CN106674211A - Noxafil impurities and preparation methods thereof - Google Patents
Noxafil impurities and preparation methods thereof Download PDFInfo
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- CN106674211A CN106674211A CN201510753583.XA CN201510753583A CN106674211A CN 106674211 A CN106674211 A CN 106674211A CN 201510753583 A CN201510753583 A CN 201510753583A CN 106674211 A CN106674211 A CN 106674211A
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- 0 *CCC*(*)[N+](*)[I-] Chemical compound *CCC*(*)[N+](*)[I-] 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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Abstract
The invention relates to three Noxafil oxide impurities as shown in the formula I to III, and discloses preparation methods and structural characterization of the three impurities and uses of the three impurities as impurity reference substances for controlling the purity of Noxafil raw materials or preparations.
Description
Technical field
The present invention relates to three kinds of impurity of posaconazole and preparation method thereof.
Background technology
Posaconazole in October, 2005 is in European Initial Public Offering, trade nameU.S. FDA is in September, 2006
Have approved Posaconazole Oral Suspension (specification：40mg/mL), Yuan Yan enterprises are Schering Plough, and Schering Plough is by Mo Shadong receipts
After purchase, Mo Shadong subsequent developments posaconazole slow releasing tablet and injection.In November, the 2013 and U.S. FDA of in March, 2014
(specification is 16.7mL for approval posaconazole slow releasing tablet (specification is 100mg/ pieces) and injection respectively:0.3g).Posaconazole is fitted
Patient for causing aggressive aspergillosiss and monilial infection risk to increase because of severe immunodeficiency includes hematopoietic stem cell transplantation
(HSCT) patient of graft versus host disease (GVHD) or chemotherapy occur afterwards causes the blood of long-time neutrophilic granulocytopenia
The prophylactic treatment of the invasive infections with fungi of liquid System Malignant Tumor patient.It is applied to treatment oral candidiasis, including she simultaneously
Triaconazole and/or the intractable oral candidiasis of fluconazole.
The chemical structural formula of posaconazole is as shown in formula IV：
It is known in the art, in human administration's security consideration, before a kind of product commercialization of effective ingredient (API)
Need the extremely low lower limit of the identification of non-characteristic impurity in toxicology is set up by country and international management.The limit of usual every kind of impurity
Amount less than about 0.15% weight ratio.The limit of unidentified and/or non-characteristic impurity is considerably lower, typically less than 0.1% weight ratio.
In this area it is also known that, the impurity in any effective ingredient of posaconazole (API) is may be from the degraded of API itself
And manufacture process, including chemosynthesis.Process contaminants include contained impurity and its chemistry in unreacted raw material, raw material
Derivant, synthesising by-product and catabolite.
With regard to the impurity of posaconazole, document (Structural characterization of impurities and degradation
Products 164-177) have been reported, but the oxidation impurities formed in oxidative degradation by posaconazole, especially nitrogen oxidation
Impurity, is not related at present.
Therefore, for posaconazole oxidation impurities preparation and sign, for the stability of posaconazole crude drug and preparation is ground
Study carefully particularly important with quality control.
The applicant is during posaconazole stability study, it was found that the oxidation impurities of three kinds of posaconazoles, to its chromatograph row
To be studied.The invention provides three kinds of posaconazole oxidation impurities and preparation method thereof, and structural characterization has been carried out to which.
The content of the invention
An object of the present invention is to provide a kind of impurity of posaconazole, i.e. compound of formula I, and the impurity is
1- (4- (((3R, 5R) -5- ((1H-1,2,4- triazol-1-yls) methyl) -5- (2,4 difluorobenzene base) tetrahydrofuran base -3- bases) methoxyl group) phenyl) -4
- (4- (1- ((2S, 3S) -2- hydroxyl pentyl -3- bases) -5- oxo -1H-1, -4 (5H)-yl of 2,4- triazole) phenyl) piperazinyl-Isosorbide-5-Nitrae-oxide.
Above-mentioned compound of formula I is separated into the purity with least 50% in some embodiments, or at least 60% purity,
Or at least 70% purity, or at least 80% purity, or at least 90% purity, or at least 95% purity,
Or at least 96% purity, or at least 97% purity, or at least 98% purity, or at least 99% purity,
The purity is generally the purity of HPLC area normalizations.
The present invention provides a kind of method for preparing compound of formula I, including：
By posaconazole under oxidant effect, reaction in a solvent obtains compound of formula I.
Wherein solvent includes but is not limited to N,N-dimethylformamide, dichloromethane, N-Methyl pyrrolidone, tetrahydrofuran, second
Nitrile, Isosorbide-5-Nitrae-dioxane, one or more in ethyl acetate, dimethyl sulfoxide, toluene, ethanol, water.
Wherein oxidant is included but is not limited in hydrogen peroxide, tert-butyl hydroperoxide, metachloroperbenzoic acid or peracetic acid
One or more.
Wherein reaction temperature does not have particular/special requirement, can prepare the temperature range of impurity I～III, the boiling of preferably 10 DEG C～solvent
Point.
Response time does not have particular/special requirement, can be according to TLC or HPLC monitoring reaction process.
Further, it is to help posaconazole dissolving, it is also possible to the enriching hydrochloric acid in reaction system.
It is a further object of the present invention to provide a kind of impurity of posaconazole, i.e. Formula II compound, the impurity is 1- (4-
(((3R, 5R) -5- ((1H-1,2,4- triazol-1-yls) methyl) -5- (2,4 difluorobenzene base) tetrahydrofuran base -3- bases) methoxyl group) phenyl) -
4- (4- (1- ((2S, 3S) -2- hydroxyl pentyl -3- bases) -4 (5H)-yl of -5- oxo -1H-1,2,4- triazoles) phenyl) piperazinyl 1- oxides.
Above-mentioned Formula II compound is separated into the purity with least 50% in some embodiments, or at least 60% purity,
Or at least 70% purity, or at least 80% purity, or at least 90% purity, or at least 95% purity,
Or at least 96% purity, or at least 97% purity, or at least 98% purity, or at least 99% purity,
The purity is generally the purity of HPLC area normalizations.
The present invention provides a kind of method for preparing Formula II compound, including：
By posaconazole under oxidant effect, reaction in a solvent obtains Formula II compound.
Wherein solvent includes but is not limited to N,N-dimethylformamide, dichloromethane, N-Methyl pyrrolidone, tetrahydrofuran, second
Nitrile, Isosorbide-5-Nitrae-dioxane, one or more in ethyl acetate, dimethyl sulfoxide, toluene, ethanol, methanol, water.
Wherein oxidant is included but is not limited in hydrogen peroxide, tert-butyl hydroperoxide, metachloroperbenzoic acid, peracetic acid
One or more.
Wherein reaction temperature does not have particular/special requirement, can prepare the temperature range of impurity I～III, the boiling of preferably 10 DEG C～solvent
Point.
Response time does not have particular/special requirement, can be according to TLC or HPLC monitoring reaction process.
Further, it is to help posaconazole dissolving, it is also possible to the salt adding acid in reaction system.
Further, it is to simplify post processing, reaction can add alkali that solution is adjusted pH value to 8～9 after terminating, wherein, the alkali choosing
From sodium hydroxide solution.
It is a still further object of the present invention to provide a kind of impurity of posaconazole, i.e. formula III compound, the impurity is
4- (4- (((3R, 5R) -5- ((1H-1,2,4- triazol-1-yls) methyl) -5- (2,4 difluorobenzene base) tetrahydrofuran base -3- bases) methoxyl group) benzene
Base) -1- (4- (1- ((2S, 3S) -2- hydroxyl pentyl -3- bases) -4 (5H)-yl of -5- oxo -1H-1,2,4- triazoles) phenyl) piperazinyl -1- oxides.
Above-mentioned formula III compound is separated into the purity with least 50% in some embodiments, or at least 60% it is pure
Degree, or at least 70% purity, or at least 80% purity, or at least 90% purity, or at least 95% it is pure
Degree, or at least 96% purity, or at least 97% purity, or at least 98% purity, or at least 99% it is pure
Degree, the purity are generally the purity of HPLC area normalizations.
The present invention provides a kind of method for preparing formula III compound, including：
By posaconazole under oxidant effect, reaction in a solvent obtains formula III compound.
Wherein solvent includes but is not limited to N,N-dimethylformamide, dichloromethane, N-Methyl pyrrolidone, tetrahydrofuran, second
Nitrile, Isosorbide-5-Nitrae-dioxane, one or more in ethyl acetate, dimethyl sulfoxide, toluene, ethanol, methanol, water.
Wherein oxidant is included but is not limited in hydrogen peroxide, tert-butyl hydroperoxide, metachloroperbenzoic acid or peracetic acid
One or more.
Wherein reaction temperature does not have particular/special requirement, can prepare the temperature range of impurity I～III, the boiling of preferably 10 DEG C～solvent
Point.
Response time does not have particular/special requirement, can be according to TLC or HPLC monitoring reaction process.
Further, it is to help posaconazole dissolving, it is also possible to the enriching hydrochloric acid in reaction system.
The beneficial effect of the technical solution used in the present invention is simple operation, and reaction condition is gently controllable, and the stability of reaction is high,
Also, product high income, purity are high.
Also, above-mentioned Formulas I～formula III compound can control the purity of posaconazole raw material or preparation as impurity reference substance.
Description of the drawings
Fig. 1：Impurity I, II, III HPLC detects collection of illustrative plates
Fig. 2:Compound II nuclear magnetic resonance, NMR HMBC collection of illustrative plates
Fig. 3:Compound III nuclear magnetic resonance, NMR HMBC collection of illustrative plates
Specific embodiment
The present invention will by embodiment more detailed description, these embodiments be exemplarily used for further illustrating in hereafter, and
It is not construed as limiting the present invention.
The preparation of impurity I, II, III
Embodiment 1：
Posaconazole (1.5g) is suspended in water (20.0mL), ethanol (10.0mL) is added, and pH value is adjusted using concentrated hydrochloric acid
To 1～2,30% hydrogen peroxide (2.0mL) is added, stirred 24 hours at 15～30 DEG C, adjusted using 25% sodium hydroxide solution
PH value will separate out a small amount of solid and filter, take filtrate, be extracted twice with dichloromethane (each 15.0mL), merge two to 8～9
Chloromethanes layer, is washed using 20% sodium sulfite solution (10.0g), with preparation liquid phase purifies and separates after the organic faciess concentration for obtaining,
Obtain impurity I solid 0.19g (21.1%)；Obtain impurity II solid 0.13g (8.5%)；Obtain impurity III solid 0.15g (9.8%).
Embodiment 2：
Posaconazole (1.5g) is dissolved in DMF (6.0mL), 70% tert-butyl hydroperoxide (2.0mL) is added,
Stir 5 hours at 70～80 DEG C, water (20.0mL) is added after being cooled to 25～30 DEG C, is adjusted using 25% sodium hydroxide solution
PH value filters the solid of precipitation to 8～9, and gained filtrate is extracted twice using dichloromethane (each 10.0mL), merges two
Chloromethanes layer, is washed using 20% sodium sulfite solution (10.0g), with liquid phase separation is prepared after the organic faciess concentration for obtaining, is obtained
Impurity I solid 0.20g (12.8%)；Obtain impurity II solid 0.12g (7.8%)；Obtain impurity III solid 0.16g (10.4%).
Embodiment 3：
Posaconazole (1.0g) is suspended in water (10.0mL), 50 DEG C of molten clear, additions metachloroperbenzoic acid (0.6g) are warming up to,
In room temperature reaction 48 hours.The lower 25%NaOH aqueous solutions of stirring adjust pH to 8-9, are extracted with dichloromethane (each 10.0mL)
Take twice, washed once with 8% sodium sulfite solution (10.0mL) after combined dichloromethane layer, and use anhydrous sodium sulfate drying.To have
Machine is used after mutually concentrating and prepares liquid phase separation, obtains impurity I solid 0.132g (12.6%)；Obtain impurity II solid 0.085g (8.3%)；
Obtain impurity III solid 0.091g (8.9%).
Embodiment 4：
Posaconazole outstanding (2.0g) is suspended in methanol (10.0mL), system is adjusted to into pH2-3 with dilute hydrochloric acid, 50 DEG C are warming up to
It is molten clear, 20% peracetic acid (2.0mL) is added, in room temperature reaction 12 hours.The lower 25%NaOH aqueous solutions of stirring adjust pH
To 8-9, the solid of precipitation is filtered, water (20.0mL) is added in filtrate, is extracted twice with dichloromethane (each 10.0mL),
Washed once with 8% sodium sulfite solution (10.0mL) after combined dichloromethane layer, and use anhydrous sodium sulfate drying.Organic faciess are concentrated
Afterwards with liquid phase purifies and separates are prepared, impurity I solid 0.31g (14.8%) is obtained；Obtain impurity II solid 0.16g (7.8%)；
Obtain impurity III solid 0.18g (8.8%).
Impurity I：
MS-ESI(M+1)：732.91H NMR:(400MHz,d6-DMSO)δ:8.59(s,1H),8.37(s,1H),8.33(d,2H),8.08
(d,2H),7.94(d,2H),7.80(s,1H),7.31(m,1H),7.29(m,1H),7.04(d,2H),7.01(m,1H),4.85
(m,2H),4.61(d,2H),4.06(d,1H),3.84(m,1H),3.83(m,1H),3.82(m,1H),3.80(m,1H),3.78(m,
1H),3.13(m,2H),2.61(m,1H),2.43(m,1H),2.19(m,1H),1.13(m,2H),1.15(d,3H),0.76(t,
3H)；
Impurity II：
MS-ESI(M+1)：716.9
1H NMR:(400MHz,d6-DMSO)δ:8.35(s,1H),8.35(s,1H),8.11(d,2H),7.78(s,1H),7.56(d,2H),
7.33(m,1H),7.28(m,1H),7.16(d,2H),7.02(m,1H),6.97(d,2H),4.68(d,1H),4.60(m,2H),
4.09(m,2H),4.07(m,1H),3.83(m,1H),3.82(m,1H),3.81(m,1H),3.79(m,1H),3.76(m,1H),
3.68(m,4H),2.98(m,2H),2.58(m,1H),2.42(m,1H),2.16(m,1H),1.72(m,2H),1.13(d,3H),
0.56(t,3H)；
Impurity III：
MS-ESI(M+1)：716.9
1H NMR:(400MHz,d6-DMSO)δ:8.56(s,1H),8.38(s,2H),8.36(s,1H),7.88(d,2H),7.79(s,1H),
7.32(m,1H),7.26(m,1H),7.02(m,1H),6.98(d,2H),6.84(d,2H),4.75(d,1H),4.60(d,2H),4.15
(t,2H),4.04(m,1H),3.83(m,1H),3.81(m,1H),3.76(m,2H),3.70(m,2H),3.62(t,2H),3.45(d,
2H),3.01(d,2H),2.55(m,1H),2.45(m,1H),2.18(m,1H),1.72(m,2H),1.14(d,3H),0.76(t,
3H)；
I, II, III's prepares liquid phase process：
Instrument：Yi Lite (P270 pump-U230 detectors)
Chromatographic column：Boston C18 50*250mm 10um
Mobile phase：A acetonitrile B water flow velocities：80ml/min
Wavelength：The molten sample solvents of 260nm：Methanol
Impurity I, II, III HPLC analysis methods：
Chromatographic column：ZORBAX SB-Phenyl 4.6×75mm,3.5um
Mobile phase A：Water-tetrahydrofuran-phosphoric acid (1550：450：3)
Mobile phase B：Water-acetonitrile-tetrahydrofuran-phosphoric acid (250：500：250：1.5)
Solvent：Water-acetonitrile-phosphoric acid (75：25：1)
Sample concentration：1mg/ml
Wavelength：260nm；Column temperature：40℃；Sample size：10ul；Flow velocity：1.5ml/min
Gradient elution：
Claims (10)
1. a kind of compound of formula I：
2. a kind of Formula II compound：
3. a kind of formula III compound：
4. a kind of method for preparing compound of formula I, it is characterised in that：By posaconazole under oxidant effect, react in a solvent
To compound of formula I,
5. a kind of method for preparing Formula II compound, it is characterised in that：By posaconazole under oxidant effect, react in a solvent
Formula II compound is obtained,
6. a kind of method for preparing formula III compound, it is characterised in that：By posaconazole under oxidant effect, react in a solvent
Formula III compound is obtained,
7. the method as any one of claim 4-6, wherein oxidant are selected from hydrogen peroxide, tert-butyl hydroperoxide, m-chloro
One or more in benzoyl hydroperoxide or peracetic acid.
8. the method as any one of claim 4-6, wherein solvent are selected from DMF, dichloromethane, N-
Methyl pyrrolidone, tetrahydrofuran, acetonitrile, Isosorbide-5-Nitrae-dioxane, ethyl acetate, dimethyl sulfoxide, toluene, ethanol, methanol,
One or more in water.
9. the method as any one of claim 4-6, wherein reaction temperature are 10 DEG C～solvent boiling point.
10. application of the Formulas I described in the claim 1-3～formula III compound in the impurity reference substance of posaconazole raw material or preparation is prepared.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107540665A (en) * | 2016-06-24 | 2018-01-05 | 南京海润医药有限公司 | A kind of impurity of posaconazole and the detection method of preparation method and posaconazole about material |
| CN111638281A (en) * | 2020-05-28 | 2020-09-08 | 上海宣泰海门药业有限公司 | Analysis method of related substances of posaconazole enteric-coated tablets |
| CN112697945A (en) * | 2020-12-18 | 2021-04-23 | 卓和药业集团有限公司 | Method for analyzing content of posaconazole enteric-coated tablets |
| CN114113412A (en) * | 2021-12-15 | 2022-03-01 | 卓和药业集团股份有限公司 | Analysis method of posaconazole impurity related substances |
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|---|---|---|---|---|
| CN101381342A (en) * | 2007-09-06 | 2009-03-11 | 华东理工大学 | Piperazine derivatives and applications thereof |
| CN103852528A (en) * | 2012-12-07 | 2014-06-11 | 重庆莱美药业股份有限公司 | Method for detecting posaconazole |
| CN104974143A (en) * | 2015-05-12 | 2015-10-14 | 深圳致君制药有限公司 | Quaternary ammonium salt compounds, and preparation method and application thereof |
-
2015
- 2015-11-06 CN CN201510753583.XA patent/CN106674211A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101381342A (en) * | 2007-09-06 | 2009-03-11 | 华东理工大学 | Piperazine derivatives and applications thereof |
| CN103852528A (en) * | 2012-12-07 | 2014-06-11 | 重庆莱美药业股份有限公司 | Method for detecting posaconazole |
| CN104974143A (en) * | 2015-05-12 | 2015-10-14 | 深圳致君制药有限公司 | Quaternary ammonium salt compounds, and preparation method and application thereof |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107540665A (en) * | 2016-06-24 | 2018-01-05 | 南京海润医药有限公司 | A kind of impurity of posaconazole and the detection method of preparation method and posaconazole about material |
| CN111638281A (en) * | 2020-05-28 | 2020-09-08 | 上海宣泰海门药业有限公司 | Analysis method of related substances of posaconazole enteric-coated tablets |
| CN112697945A (en) * | 2020-12-18 | 2021-04-23 | 卓和药业集团有限公司 | Method for analyzing content of posaconazole enteric-coated tablets |
| CN114113412A (en) * | 2021-12-15 | 2022-03-01 | 卓和药业集团股份有限公司 | Analysis method of posaconazole impurity related substances |
| CN114113412B (en) * | 2021-12-15 | 2024-04-16 | 卓和药业集团股份有限公司 | Analysis method of posaconazole impurity related substances |
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