CN115724829A - Liquid chromatography preparation method for separating impurities of fungal drug intermediate - Google Patents
Liquid chromatography preparation method for separating impurities of fungal drug intermediate Download PDFInfo
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- CN115724829A CN115724829A CN202211660126.2A CN202211660126A CN115724829A CN 115724829 A CN115724829 A CN 115724829A CN 202211660126 A CN202211660126 A CN 202211660126A CN 115724829 A CN115724829 A CN 115724829A
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- 239000012535 impurity Substances 0.000 title claims abstract description 43
- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- 239000003814 drug Substances 0.000 title abstract description 22
- 229940079593 drug Drugs 0.000 title abstract description 12
- 230000002538 fungal effect Effects 0.000 title abstract description 5
- 238000004811 liquid chromatography Methods 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 26
- 239000007788 liquid Substances 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 21
- 238000000926 separation method Methods 0.000 claims abstract description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 10
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000000178 monomer Substances 0.000 claims abstract description 8
- 238000010829 isocratic elution Methods 0.000 claims abstract description 7
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 5
- 230000005526 G1 to G0 transition Effects 0.000 claims abstract description 4
- 238000004262 preparative liquid chromatography Methods 0.000 claims abstract description 4
- 229960004740 voriconazole Drugs 0.000 claims description 43
- BCEHBSKCWLPMDN-MGPLVRAMSA-N voriconazole Chemical compound C1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=NC=C1F BCEHBSKCWLPMDN-MGPLVRAMSA-N 0.000 claims description 43
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 239000012452 mother liquor Substances 0.000 claims description 14
- 239000002699 waste material Substances 0.000 claims description 12
- 229940126062 Compound A Drugs 0.000 claims description 7
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 7
- 238000002347 injection Methods 0.000 claims description 7
- 239000007924 injection Substances 0.000 claims description 7
- 239000012071 phase Substances 0.000 claims description 7
- 241001251200 Agelas Species 0.000 claims description 6
- 238000001514 detection method Methods 0.000 claims description 3
- 239000000945 filler Substances 0.000 claims description 3
- 239000007791 liquid phase Substances 0.000 claims description 3
- 238000004458 analytical method Methods 0.000 claims description 2
- 238000004440 column chromatography Methods 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 238000007710 freezing Methods 0.000 claims description 2
- 230000008014 freezing Effects 0.000 claims description 2
- 238000005191 phase separation Methods 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 1
- 238000010828 elution Methods 0.000 abstract description 5
- 238000004108 freeze drying Methods 0.000 abstract description 5
- 239000000543 intermediate Substances 0.000 description 36
- 238000011160 research Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000010025 steaming Methods 0.000 description 3
- -1 2-fluoropropionyl ethyl Chemical group 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 239000013076 target substance Substances 0.000 description 2
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- BTANRVKWQNVYAZ-UHFFFAOYSA-N 2-butanol Substances CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 1
- 201000002909 Aspergillosis Diseases 0.000 description 1
- 208000036641 Aspergillus infections Diseases 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 238000006298 dechlorination reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical class C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 229910052611 pyroxene Inorganic materials 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
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Abstract
The invention provides a liquid chromatography preparation method for separating impurities of a fungal drug intermediate. It is a preparative liquid chromatography of a specific impurity (compound B) in compound a. The preparation method is mainly characterized by adopting a preparative liquid chromatography, taking octadecylsilane chemically bonded silica as a stationary phase and acetonitrile-water as a mobile phase for isocratic elution, collecting effluent liquid with the wavelength of 256nm, enriching, and freeze-drying to obtain the product. The method has high separation degree, and the purity of the impurity monomer can reach more than 95 percent; the acetonitrile-water is used as a mobile phase for elution, so that the method is simple and efficient; is suitable for separating components difficult to separate.
Description
Technical Field
The invention relates to the technical field of chemical pharmacy, in particular to a preparation method for separating specific impurities in a voriconazole intermediate serving as a fungal drug.
Background
Voriconazole is a second-generation triazole antifungal new drug developed and developed by the american pyroxene company, which is marketed in the united states in 2002, and compared with the existing fungal drugs, voriconazole as a fluconazole derivative has the advantages of wider antibacterial spectrum, better safety, oral administration and injection, and particularly good curative effect on invasive aspergillus infection.
The impurities of the medicine refer to substances which have no treatment effect or influence the stability and the curative effect of the medicine and are even harmful to the health of human bodies. In the aspects of research, production, storage, clinical application and the like of the medicine, the purity of the medicine must be maintained, and the impurities of the medicine are reduced, so that the effectiveness and the safety of the medicine can be ensured. Therefore, the impurity inspection of the medicine is a very important link for controlling the purity of the medicine and improving the quality of the medicine
Compound A
Compound B
The synthetic routes of voriconazole can be mainly divided into two main categories: the first type uses 2-fluoropropionyl ethyl acetate as a raw material, and the second type uses 5-fluorouracil as an initial raw material. Both the two processes involve an important intermediate (hereinafter referred to as compound A), and the intermediate is subjected to catalytic dechlorination and resolution to obtain the voriconazole bulk drug. Through research, the (2RS, 3RS) -2- (2, 4-difluorophenyl) -3- (6-chloro-5-fluoropyrimidin-4-yl-1- (1H-1, 2, 4-triazolyl-1-yl) -2-butanol (hereinafter referred to as compound B) is a specific impurity of the intermediate and is a byproduct in the synthesis process.
At present, there are many studies on the synthetic route of voriconazole, such as liubo et al (zhonghao chen optical chemical research institute limited) [ voriconazole synthetic method review, organic fluorine industry, p.52 of 3 rd of 2015 ], and several common methods for synthesizing voriconazole reported in the literature are described and compared on the advantages, disadvantages and yields of the synthetic process of each method. However, the existing research lacks the research on the synthesis and preparation method of the impurities in the bulk drug, the intermediate and the preparation of the voriconazole, and the invention provides a detection method and a judgment basis for the production and medication safety of the voriconazole.
Disclosure of Invention
The invention aims to overcome the technical defects and solve the problem that a preparation method and research on a compound B are not available in the prior art, so that the invention provides a preparation method of specific impurities in a voriconazole intermediate, ensures the effectiveness and safety of a medicament, and is simple and efficient.
The technical scheme provided by the invention comprises the following steps:
(1) Collecting and treating waste mother liquor of a compound A generated in the voriconazole technological process;
(2) Separation: taking the sample obtained in the step (1), and preparing the sample through preparative high-pressure liquid phase separation, wherein the preparation method comprises the following specific steps:
the instrument comprises the following steps: preparing a liquid chromatograph; a chromatographic column: chromatographic column with octadecylsilane chemically bonded silica filler as stationary phase; performing isocratic elution by using acetonitrile-water (40; the flow rate is 10 ml/min-25 ml/min; the wavelength is 200nm to 400nm; the column temperature is 25-35 ℃; the sample injection volume is 0.5ml to 3.0ml;
(3) And (3) collecting the preparation liquid in the step (2), enriching, freezing and drying to finally obtain a compound B.
In the invention, the used sample is the waste mother liquor of the compound A, and the mother liquor is subjected to concentration and column chromatography treatment and is suitable for subsequent separation and analysis.
In the present invention, the preparative instrument used is a preparative liquid chromatography instrument conventional in the art, such as Agela HP100, the parameters and operation of which are conventional in the art.
In the present invention, the chromatographic column used is preferably a column using octadecylsilane bonded silica filler as a stationary phase, for example, innoval ODS-2, which has a column size of 30 mm. Times.250mm, 5 μm.
In the present invention, it is preferable that the volume ratio of acetonitrile-water in the mobile phase is 50:50 (v/v).
In the present invention, the flow rate is preferably 20ml per minute.
In the present invention, it is preferable that the detection wavelength is 256nm.
In the present invention, it is preferable that the column temperature is 30 ℃.
In the present invention, preferably, an autosampler is used, and the sample injection volume is 1.0ml.
The invention mainly solves the problem that the existing research lacks a method for synthesizing and preparing impurities in voriconazole bulk drugs, intermediates and preparations, mainly considers a separation method for preparing voriconazole intermediate impurity monomer B by using a preparation liquid phase, and has the main difficulties of simplifying operation, improving efficiency and obtaining high purity compound monomer.
The invention further discloses application of the liquid chromatography method for separating the intermediate impurities of the fungi drugs in preparing the high-purity voriconazole intermediate impurity monomer B; the experimental results show that: the obtained purified product can be used as an impurity reference substance for the quality research of voriconazole intermediates and voriconazole bulk drugs, and provides guarantee for the safe medication of voriconazole.
The invention mainly provides a preparation method of specific impurities in voriconazole intermediate, which has simple operation and high efficiency, and the purity of the obtained compound monomer can reach more than 95%; by using the separation preparation method, the impurity (compound B) in the voriconazole intermediate can be effectively prepared, the specificity is good, and the target substance can be effectively separated.
Drawings
FIG. 1 preparative liquid chromatogram of voriconazole intermediate impurity (compound B) in example 1;
FIG. 2 liquid chromatogram of voriconazole intermediate impurity (compound B) in example 1;
FIG. 3 mass spectrum of voriconazole intermediate impurity (compound B) in example 1;
FIG. 4 preparation of voriconazole intermediate impurity (Compound B) in example 1 1 HNMR spectrogram;
FIG. 5 preparative liquid chromatogram of voriconazole intermediate impurity (compound B) in example 2;
FIG. 6 preparation of liquid chromatogram of voriconazole intermediate impurity in example 3;
FIG. 7 preparation of a liquid chromatogram of voriconazole intermediate impurity in example 4;
figure 8 liquid chromatogram of voriconazole intermediate impurity in example 4.
Detailed Description
The invention is described below by means of specific embodiments. Unless otherwise specified, the technical means used in the present invention are well known to those skilled in the art. In addition, the embodiments should be considered illustrative, and not restrictive, of the scope of the invention, which is defined solely by the claims. It will be apparent to those skilled in the art that various changes or modifications in the components and amounts of the materials used in these embodiments can be made without departing from the spirit and scope of the invention. The voriconazole intermediate compound a and compound B used as raw materials in the present invention are commercially available, and other reagents used are also commercially available.
Example 1
(1) Laboratory apparatus and conditions
The instrument comprises: preparative high pressure liquid chromatograph Agela HP100;
a chromatographic column: innoval ODS-2 with a specification of 30mm x 250mm,5 μm;
a detector: an ultraviolet detector;
and (3) an elution mode: isocratic elution;
mobile phase: acetonitrile-water (50;
column temperature: 30 ℃;
flow rate: 20ml per minute;
sample injection volume: 1.0ml.
(2) Experimental procedure
Solution preparation: taking a certain amount of waste mother liquor of the voriconazole intermediate after treatment, adding 75% acetonitrile to dissolve and dilute the waste mother liquor into a solution containing about 0.1g of the voriconazole intermediate in every 1 ml.
Preparing impurities: collecting effluent liquid with the wavelength of 256nm according to the method in the item (1), enriching, rotary evaporating, and freeze-drying to obtain impurities.
As shown in fig. 1 to 4, the nuclear magnetic and mass spectrometric data analysis of the structure of the voriconazole intermediate impurity (compound B) obtained in the above example is as follows: 1 HNMR（600MHz，DMSO-d6）（ppm），8.73（s，1H，ArH），8.27（s，1H，ArH），7.66（s，1H，ArH），7.12~7.07（t，1H，ArH），7.05~7.03（m，1H，ArH），6.74~6.70（t，1H，ArH），5.94（s，1H，OH），4.98~4.71（m，2H，CH 2 ），4.08~4.06（d，2H，CH），1.50~1.49（d，3H，CH 3 ）；ESI-MS（m/z）：384.1[M+H] + . Therefore, the impurity (compound B) in the voriconazole intermediate can be effectively prepared by using the separation preparation method, the separation degree is high, and the purity of the impurity monomer can reach 99.76%.
Example 2
(2) Laboratory apparatus and conditions
The instrument comprises the following steps: preparative high pressure liquid chromatograph Agela HP100;
and (3) chromatographic column: innoval ODS-2 with a specification of 30mm x 250mm,5 μm;
a detector: an ultraviolet detector;
and (3) an elution mode: isocratic elution;
mobile phase: acetonitrile-water (40;
column temperature: 30 ℃;
flow rate: 20ml per minute;
sample injection volume: 1.0ml.
(2) Experimental procedure
Solution preparation: taking a certain amount of waste mother liquor of the voriconazole intermediate after treatment, adding 75% acetonitrile to dissolve and dilute the waste mother liquor into a solution containing about 0.1g of the voriconazole intermediate in every 1 ml.
Preparing impurities: collecting effluent liquid with the wavelength of 256nm according to the method in the item (1), enriching, rotary-steaming, and freeze-drying to obtain impurities.
As shown in fig. 5, for the preparative liquid chromatogram of the visible voriconazole intermediate impurity (compound B) of the voriconazole intermediate impurity (compound B) obtained in the above example, the impurity (compound B) in the voriconazole intermediate can be efficiently prepared by using the separation preparation method of the present application, and the monomer purity is 99.30%.
Example 3
(3) Laboratory apparatus and conditions
The instrument comprises the following steps: preparative high pressure liquid chromatograph Agela HP100;
a chromatographic column: innoval ODS-2 with a specification of 30mm x 250mm,5 μm;
a detector: an ultraviolet detector;
and (3) an elution mode: isocratic elution;
mobile phase: methanol-water (10;
column temperature: 30 ℃;
flow rate: 20ml per minute;
sample introduction volume: 1.0ml.
(2) Experimental procedure
Solution preparation: taking a certain amount of waste mother liquor of the voriconazole intermediate after treatment, adding 75% acetonitrile to dissolve and dilute the waste mother liquor into a solution containing about 0.1g of the intermediate in every 1 ml.
Preparing impurities: collecting effluent liquid with the wavelength of 256nm according to the method in the item (1), enriching, rotary-steaming, and freeze-drying to obtain impurities.
As shown in fig. 6, it can be seen from the preparative liquid chromatogram obtained in the above example that the target compound cannot be eluted efficiently by using the separation preparative method of the present application, and no peak is found in the preparative liquid chromatogram, indicating that the preparative separation method of the present application is obtained by screening optimization.
Example 4
(1) Laboratory apparatus and conditions
The instrument comprises the following steps: preparative high pressure liquid chromatograph Agela HP100;
a chromatographic column: innoval ODS-2 with a specification of 30mm x 250mm,5 μm;
a detector: an ultraviolet detector;
an elution mode: isocratic elution;
mobile phase: acetonitrile-water (75;
column temperature: 30 ℃;
flow rate: 20ml per minute;
sample injection volume: 1.0ml.
(2) Experimental procedure
Solution preparation: taking a certain amount of waste mother liquor of the voriconazole intermediate after treatment, adding 75% acetonitrile to dissolve and dilute the waste mother liquor into a solution containing about 0.1g of the intermediate in every 1 ml.
Preparing impurities: collecting effluent liquid with the wavelength of 256nm according to the method in the item (1), enriching, rotary-steaming, and freeze-drying to obtain impurities. As can be seen from fig. 7 to 8, the substance obtained by the isolation preparation method of the present application was not the target substance (compound B) when detected by high performance liquid chromatography, which indicates that the isolation preparation method of the present application was optimized by screening.
Claims (8)
1. A preparative liquid chromatography for separating a specific impurity compound B in a voriconazole intermediate compound A is characterized by comprising the following steps:
(1) Collecting and treating waste mother liquor of a compound A generated in the voriconazole process;
(2) Separation: taking the sample obtained in the step (1), and preparing the sample through preparative high-pressure liquid phase separation, wherein the preparation method comprises the following specific steps,
the instrument comprises: preparing a liquid chromatograph; a chromatographic column: a chromatographic column using octadecylsilane chemically bonded silica filler as a stationary phase; mixing acetonitrile-water 40:60 v/v-70: 30 v/v is the mobile phase for isocratic elution; the flow rate is 10 ml/min-25 ml/min; the wavelength is 200nm to 400nm; the column temperature is 25-35 ℃; the sample injection volume is 0.5ml to 3.0ml;
(3) And (3) collecting the preparation liquid in the step (2), enriching, freezing and drying to finally obtain a compound B.
2. The preparation method as claimed in claim 1, wherein the sample used is waste mother liquor of compound A, and the mother liquor is subjected to concentration and column chromatography, and is suitable for subsequent separation and analysis.
3. The process according to claim 1, wherein the apparatus used for the preparation is Agela HP100, the parameters and the operation of which are conventional.
4. The method according to claim 1, wherein the chromatographic column used is an octadecylsilane bonded silica chromatographic column, innoval ODS-2, having a size of 30mm x 250mm,5 μm.
5. The process of claim 1, wherein the mobile phase has a volume ratio of acetonitrile to water of 50:50 (v/v).
6. The method of claim 1, wherein the flow rate is 20ml/min; the detection wavelength was 256nm.
7. The method according to claim 1, wherein the column temperature is 30 ℃; an autosampler was used, and the sample volume was 1.0ml.
8. Use of the process of claim 1 for the preparation of high purity voriconazole intermediate impurity monomer B.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1100421A (en) * | 1990-02-02 | 1995-03-22 | 美国辉瑞有限公司 | Process for preparation of a pharmaceutical composition containing a triazole derivative |
| CN1195346A (en) * | 1995-08-05 | 1998-10-07 | 辉瑞研究开发公司 | Preparation of triazoles by organometallic addition to ketones and intermediates therefor |
| US20110312977A1 (en) * | 2009-02-17 | 2011-12-22 | Glenmark Generics Limited | Process for the preparation of voriconazole |
| CN105503834A (en) * | 2015-12-23 | 2016-04-20 | 浙江华海药业股份有限公司 | Synthetic method of voriconazole intermediate |
| CN110308212A (en) * | 2018-03-27 | 2019-10-08 | 成都倍特药业有限公司 | A kind of related substance detecting method of voriconazole |
-
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- 2022-12-23 CN CN202211660126.2A patent/CN115724829A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1100421A (en) * | 1990-02-02 | 1995-03-22 | 美国辉瑞有限公司 | Process for preparation of a pharmaceutical composition containing a triazole derivative |
| CN1195346A (en) * | 1995-08-05 | 1998-10-07 | 辉瑞研究开发公司 | Preparation of triazoles by organometallic addition to ketones and intermediates therefor |
| US20110312977A1 (en) * | 2009-02-17 | 2011-12-22 | Glenmark Generics Limited | Process for the preparation of voriconazole |
| CN105503834A (en) * | 2015-12-23 | 2016-04-20 | 浙江华海药业股份有限公司 | Synthetic method of voriconazole intermediate |
| CN110308212A (en) * | 2018-03-27 | 2019-10-08 | 成都倍特药业有限公司 | A kind of related substance detecting method of voriconazole |
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