CN116751188A - Synthesis method of process impurities generated by voriconazole key intermediate - Google Patents
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- 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 title claims abstract description 54
- 229960004740 voriconazole Drugs 0.000 title claims abstract description 53
- 238000000034 method Methods 0.000 title claims abstract description 43
- 239000012535 impurity Substances 0.000 title claims abstract description 29
- 238000001308 synthesis method Methods 0.000 title claims abstract description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 30
- 239000000543 intermediate Substances 0.000 claims abstract description 29
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims abstract description 24
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 claims abstract description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000007858 starting material Substances 0.000 claims abstract description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 12
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000002994 raw material Substances 0.000 claims abstract description 12
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims abstract description 12
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000004440 column chromatography Methods 0.000 claims abstract description 8
- 239000007864 aqueous solution Substances 0.000 claims abstract description 7
- 238000010791 quenching Methods 0.000 claims abstract description 7
- 230000000171 quenching effect Effects 0.000 claims abstract description 7
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229960000583 acetic acid Drugs 0.000 claims abstract description 6
- 239000012362 glacial acetic acid Substances 0.000 claims abstract description 6
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 6
- 239000011630 iodine Substances 0.000 claims abstract description 6
- 235000010265 sodium sulphite Nutrition 0.000 claims abstract description 6
- 239000003513 alkali Substances 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 4
- 230000001105 regulatory effect Effects 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 15
- 230000015572 biosynthetic process Effects 0.000 claims description 9
- 238000003786 synthesis reaction Methods 0.000 claims description 9
- 230000002194 synthesizing effect Effects 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 abstract description 12
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 239000013558 reference substance Substances 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 3
- 238000003908 quality control method Methods 0.000 abstract description 2
- -1 extracted Substances 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 description 11
- 239000000243 solution Substances 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 230000001276 controlling effect Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 206010007134 Candida infections Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 229940121375 antifungal agent Drugs 0.000 description 2
- 201000003984 candidiasis Diseases 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 238000010606 normalization Methods 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- LKTGVRWVTAJGMS-UHFFFAOYSA-N 4-chloro-6-ethyl-5-fluoropyrimidine Chemical compound CCC1=NC=NC(Cl)=C1F LKTGVRWVTAJGMS-UHFFFAOYSA-N 0.000 description 1
- 241000228212 Aspergillus Species 0.000 description 1
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000000945 filler Substances 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
- 235000019253 formic acid Nutrition 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 206010033675 panniculitis Diseases 0.000 description 1
- 239000013074 reference sample Substances 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 210000004304 subcutaneous tissue Anatomy 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 229940010175 vfend Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthesis method of a process impurity D generated by a voriconazole key intermediate, which comprises the following steps: reacting the starting material A, N-bromosuccinimide and azodiisobutyronitrile in dichloromethane, quenching by sodium sulfite aqueous solution, extracting, and distilling to obtain an intermediate B; the intermediate B, the initial raw material C, zinc powder and iodine are reacted in tetrahydrofuran solvent, quenched by glacial acetic acid, extracted, alkali regulated and column chromatography to obtain the compound D. The purity of the synthesized process impurity D can reach more than 95%, and the process impurity D can be used as an impurity reference substance when relevant substances of voriconazole intermediates, bulk drugs and preparations are detected, so that stricter quality control of voriconazole is realized.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry synthesis, and particularly relates to a synthesis method of process impurities in the process of producing a key intermediate of voriconazole.
Background
Voriconazole (Voriconazole) is a second generation triazole antifungal agent developed by the american-type scion company, marketed in the united states in 2002, and is mainly used clinically for treating acute or chronic deep fungal infections, and has the trade name Vfend. Compared with the traditional fungus medicines, the voriconazole as the fluconazole derivative has wider antibacterial spectrum, better safety, and good curative effect on oral administration and injection, especially invasive aspergillus infiltration infection, and is mainly used for treating candida diseases, deep subcutaneous tissue candida infection and candida infection of abdomen, kidney, bladder wall and wounds. The voriconazole has been a new market with the characteristic of high efficiency and low toxicity, and has great economic value and market prospect, so that the synthesis process of the voriconazole is necessary to be optimized, which is more beneficial to industrialized production and has better economic benefit.
There is a great deal of technical accumulation for the production and preparation of voriconazole. The invention discloses a synthesis process of voriconazole with the publication number of CN 113354625A; the publication number is CN111440152A, and the publication number is Voriconazole preparation method; the publication number is CN106632267A, and the publication number is Voriconazole synthesis method; the publication No. CN104884450A, entitled "method for preparing voriconazole and analogues thereof", discloses various preparation processes of voriconazole. The main synthetic route is as follows: 4-chloro-6-ethyl-5-fluoropyrimidine is used as a raw material to prepare voriconazole; wherein the reaction equation is as follows:
in the production of voriconazole according to the disclosed preparation process, it was found that a distinct impurity peak appears during the production of the intermediate 2 condensate and that this impurity is derivatised in the final voriconazole product. The impurities will have an impact on quality. At present, no effective synthesis method for the process impurity D in the synthesis process of the voriconazole intermediate condensate is reported so far, the impurity is researched by the patent with application number 202211660126.4 of the company, and the impurity is prepared by a high-pressure liquid chromatography method, but the high-pressure liquid chromatography is needed by adopting the liquid phase preparation method, so that the cost is high, and the impurity amount is low. In order to solve the problems of the prior art, a method for synthesizing the groceries is developed, which can use conventional synthesis equipment, adopts a simple process, has easily controlled preparation conditions, and is suitable for industrial production. The method for synthesizing the impurity can effectively help us to determine the mode for effectively removing the impurity, improves the purity of the voriconazole condensate from 90.3% to 97.6%, and greatly improves the purity of the voriconazole intermediate, thereby improving the quality of the voriconazole finished product.
Disclosure of Invention
Aiming at the technical problems in the prior art, the invention provides a synthesis method of voriconazole intermediate impurities, which can synthesize the impurities stably, with high yield and high purity, and can be used as an impurity reference substance for strictly and accurately controlling the quality of voriconazole in the preparation process. Therefore, the invention provides a simple synthesis method for synthesizing process impurities.
In order to achieve the above object, the present invention provides the following technical solutions:
the synthesis method of the process impurity D generated by the voriconazole key intermediate is characterized by comprising the following steps of:
(1) Reacting the initial raw materials A, N-bromosuccinimide and azodiisobutyronitrile in dichloromethane at the reaction temperature of 30-50 ℃ for 10-12 hours, quenching with sodium sulfite aqueous solution, extracting, and distilling to obtain an intermediate B; the starting material a: the molar ratio of N-bromosuccinimide is 1:1.0- -1.5
(2) Reacting the intermediate B obtained in the step 1) with the initial raw material C, zinc powder and iodine in tetrahydrofuran solvent, quenching with glacial acetic acid, extracting, regulating alkali, and performing column chromatography to obtain a compound D; the starting material C: the ratio of zinc powder is 1: 1-5.5;
the process impurity D is mainly in the voriconazole condensate, and can be used as a reference substance for voriconazole quality research.
The invention also discloses application of the process impurity D generated by the voriconazole condensate in preparing a control sample and controlling the quality of the voriconazole condensate, and experimental results prove that: the impurity D monomer is taken in proper amount, a solution of 0.5mg/ml is prepared by a diluent, the purity of the main peak is 97.6 percent calculated by an area normalization method according to the detection method of relevant substances of voriconazole condensate. The high-quality voriconazole raw material and the preparation can better meet the continuously and rapidly growing demands of antifungal drugs in the domestic market, are more beneficial to industrial production, and generate good economic benefit.
The beneficial effects of the process impurities generated in the process of producing voriconazole condensate disclosed by the invention are as follows:
(1) The invention provides a novel synthesis method of voriconazole impurities, and the structure is confirmed, so that the content of the impurities in voriconazole can be accurately and quantitatively analyzed, the accurate control of the content of the impurities in the production process is facilitated, and a research basis is provided for monitoring the production quality and improving the production process level; the preparation method of the invention can synthesize the impurity stably, with high yield and high purity, and provides a contrast basis for intensive study of the quality of raw materials and preparations.
(2) Since the voriconazole intermediate condensate can generate about 10% of impurity D during the production process, the purification by the subsequent prior art confirms that the impurity can be derived or transferred to the voriconazole finished product in the subsequent step, affecting the quality of the product. The derivative of the detected impurity D can be effectively controlled below 0.1% in the voriconazole finished product, and meets the requirements of the existing pharmacopoeia quality standard. Therefore, the preparation and structure of the impurity have great guiding significance for quality control and curative effect of voriconazole mass production.
(3) The process impurity D generated by the voriconazole key intermediate can be used for preparing a reference sample and controlling the quality of the voriconazole condensate.
The invention is described in more detail below:
the synthesis route of the synthesis method of the voriconazole condensate process impurity D disclosed by the invention is as follows:
(1) Reacting the initial raw materials A, N-bromosuccinimide and azodiisobutyronitrile in dichloromethane at the reaction temperature of 30-50 ℃ for 10-12 hours, quenching with sodium sulfite aqueous solution, extracting, and distilling to obtain an intermediate B; the starting material a: the molar ratio of N-bromosuccinimide is 1:1.0 to 1.5;
(2) Reacting the intermediate B obtained in the step 1) with the initial raw material C, zinc powder and iodine in tetrahydrofuran solvent, quenching with glacial acetic acid, extracting, regulating alkali, and performing column chromatography to obtain a compound D; the starting material C: the ratio of zinc powder is 1: 1-5.5;
in the synthesis method of the present invention, the starting material a is preferably: the ratio of N-bromosuccinimide is 1:1.2.
in the synthesis method of the invention, the ratio of the starting raw material C to zinc powder is preferably 1:2.5.
in the synthesis method of the present invention, the reaction condition temperature in step 1) is preferably 35 ℃ for 10 hours.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of process impurity D;
FIG. 2 is a nuclear magnetic carbon spectrum of process impurity D;
fig. 3 is a mass spectrum of process impurity D positive ions.
Detailed Description
For the sake of simplicity and clarity, descriptions of well-known techniques are omitted appropriately below to avoid those unnecessary detail from affecting the description of the present solution. The following describes a further embodiment of the process for the synthesis of the process impurity D produced in the production of voriconazole according to the invention, in particular the starting materials A and C which can be synthesized by the process provided in CN104884450A or are commercially available; intermediate B, N-bromosuccinimide, azobisisobutyronitrile, and zinc powder, iodine, and the like used are commercially available.
Example 1
A synthetic method of a process impurity D generated in the production of a key intermediate of voriconazole, comprising the following steps:
1) 51.5g (0.321 mol) of the starting material A,400ml of methylene chloride, 68.6g (0.385 mol) of N-bromosuccinimide and 1.58g (0.010 mol) of azobisisobutyronitrile were each put into a 500ml three-necked flask equipped with a thermometer and mechanically stirred, and reacted at a temperature of 35℃for 10 hours, after the completion of the reaction, the aqueous sodium sulfite solution was quenched, washed with water twice, and distilled under reduced pressure to remove methylene chloride to obtain a crude product, and then 62.3g of intermediate B was obtained by column chromatography in a yield of 81.1% and a content of 95.3%.
2) To a 500ml three-necked flask equipped with a thermometer under nitrogen atmosphere and mechanically stirred, 28.2 g (0.434 mol) of zinc powder and 87.0ml of tetrahydrofuran were added, a solution of 19.36g (0.077 mol) of iodine in 58.0ml of tetrahydrofuran was slowly added at 20℃and reacted for 0.5 hour, 51.5g (0.215 mol) of intermediate B was weighed, 38.73g (0.174 mol) of starting material C was dissolved in 190ml of tetrahydrofuran, and the mixture was dropped into the reaction flask at a temperature of 10℃or below. A289 ml aqueous solution of 48.2g glacial acetic acid was added dropwise thereto at a temperature of 10℃or below, followed by stirring for 0.5 hours. The reaction solution was filtered, and after concentrating the filtrate, 289ml of dichloromethane was extracted with petroleum ether/ethyl acetate=1: column chromatography on 1 column gave 26.5g of impurity D in 82.0% yield with a content of 99.72%.
As shown in fig. 1 1 H NMR(DMSO-d 6 )8.968(s,1H),8.880(s,1H),8.256(d,1H),7.630(d,1H),
7.290(dt,1H),7.086-7.203(m,1H),6.944-6.898(td,1H),5.997(s,1H),5.048(m,1H),4.821(d,1H),4.297-4.382(q,2H), 1.677(t,3H),1.104-1.150（dd，3H）.
As shown in fig. 2 13 C NMR(DMSO-d 6 ) The method comprises the steps of carrying out a first treatment on the surface of the MS as shown in fig. 3: [ M+H ]] + =508.1.
The synthetic process impurity D with high efficiency and high quality can be synthesized according to the formula. The impurity in the reaction process is less, the reaction is quick, the purification is simple, and the synthetic process impurity D is easy to obtain.
Example 2
1) 51.5g (0.321 mol) of the starting material A,400ml methylene chloride, 74.23g (0.417 mol) of N-bromosuccinimide and 1.58g (0.010 mol) of azodiisobutyronitrile are respectively added into a 500ml three-necked flask equipped with a thermometer and mechanically stirred, the reaction is carried out for 12 hours at the temperature of 45 ℃, after the reaction is finished, the aqueous solution of sodium sulfite is quenched, the reaction is washed twice, the methylene chloride is removed by reduced pressure distillation to obtain a crude product, and 61.8g of intermediate B is obtained by column chromatography, the yield is 80.5%, and the content is 92.1%.
2) 33.93g (0.522 mol) of zinc powder and 87.0ml of tetrahydrofuran are added into a 500-ml three-necked flask which is mechanically stirred under the protection of nitrogen, 19.36g (0.077 mol) of iodine and 58.0ml of tetrahydrofuran solution are slowly added at 20 ℃ to react for 0.5 hour, 51.5g (0.215 mol) of intermediate B and 38.73g (0.174 mol) of initial raw material C are weighed and dissolved in 190ml of tetrahydrofuran, the temperature is controlled to be lower than 10 ℃,289ml of aqueous solution of glacial acetic acid is controlled to be lower than 10 ℃, and stirring is carried out for 0.5 hour. The reaction solution was filtered, and after concentrating the filtrate, 289ml of dichloromethane was extracted with petroleum ether/ethyl acetate=1: column chromatography on 1 column gave 21.2g of impurity D, yield 65.6% and content 96.5%.
Example 3
Octadecylsilane chemically bonded silica is used as filler (Kromasil 100-5-C18,4.6mm×250mm,5 μm or chromatographic column with equivalent efficacy); gradient elution was performed according to Table 1 with 0.02mol/L ammonium formate solution (containing 0.1% formic acid) as mobile phase A and acetonitrile as mobile phase B; the flow rate is 0.8ml per minute; the column temperature is 30 ℃; the detection wavelength is 256nm; the temperature of the sample chamber is 5 ℃; the sample volume was 10. Mu.l. Under the chromatographic conditions, the voriconazole condensate peaks for about 29 minutes and impurity D peaks for about 34 minutes.
The impurity monomer is taken in proper amount, a solution of 0.5mg/ml is prepared by a diluent, the purity of the main peak is 97.6 percent calculated by an area normalization method according to the detection method of relevant substances of voriconazole condensate. No peak was observed at 34 minutes. For further verification, the test solution was added to the voriconazole condensate sample solution as a mixed solution for HPLC measurement, and a peak was found at 34 minutes, which confirmed by a chromatogram that the voriconazole condensate sample had no target impurity peak.
TABLE 1 gradient elution procedure
After the preferred embodiments have been described in detail, those skilled in the art will readily appreciate that various changes and modifications may be made therein without departing from the spirit and scope of the present invention as defined in the appended claims. And the invention is not limited to the example embodiments illustrated in the specification.
Claims (4)
1. The synthesis method of the process impurity D generated by the voriconazole key intermediate is characterized by comprising the following steps of:
1) Reacting the initial raw materials A, N-bromosuccinimide and azodiisobutyronitrile in dichloromethane at the reaction temperature of 30-50 ℃ for 10-12 hours, quenching with sodium sulfite aqueous solution, extracting, and distilling to obtain an intermediate B; the starting material a: the molar ratio of N-bromosuccinimide is 1:1.0 to 1.5;
reacting the intermediate B obtained in the step 1) with the initial raw material C, zinc powder and iodine in tetrahydrofuran solvent, quenching with glacial acetic acid, extracting, regulating alkali, and performing column chromatography to obtain a compound D; the starting material C: the ratio of zinc powder is 1: 1-5.5;
。
2. a process for the synthesis of process impurities derived from key intermediates of voriconazole according to claim 1, wherein step 1) is performed starting material a: the ratio of N-bromosuccinimide is 1:1.2.
3. the method for synthesizing process impurities generated by key intermediates of voriconazole according to claim 1, wherein the reaction temperature in step 1) is 35 ℃ for 10 hours.
4. A process for the synthesis of process impurities derived from key intermediates of voriconazole according to claim 1, wherein step 2) is performed starting material C: the ratio of zinc powder is 1:1- -2.5.
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