CN106565699B - A kind of Chinese mugwort Saperconazole vitriol and preparation method thereof - Google Patents
A kind of Chinese mugwort Saperconazole vitriol and preparation method thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract
The present invention relates to a kind of Chinese mugwort Saperconazole vitriol form and preparation method thereof and pharmaceutical compositions.The stable crystal form, purity is high, favorable reproducibility, suitable for preparing medicine preparation；The preparation method is that first Chinese mugwort Saperconazole hydrochloride alkali dissociates at low temperature, then carries out salt exchange using the concentrated sulfuric acid and hydrogen peroxide, is recrystallized later.This method reaction condition is mild, and product postprocessing is simple, with high purity, meets the basic demand of industry's enlarging production.
Description
Technical field
The invention belongs to pharmaceutical chemistry crystallization technique fields, in particular it relates to a kind of antifungal drug Ai Sha
Health azoles sulfate crystalline forms and preparation method thereof.
Background technique
Chinese mugwort Saperconazole (Isavuconazole, CAS 241479-67-4) is by Ba Sai Leah pharmaceutcal corporation, Ltd, Switzerland
The antifungal drug developed jointly with Japanese Astellas, water-soluble prodrug is sulfate, and chemical structural formula is as follows
It is shown:
Chinese mugwort Saperconazole has the following characteristics that compared with other similar drugs as a kind of New-type wide-spectrum triazole type medicine
(1) patent medicine ingredient is water-soluble prodrug, be can be developed into as oral and intravenously administrable, and cyclodextrin, nothing are not contained in intravenous formulations
The potential nephrotoxic risks of auxiliary material；(2) bioavilability is high, and two kinds of administration routes can facilitate conversion.It is true with treatment system
The excellent pharmacokinetic characteristics of bacterium medicine: clearance rate is low, long half time, volume of distribution are big.Load is also needed when use
Dosage, but support medicining mode one time a day, and do not influenced by feed.Drug interaction is less than voriconazole；(3) external
Antibacterial tests show that Chinese mugwort Saperconazole is better than the activity of the saccharomycete such as candida albicans, Aspergillus, mucor, cryptococcus or is not inferior to it
His most of antifungal, it is mould less sensitive to sickle-like bacteria and dark-coloured silk spore.In addition, Chinese mugwort Saperconazole has obtained the multinomial qualification of FDA
Identification, medicine generation and pharmacodynamics feature are supported very potential as studies of invasive fungal infections fiest-tire medication after listing.U.S. FDA at present
For the Chinese mugwort Saperconazole of approval there are two types of administration route, respectively capsule preparations and ejection preparation, principal component is Chinese mugwort Saperconazole sulfuric acid
Salt.
The synthetic method and antimycotic purposes of Chinese mugwort Saperconazole and its a variety of salt are made public for the first time in patent WO0132652,
But it is not directed to its sulphate form and its preparation and crystal form problem, at present the domestic relevant report about Chinese mugwort Saperconazole sulfate
Also less, knowledge more has no relevant report in terms of crystal form.
Such as there may be different crystalline forms for Chinese mugwort Saperconazole sulfate for a kind of drug, and the crystal form of same drug is to drug
The quality of physicochemical property, bioavilability and pharmaceutical preparation has great influence.Same drug crystal forms are different, the stabilization of preparation
All there is larger difference in property, water solubility, dissolution rate, storage stability, preparation easiness etc., also seriously affect the activity of drug.
It is a kind of when being considered key in terms of the easiness, stability, water solubility and the excellent pharmacokinetics that such as prepare in some aspects
Crystal form may be better than another crystal form.Therefore need to obtain purity is high, stability height, with the Ai Sha for determining crystal form
Health azoles vitriol form, it is also desirable to study a kind of work of preparation Chinese mugwort Saperconazole sulfate crystal form inexpensive, industry is friendly
Skill.
Summary of the invention
That the object of the present invention is to provide a kind of stability is good, is suitable for preparing the Chinese mugwort Saperconazole sulfate of stabilised pharmaceutical preparation
Crystal and preparation method thereof.
Specifically, the present invention provides:
A kind of crystal form for the Saperconazole sulfate that ends, it is characterised in that the X-ray powder diffraction figure of the crystal is following
At 2 θ of the angle of diffraction have characteristic peak: 6.399 ± 0.2 °, 11.198 ± 0.2 °, 12.933 ± 0.2 °, 15.170 ± 0.2 °,
18.947±0.2°。
Further, the X-ray powder diffraction figure of the Chinese mugwort Saperconazole vitriol has at following 2 θ of the angle of diffraction
Characteristic peak and its relative intensity:
Without limitation, an exemplary embodiments of Chinese mugwort Saperconazole vitriol form of the present invention have as schemed
X-ray diffracting spectrum shown in 1.
Chinese mugwort Saperconazole vitriol form of the present invention has in 3440.91cm-1、2226.89cm-1、
1752.95cm-1、1725.03cm-1、1631.69cm-1、1607.99cm-1、1577.54cm-1、1528.05cm-1、
1487.89cm-1、1448.70cm-1、1383.6cm-1、1131.18cm-1、1111.86cm-1、765.02cm-1、618.75cm-1Wave
Number includes the infrared spectroscopy of absorption band.
Further, the present invention provides the preparation method of the Chinese mugwort Saperconazole vitriol form.
The specific synthetic route of preparation method of the Chinese mugwort Saperconazole vitriol form is as follows:
Specific reaction step are as follows:
Step 1: the Saperconazole hydrochloride that will end is soluble in water, pH is adjusted to neutrality with alkali under low temperature, organic solvent A is added
Extraction is dissolved in organic solvent B after dry concentration, the concentrated sulfuric acid and hydrogen peroxide is added under low temperature, stirs, concentration；
Step 2: above-mentioned concentrate is added in organic solvent C, dissolve by heating, stirs cooling crystallization.
Low temperature described in preparation method first step reaction of the present invention is -20~5 DEG C, preferably -5~0 DEG C；The alkali
Selected from sodium bicarbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, ammonium hydroxide, triethylamine, diethylamine or N, N- diisopropylethylamine；Have
Solvent A is selected from or mixtures thereof methylene chloride, ethyl acetate, acetonitrile, ether, methyl tertiary butyl ether(MTBE)；Organic solvent B is selected from first
Or mixtures thereof alcohol, ethyl alcohol, tetrahydrofuran, glycol monoethyl ether, acetone；The Chinese mugwort Saperconazole hydrochloride, the concentrated sulfuric acid and dioxygen
The molar ratio of water is 1:1.0~2.0:1.0~2.0, preferably 1:1.0~1.3:1.1~1.3.
In preparation method second step of the present invention reaction organic solvent C be selected from methanol, ethyl alcohol, isopropanol, n-butanol,
Or mixtures thereof tetrahydrofuran, ethyl acetate, methylene chloride, acetone, preferred alcohol and ethyl acetate mixture；The ethyl alcohol and
The volume ratio of ethyl acetate is 1:1~20, preferably 1:1~4；The cooling temperature is 10~20 DEG C.
In the above-mentioned preparation method of the present invention, starting material ends Saperconazole hydrochloride can be real according to patent document WO0132652
The preparation of method disclosed in example 7 is applied, this asks down that mode by reference of text is incorporated into the application.
The invention further relates to pharmaceutical compositions, and it includes the above-mentioned Chinese mugwort Saperconazole vitriol shapes as active constituent
Formula, pharmaceutically acceptable carrier or diluent.In pharmaceutical composition according to the present invention, more specifically it is suitable for oral system
The pharmaceutically acceptable injectable formulation such as agent or small needle, freeze-dried powder.
Chinese mugwort Saperconazole sulfate Pharmaceutical composition of the invention can be used for treating disease caused by aspergillosis and mucormycosis
Disease.
The beneficial effects of the present invention are providing a kind of Chinese mugwort Saperconazole vitriol form, stable crystal form, purity is high,
Favorable reproducibility, suitable for preparing medicine preparation.By intense light conditions and 2-8 DEG C of placement test it is found that present invention Chinese mugwort Saperconazole sulphur
Hydrochlorate crystal form purity variation it is smaller, it is with good stability, be conducive to unit formulation preparation in accurate quantitative analysis and
The transport and storage in later period, are conducive to the stability of preparation.
The present invention also provides a kind of method of environmentally protective preparation Chinese mugwort Saperconazole sulfate, synthetic reaction steps simultaneously
Rapid novel, mild condition, does not need high temperature；Solvent used in reaction process is Conventional solvents, and environmental pollution is small, cost
It is low；Product postprocessing is simple, with high purity, is easy to apply in actual production, meets the requirement of industry's enlarging production.
Chinese mugwort Saperconazole sulfate of the invention be it is pure, single, do not mix any other crystal form or unformed substantially
Object.In the present invention, " not having substantially " refers to other crystal forms or amorphous article contained in this novel crystal forms when being used to refer to novel crystal forms
Less than 20% (weight), more refer to less than 10% (weight), be especially less than 5% (weight), particularly relates to less than 1% (weight).
In the present invention, " crystal " refers to what the characterization of the X ray diffracting spectrum by shown in was confirmed.Those skilled in the art
It is understood that experimental error therein depends on condition, the preparation of sample and the purity of sample of instrument.In particular, this field
Known in technical staff, X-ray diffractogram would generally be changed with the condition of instrument.In particular, it should be pointed out that X-ray
The relative intensity of diffraction pattern may also change with the variation of experiment condition, thus the sequence of peak intensity cannot function as it is unique or
Deciding factor.In addition, the experimental error of peak angle degree is usually 5% or less, the error of these angles should also be considered into
It goes, allows generally for ± 0.2 ° of error.In addition, will cause the whole of peak angle degree due to the influence of the empirical factors such as height of specimen
Solid offsetting allows generally for certain offset.Thus, it will be appreciated by persons skilled in the art that any have and present invention figure
The same or similar crystal form in spectrum signature peak belongs in scope." single crystal form " refers to through X-ray powder diffraction
Detection is single crystal form.
Detailed description of the invention
The X ray diffracting spectrum of Fig. 1 Chinese mugwort Saperconazole vitriol form；
The infrared spectroscopy map of Fig. 2 Chinese mugwort Saperconazole vitriol form；
Specific embodiment
The present invention is limited with further reference to following embodiment, the embodiment detailed description of the present invention crystal form, its preparation
Methods and applications.It will be apparent for a person skilled in the art that can not taken off for many changes of both material and method
Implement in the case where from the scope of the invention.
Detecting instrument and method:
Instrument used in X-ray powder diffraction (XPRD) is combined multifunctional horizontal X-x ray diffractometer x Ultima
IV is configured with 3KW x-ray generator, horizontal angular instrument, high speed detector D/teX Ultra.Instrument uses instrument before use
Included standard items (generally corundum) calibration.Unless stated otherwise, sample is not ground before detection.
Instrument used in infrared spectroscopy (IR) map are as follows: VERTEX80
Thermogravimetric analysis (TGA) data are picked up from Pyris Diamond DSC differential thermal analyzer.Usually take 5~15mg sample
It is placed in platinum crucible, by the way of being segmented high resolution detection, with the heating rate N of 10 DEG C/min2By sample under protection
Heating, while recording weight change of the sample in temperature-rise period.
The synthetic route of Chinese mugwort Saperconazole sulfate according to the present invention are as follows:
The preparation of the Chinese mugwort Saperconazole vitriol form of embodiment 1
Chinese mugwort Saperconazole hydrochloride 0.9g (1mmol) is dissolved in 9mL water, 0 DEG C is cooled to, is adjusted with sodium bicarbonate aqueous solution
The extraction of 9mL methylene chloride is added in pH to 7, after liquid separation after dry concentration, the dissolution of 10mL methanol is added, cools to -5 DEG C, drips respectively
Enter the hydrogen peroxide of 0.09g (1mmol) concentrated sulfuric acid and 0.11g (1mmol) 30%, stir 30min, 95% second of 5mL is added in concentration
Pure and mild 5mL re-crystallizing in ethyl acetate is heated to 40 DEG C of dissolutions, and stirring is cooled to 20 DEG C, and crystallization filters, is dried in vacuo to obtain 0.62g
White solid, yield 76%, purity 97.6%, XRPD map are as shown in Figure 1.
The preparation of the Chinese mugwort Saperconazole vitriol form of embodiment 2
Chinese mugwort Saperconazole hydrochloride 0.9g (1mmol) is dissolved in 9mL water, is cooled to -5 DEG C, adjusts pH to 7 with ammonium hydroxide liquid,
The extraction of 9mL methylene chloride is added, after liquid separation after dry concentration, the dissolution of 10mL methanol is added, cools to -5 DEG C, is respectively dropped into
The hydrogen peroxide of 0.12g (1.2mmol) concentrated sulfuric acid and 0.15g (1.3mmol) 30%, stirs 30min, and 5mL 95% is added in concentration
Ethyl alcohol and 10mL re-crystallizing in ethyl acetate are heated to 40 DEG C of dissolutions, and stirring is cooled to 10 DEG C, and crystallization is filtered, is dried in vacuo
0.55g white solid, yield 67%, purity 97.4%.
The preparation of the Chinese mugwort Saperconazole vitriol form of embodiment 3
Chinese mugwort Saperconazole hydrochloride 0.9g (1mmol) is dissolved in 9mL water, -3 DEG C is cooled to, is adjusted with aqueous sodium carbonate
The extraction of 9mL methylene chloride is added in pH to 7, after liquid separation after dry concentration, the dissolution of 10mL ethyl alcohol is added, cools to -5 DEG C, drips respectively
Enter the hydrogen peroxide of 0.13g (1.3mmol) concentrated sulfuric acid and 0.12g (1.1mmol) 30%, stir 30min, 5mL is added in concentration
95% ethyl alcohol and 20mL re-crystallizing in ethyl acetate are heated to 40 DEG C of dissolutions, and stirring is cooled to 20 DEG C, and crystallization filters, vacuum drying
Obtain 0.50g white solid, yield 62%, purity 97.7%.
The preparation of the Chinese mugwort Saperconazole vitriol form of embodiment 4
Chinese mugwort Saperconazole hydrochloride 0.9g (1mmol) is dissolved in 9mL water, 5 DEG C is cooled to, is adjusted with sodium bicarbonate aqueous solution
The extraction of 9mL ethyl acetate is added in pH to 7, after liquid separation after dry concentration, the dissolution of 10mL methanol is added, cools to -0 DEG C, drips respectively
Enter the hydrogen peroxide of 0.18g (2mmol) concentrated sulfuric acid and 0.22g (2mmol) 30%, stir 30min, concentration, be added 5mL normal propyl alcohol and
5mL re-crystallizing in ethyl acetate is heated to 40 DEG C of dissolutions, and stirring is cooled to 20 DEG C, and crystallization filters, and is dried in vacuo to obtain 0.41g white
Solid, yield 50%, purity 97.4%.
The preparation of the Chinese mugwort Saperconazole vitriol form of embodiment 5
Chinese mugwort Saperconazole hydrochloride 0.9g (1mmol) is dissolved in 9mL water, 5 DEG C is cooled to, is adjusted with sodium bicarbonate aqueous solution
The extraction of 9mL ethyl acetate is added in pH to 7, after liquid separation after dry concentration, the dissolution of 10mL ethyl alcohol is added, cools to -0 DEG C, drips respectively
Enter the hydrogen peroxide of 0.13g (1.3mmol) concentrated sulfuric acid and 0.12g (1.1mmol) 30%, stir 30min, 5mL methanol is added in concentration
With 5mL re-crystallizing in ethyl acetate, be heated to 40 DEG C of dissolutions, stirring is cooled to 20 DEG C, and crystallization filters, be dried in vacuo 0.45g is white
Color solid, yield 55%, purity 97.4%.
Embodiment 2~5 prepare sample have with the same or similar XRPD map of 1 sample of embodiment, illustrate embodiment 2
~5 samples and 1 sample of embodiment are identical crystal forms.
6 injection of embodiment Chinese mugwort Saperconazole sulfate pharmaceutical composition
Preparation method: weighing Chinese mugwort Saperconazole sulfate, the mannitol of recipe quantity, and water for injection dissolution is added；It takes appropriate dense
Sulfuric acid dilutes the concentrated sulfuric acid with ultrapure water, is added in lysate after its cooling and adjusts 1.0 or less pH to；Add water for injection constant volume；
Solution through aseptic filtration, packing, freeze-drying to get.
The stability of effect example Chinese mugwort Saperconazole vitriol form
1. differential scanning calorimetery (DSC) is tested
Instrument: 204 type differential thermal analyzer of NETZSC H DSC；
Heating rate: 10 DEG C/min；
DSC peak temperature: 150.21 DEG C.
The results show that Chinese mugwort Saperconazole vitriol form peak-peak occurs at 150.21 DEG C, and peak value is single, it was demonstrated that
Chinese mugwort Saperconazole vitriol has stable heat exchange range, and crystal form itself is relatively stable.
2. stability test
Sample is placed in packaging bag, inner packing is medicinal low density polyethylene (LDPE) bag, and outer packing is polyester/aluminum foil/poly- second
Alkene compound membrane bag is placed 30 days, sample detection in 2-8 DEG C (former triturate regulation storage temperature).With 0 day data and former triturate
Compare, the results are shown in Table 2:
The Chinese mugwort Saperconazole vitriol stability test result of table 2
The results show that Chinese mugwort Saperconazole vitriol according to the present invention has good stability in 2-8 DEG C of placement,
Character and clarity are unchanged, and content and relative substance are within the scope of reasonable error.
3. exposure experiments to light
Sample is had and is shared into open culture dish, thickness about 1mm, adjustable range, intensity of illumination be 4500 ±
It is placed 10 days in the lighting box of 500Lx, in the 10th day sample detection.Compared with 0 day data, it the results are shown in Table 3:
The Chinese mugwort Saperconazole vitriol exposure experiments to light result table of table 3
The above results can obtain, and Chinese mugwort Saperconazole vitriol according to the present invention is shown in long-term exposure experiments to light
Good stability, character, content and relative substance are within the scope of reasonable error, therefore with the pharmaceutical preparation prepared by it
It is suitble to storage steady in a long-term.
Claims (10)
1. a kind of preparation method for the Saperconazole vitriol that ends, it is characterised in that comprise the steps of: step 1: by iodine Ai Sha
Health triazole hydrochloride is soluble in water, adjusts pH to neutrality with alkali under low temperature, organic solvent A extraction is added, is dissolved in after dry concentration
In organic solvent B, the concentrated sulfuric acid and hydrogen peroxide are added under low temperature, stirs, concentration；Step 2: above-mentioned concentrate is added organic molten
It in agent C, is heated to dissolving, stirring cooling crystallization filters to obtain Chinese mugwort Saperconazole vitriol；
Low temperature described in first step reaction is -20~5 DEG C；Alkali described in first step reaction is selected from sodium bicarbonate, sodium carbonate, hydrogen-oxygen
Change sodium, potassium hydroxide, ammonium hydroxide, triethylamine, diethylamine or N, N- diisopropylethylamine；Organic solvent A is selected from methylene chloride, acetic acid
Or mixtures thereof ethyl ester, acetonitrile, ether, methyl tertiary butyl ether(MTBE)；Organic solvent B is selected from methanol, ethyl alcohol, tetrahydrofuran, ethylene glycol
Or mixtures thereof monomethyl ether, acetone；Organic solvent C is selected from methanol, ethyl alcohol, isopropanol, n-butanol, tetrahydro furan in second step reaction
It mutters, or mixtures thereof ethyl acetate, methylene chloride, acetone；
The X-ray powder diffraction figure of the Chinese mugwort Saperconazole vitriol is at following 2 θ of the angle of diffraction with characteristic peak: 6.399
±0.2°、11.198±0.2°、12.933±0.2°、15.170±0.2°、18.947±0.2°。
2. preparation method according to claim 1, it is characterised in that the X-ray powder of the Chinese mugwort Saperconazole vitriol
Last diffraction pattern has characteristic peak at following 2 θ of the angle of diffraction:
3. preparation method according to claim 1, it is characterised in that the Chinese mugwort Saperconazole vitriol has
3440.91cm-1、2226.89cm-1、1752.95cm-1、1725.03cm-1、1631.69cm-1、1607.99cm-1、
1577.54cm-1、1528.05cm-1、1487.89cm-1、1448.70cm-1、1383.6cm-1、1131.18cm-1、1111.86cm-1、765.02cm-1、618.75cm-1Wave number includes the infrared spectroscopy of absorption band.
4. preparation method according to claim 1, it is characterised in that the low temperature is -5~0 DEG C.
5. preparation method according to claim 1, it is characterised in that iodine Chinese mugwort Saperconazole hydrochloride, dense in first step reaction
The molar ratio of sulfuric acid and hydrogen peroxide is 1:1.0~2.0:1.0~2.0.
6. preparation method according to claim 1, it is characterised in that iodine Chinese mugwort Saperconazole hydrochloride, dense in first step reaction
The molar ratio of sulfuric acid and hydrogen peroxide is 1:1.1~1.3:1.1~1.3.
7. preparation method according to claim 1, it is characterised in that organic solvent C is ethyl alcohol and acetic acid in second step reaction
Ethyl ester mixture.
8. preparation method according to claim 7, it is characterised in that ethyl alcohol and ethyl acetate described in second step reaction
Volume ratio is 1:1~20.
9. preparation method according to claim 8, it is characterised in that ethyl alcohol and ethyl acetate described in second step reaction
Volume ratio is 1:1~4.
10. preparation method according to claim 1, it is characterised in that cooling temperature is 10~20 DEG C in second step reaction.
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| CN106916152B (en) * | 2017-04-27 | 2019-09-17 | 扬子江药业集团有限公司 | The method of redox reaction preparation Chinese mugwort Saperconazole monosulfate |
| BR112021000486A2 (en) | 2018-08-01 | 2021-04-06 | Basilea Pharmaceutica International AG | METHODS FOR PURIFYING ISAVUCONAZONIAN SULFATE |
| WO2024189550A1 (en) * | 2023-03-13 | 2024-09-19 | Apitoria Pharma Private Limited | Process for the preparation of isavuconazonium sulfate and its crystalline forms |
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| WO1999045008A1 (en) * | 1998-03-06 | 1999-09-10 | F. Hoffmann-La Roche Ag | 3-[4-(4-cyanophenyl)thiazol-2-y)]-1-(1h-1,2,4-triazol-1-yl)-butan-2-ol derivatives having antifungal activity |
| CN1387529A (en) * | 1999-11-02 | 2002-12-25 | 巴斯利尔药物股份公司 | N-substd. carbamoyloxyalkyl-azolium derivs. |
| US6812238B1 (en) * | 1999-11-02 | 2004-11-02 | Basilea Pharmaceutica Ag | N-substituted carbamoyloxyalkyl-azolium derivatives |
| WO2015150947A1 (en) * | 2014-03-29 | 2015-10-08 | Wockhardt Limited | A process for the preparation of isavuconazole and its intermediates |
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2015
- 2015-10-10 CN CN201510654387.7A patent/CN106565699B/en active Active
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999045008A1 (en) * | 1998-03-06 | 1999-09-10 | F. Hoffmann-La Roche Ag | 3-[4-(4-cyanophenyl)thiazol-2-y)]-1-(1h-1,2,4-triazol-1-yl)-butan-2-ol derivatives having antifungal activity |
| CN1387529A (en) * | 1999-11-02 | 2002-12-25 | 巴斯利尔药物股份公司 | N-substd. carbamoyloxyalkyl-azolium derivs. |
| US6812238B1 (en) * | 1999-11-02 | 2004-11-02 | Basilea Pharmaceutica Ag | N-substituted carbamoyloxyalkyl-azolium derivatives |
| WO2015150947A1 (en) * | 2014-03-29 | 2015-10-08 | Wockhardt Limited | A process for the preparation of isavuconazole and its intermediates |
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