has almost no change, while observing its crystal form appearance, and crystalline and color does not also change, and shows halofuginone hydrobromide prepared by the present invention
Lactate novel crystal forms have good stability of crystal form, easy to manufacture, transport and storage.
Applicant does the halofuginone hydrobromide lactate of the novel crystal forms of the present invention and unformed halofuginone hydrobromide lactate further
Contrast experiment preserves sample 1 year or more, the results showed that, novel crystal forms halofuginone hydrobromide lactate of the invention is kept under normal temperature condition
Crystal form does not change substantially within 1 year or more, and quality hardly changes, and product content does not reduce substantially, and purity remains at 99.5%
More than, major impurity cis-isomer is maintained at 0.1%~0.3%, complies fully with the quality requirement of drug.Unformed Changshan
Ketone lactic acid salt-stable is bad, is kept for 1 year or more under normal temperature condition, and major impurity cis-isomer is increased by 0.2% or so
To 2.0% or more, product purity is reduced to 98.0% hereinafter, show unformed halofuginone hydrobromide lactate unstable quality, is not inconsistent
The quality requirement of composite medicine is also not suitable for production, transport and storage.
Claims (6)
1. a kind of halofuginone hydrobromide lactate crystal form, it is characterised in that：The X-ray powder indicated with 2 θ angles and interplanar distance (d values)
Diffraction has spy at 14.5 ± 0.2 ° (6.1), 18.0 ± 0.2 ° (4.9), 20.4 ± 0.2 ° (4.4) and 25.5 ± 0.2 ° (3.5)
Levy peak.
2. halofuginone hydrobromide lactate crystal form as described in claim 1, it is characterised in that：With 2 θ angles and interplanar distance (d values) table
The X-ray powder diffraction shown 8.9 ± 0.2 ° (9.8), 11.1 ± 0.2 ° (7.9), 13.1 ± 0.2 ° (6.7), 14.5 ± 0.2 °
(6.1), there is spy at 18.0 ± 0.2 ° (4.9), 20.4 ± 0.2 ° (4.4), 23.4 ± 0.2 ° (3.8) and 25.5 ± 0.2 ° (3.5)
Levy peak.
3. halofuginone hydrobromide lactate crystal form as described in claim 1, it is characterised in that：Infrared absorption pattern 3280,3062,
2956,1742,1684,1633,1447,1381 and 1272cm-1There is characteristic absorption peak at place.
4. halofuginone hydrobromide lactate crystal form as described in claim 1, it is characterised in that：Thermogravimetric analysis-differential thermal analysis detection knot
Fruit shows that halofuginone hydrobromide lactate novel crystal forms, substantially without weightlessness, are free of free water and solvent, have at 182 ± 1 DEG C at 20~177 DEG C
Sharp absorption peak.
5. a kind of preparation method of Claims 1-4 any one of them halofuginone hydrobromide lactate crystal form, it is characterised in that：It will be normal
Mountain ketone lactate is dissolved by heating with 5~50 times of solvent I, and heating temperature is 60~75 DEG C, gradient cooling, crystallization, filtering, and 35~50
DEG C vacuum drying 5~7 hours, the solvent I are water either organic solvent or water and organic solvent 0~10 ﹕ by volume
50 mixed solvent：The organic solvent is methanol, ethyl alcohol, propyl alcohol, isopropanol, propylene glycol, butanol, isobutanol, butanediol, two
One or more of first sulfoxide, acetonitrile, n,N-Dimethylformamide, tetrahydrofuran, acetone and dioxane mixture.
6. a kind of preparation method of Claims 1-4 any one of them halofuginone hydrobromide lactate crystal form, it is characterised in that：It will be normal
Mountain ketone lactate is dissolved by heating with 5~30 times of water, and organic solvent to halofuginone hydrobromide lactic acid salt crystal is slowly added dropwise and is just precipitated, gradient
Cooling, crystallization, filtering, 35~50 DEG C are dried in vacuo 5~7 hours, or be not added with organic solvent and directly gradient cooling, crystallization,
After filtering 35~50 DEG C be dried in vacuo 5~7 hours, the organic solvent be methanol, ethyl alcohol, propyl alcohol, isopropanol, propylene glycol,
In butanol, isobutanol, butanediol, dimethyl sulfoxide, acetonitrile, n,N-Dimethylformamide, tetrahydrofuran, acetone and dioxane
Any one.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3035567A1 (en) * | 1979-08-23 | 1982-05-06 | Hoechst Ag, 6000 Frankfurt | Agents against theileriosis e.g. in the form of drench - contg. 3-piperidinyl-acetonyl-quinazolin-4(3H)-one deriv. in form of its lactate, acetate or aceturate salt |
| CN101987843A (en) * | 2010-08-20 | 2011-03-23 | 南开大学 | Method for synthesizing halofuginone hydrobromide and analogues thereof |
-
2018
- 2018-05-22 CN CN201810492141.8A patent/CN108440498A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3035567A1 (en) * | 1979-08-23 | 1982-05-06 | Hoechst Ag, 6000 Frankfurt | Agents against theileriosis e.g. in the form of drench - contg. 3-piperidinyl-acetonyl-quinazolin-4(3H)-one deriv. in form of its lactate, acetate or aceturate salt |
| CN101987843A (en) * | 2010-08-20 | 2011-03-23 | 南开大学 | Method for synthesizing halofuginone hydrobromide and analogues thereof |
Non-Patent Citations (1)
| Title |
|---|
| MICHAEL R. LINDER ET AL.: "(2R,3S)-(+)- and (2S,3R)-(-)-Halofuginone lactate: Synthesis, absolute configuration, and activity against Cryptosporidium parvum", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
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Application publication date: 20180824 |