CN115389655B - Detection of impurity of 6-formoxyl-2, 2 dimethyl-1, 3-dioxane-4-tert-butyl acetate isomer - Google Patents
Detection of impurity of 6-formoxyl-2, 2 dimethyl-1, 3-dioxane-4-tert-butyl acetate isomer Download PDFInfo
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- 239000012535 impurity Substances 0.000 title claims abstract description 128
- 238000001514 detection method Methods 0.000 title claims abstract description 43
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 title claims abstract description 27
- 239000000243 solution Substances 0.000 claims abstract description 75
- 238000000034 method Methods 0.000 claims abstract description 26
- 239000007788 liquid Substances 0.000 claims abstract description 14
- 230000004807 localization Effects 0.000 claims abstract description 12
- 238000000926 separation method Methods 0.000 claims abstract description 11
- 239000000523 sample Substances 0.000 claims description 64
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 48
- 239000011550 stock solution Substances 0.000 claims description 40
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 29
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 28
- -1 1- (5-hydrazino-2, 4-dinitrophenyl) -4-methylpiperazine Chemical compound 0.000 claims description 25
- 239000012488 sample solution Substances 0.000 claims description 23
- 238000007865 diluting Methods 0.000 claims description 12
- 238000002347 injection Methods 0.000 claims description 11
- 239000007924 injection Substances 0.000 claims description 11
- 238000002156 mixing Methods 0.000 claims description 10
- 238000012360 testing method Methods 0.000 claims description 10
- 239000012528 membrane Substances 0.000 claims description 9
- 239000011259 mixed solution Substances 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 7
- 238000005374 membrane filtration Methods 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- JEFQIIXBSQLRTF-ZJUUUORDSA-N tert-butyl 2-[(4r,6s)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate Chemical class CC(C)(C)OC(=O)C[C@H]1C[C@@H](C=O)OC(C)(C)O1 JEFQIIXBSQLRTF-ZJUUUORDSA-N 0.000 claims 2
- 239000012085 test solution Substances 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 4
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- 239000013558 reference substance Substances 0.000 description 13
- 230000014759 maintenance of location Effects 0.000 description 10
- 239000000047 product Substances 0.000 description 7
- LALFOYNTGMUKGG-BGRFNVSISA-L rosuvastatin calcium Chemical compound [Ca+2].CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O.CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O LALFOYNTGMUKGG-BGRFNVSISA-L 0.000 description 6
- 238000011835 investigation Methods 0.000 description 5
- 229960004796 rosuvastatin calcium Drugs 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- GIGCMLLQJKOOGM-UHFFFAOYSA-N tert-butyl 2-(2,2-dimethyl-1,3-dioxan-4-yl)acetate Chemical compound CC(C)(C)OC(=O)CC1CCOC(C)(C)O1 GIGCMLLQJKOOGM-UHFFFAOYSA-N 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000004817 gas chromatography Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229960003296 pitavastatin calcium Drugs 0.000 description 2
- RHGYHLPFVJEAOC-FFNUKLMVSA-L pitavastatin calcium Chemical compound [Ca+2].[O-]C(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1.[O-]C(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 RHGYHLPFVJEAOC-FFNUKLMVSA-L 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 238000002604 ultrasonography Methods 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000005220 pharmaceutical analysis Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000009210 therapy by ultrasound Methods 0.000 description 1
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- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/281—Sorbents specially adapted for preparative, analytical or investigative chromatography
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- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
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Abstract
The invention discloses detection of impurities of 6-formaldehyde-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate isomers, and belongs to the field of medicine analysis. The method comprises the following steps: 1) Preparing a (4R-cis) -6-formaldehyde-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate test solution, a control solution and an isomer impurity positioning solution; 2) Measuring a chromatogram of impurity localization by using a high performance liquid chromatograph, wherein the separation degree between impurity peaks is more than or equal to 1.5; 3) Determining a chromatogram of the control solution using a high performance liquid chromatograph; 4) And (3) measuring the chromatogram of the test solution by using a high performance liquid chromatograph, and determining the content of the isomer impurities in the test solution according to the chromatogram of the control solution. The method can effectively separate the (4R-cis) -6-formaldehyde-2, 2 dimethyl-1, 3-dioxane-4-tert-butyl acetate from each isomer, provides a reliable basis for controlling the impurity of the (4R-cis) -6-formaldehyde-2, 2 dimethyl-1, 3-dioxane-4-tert-butyl acetate isomer, and is beneficial to ensuring the quality of downstream products.
Description
Technical Field
The invention relates to the field of pharmaceutical analysis, and relates to detection of impurities of 6-formaldehyde-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate isomers.
Background
The (4R-cis) -6-formaldehyde-2, 2-dimethyl-1, 3-dioxane-4-acetic acid tert-butyl ester is often used as an important synthetic raw material of pitavastatin calcium and rosuvastatin calcium, the rosuvastatin calcium is a common drug mainly used for treating cardiovascular and cerebrovascular diseases, the current industrial production process in the preparation process of rosuvastatin calcium raw material is to use (4R-cis) -6-formaldehyde-2, 2 dimethyl-1, 3-dioxane-4-acetic acid tert-butyl ester as a starting material 2 (shown in figure 4), and 4 forms of isomers (shown in figure 5) appear in the preparation process due to two chiral centers of the compound, so that important attention is paid to enantiomer impurities (4S-cis) -6-formaldehyde-2, 2 dimethyl-1, 3-dioxane-4-acetic acid tert-butyl ester, 2- [ (4R, 6R) -6-formyl-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate ] 2- [ (4S, 2-dimethyl-1, 3-dioxane-4-dimethyl-4-acetic acid tert-butyl ester and 2, 3-dioxane-2, 3-dimethyl-4-2-formyl-4-acetic acid. The isomer impurities are produced in the production process, are not easy to remove and are easy to remain, if the isomer impurities are not effectively controlled, intermediates can be introduced, the structures are similar, the related physicochemical properties and the like are relatively consistent, the isomer impurities are not easy to remove, the reaction can be participated to lead the crude drug intermediates to contain larger isomer impurities (as shown in figure 5), and the subsequent processes need to be added for refining and removing for many times, so that the overall production cost is increased, and therefore, a reasonable subsequent process is required to be formulated according to the content of the isomer impurities in the (4R-cis) -6-formyl-2, 2 dimethyl-1, 3-dioxane-4-tert-butyl acetate sample. Therefore, a method capable of effectively detecting the impurities is developed, and the method has important guiding significance for controlling the quality and cost of pitavastatin calcium or rosuvastatin calcium bulk drug.
The reported related substance method adopts gas chromatography, uses a nonpolar column to separate impurities, can not separate main components from isomers, and has weaker ultraviolet absorption and higher detection difficulty because of the weaker ultraviolet absorption of the main components and the isomer impurities, and no related report of detecting the isomers is searched at present.
There is thus an urgent need for a method for effectively detecting the other three isomers in the starting material, by effectively controlling the content of the three isomers in the starting material, so as to avoid the economic loss caused by the reduction of the yield and the increase of the costs of the related materials due to the repeated refining in the subsequent process.
Disclosure of Invention
In order to solve the problems, the invention provides a method for detecting (4R-cis) -6-formaldehyde-2, 2 dimethyl-1, 3-dioxane-4-tert-butyl acetate isomer impurities based on liquid chromatography separation.
The first aim of the invention is to provide a separation and detection method of (4R-cis) -6-formaldehyde-2, 2 dimethyl-1, 3-dioxane-4-tert-butyl acetate isomer impurity, which comprises the following steps:
(1) Sample liquid preparation: dispersing a (4R-cis) -6-formaldehyde-2, 2 dimethyl-1, 3-dioxane-4-tert-butyl acetate sample in acetonitrile, dissolving and diluting to obtain a sample stock solution; dispersing 1- (5-hydrazino-2, 4-dinitrophenyl) -4-methylpiperazine in absolute ethyl alcohol, then adding a sample stock solution, uniformly mixing, and performing membrane filtration to obtain a sample solution;
(2) Preparing an impurity positioning solution: taking (4R-cis) -6-formaldehyde-2, 2 dimethyl-1, 3-dioxane-4-tert-butyl acetate isomer impurities, and respectively diluting the impurities into corresponding mixed solutions by acetonitrile to obtain positioning stock solutions of the impurities; dispersing 1- (5-hydrazino-2, 4-dinitrophenyl) -4-methylpiperazine in absolute ethyl alcohol, and respectively adding corresponding impurity positioning stock solutions; mixing uniformly, and filtering by a membrane to obtain an impurity positioning solution;
(3) High performance liquid chromatography detection: taking n-hexane-absolute ethyl alcohol as a mobile phase, performing high performance liquid chromatography detection on the impurity positioning solution to realize impurity separation and obtain corresponding chromatographic information; and then carrying out high performance liquid chromatography detection on the sample liquid, and separating and detecting impurities in the sample by contrasting the chromatographic information of the impurity positioning solution.
In one embodiment of the invention, in step (1), the concentration of the sample in the sample reservoir is 50mg/mL.
In one embodiment of the present invention, in step (1), the concentration of 1- (5-hydrazino-2, 4-dinitrophenyl) -4-methylpiperazine in the sample solution is 2mg/mL relative to absolute ethanol.
In one embodiment of the present invention, in step (1), the volume ratio of the sample stock solution to absolute ethanol in the sample solution is 0.3:10.
In one embodiment of the present invention, in step (2), (4R-cis) -6-carbaldehyde-2, 2 dimethyl-1, 3-dioxane-4-acetic acid tert-butyl ester isomer impurities comprise:
in one embodiment of the present invention, in step (2), the concentration of each impurity localization reservoir is 1mg/mL.
In one embodiment of the present invention, in step (2), the concentration of 1- (5-hydrazino-2, 4-dinitrophenyl) -4-methylpiperazine in the impurity localization solution is 2mg/mL relative to absolute ethanol.
In one embodiment of the present invention, in step (2), the volume ratio of the impurity localization reservoir to absolute ethanol in the impurity localization solution is 0.3:10.
In one embodiment of the present invention, in step (3), the volume ratio of n-hexane to absolute ethanol in the mobile phase is 80:20.
In one embodiment of the invention, in step (3), the chromatogram is recorded to 7 times the principal component peak retention time.
In one embodiment of the present invention, in step (3), the flow rate in high performance liquid chromatography is 1.0mL/min.
In one embodiment of the present invention, in step (3), the column temperature in high performance liquid chromatography is 35 ℃.
In one embodiment of the present invention, in step (3), the sample amount in the high performance liquid chromatography column is 20 μl.
In one embodiment of the present invention, in step (3), the detection wavelength in the high performance liquid chromatography column is 350nm.
In one embodiment of the present invention, in step (3), the column of high performance liquid chromatography is CHIRALCEL AY-3 chiral 4.6mm×250mm,5 μm.
In one embodiment of the present invention, the chromatographic conditions for the high performance liquid chromatography detection specifically include: chromatographic column: CHIRALCEL AY-3 (4.6 mm. Times.250 mm,5 μm); the mobile phase is normal hexane-absolute ethyl alcohol (80:20); detection wavelength: 350nm; flow rate: 1.0ml/min; column temperature: 35 ℃; sample injection amount: 20 μl; record to 7 times the main peak retention time.
The second object of the present invention is to provide a method for measuring the content of an impurity of a tert-butyl (4R-cis) -6-carbaldehyde-2, 2-dimethyl-1, 3-dioxane-4-acetate isomer, comprising the steps of:
s1, preparing a test sample solution: dispersing a (4R-cis) -6-formaldehyde-2, 2 dimethyl-1, 3-dioxane-4-tert-butyl acetate sample in acetonitrile, dissolving and diluting to prepare a sample stock solution; dispersing 1- (5-hydrazino-2, 4-dinitrophenyl) -4-methylpiperazine in absolute ethyl alcohol, adding a sample stock solution, uniformly mixing, and performing membrane filtration to obtain a sample solution;
s2, preparing a control solution: taking a sample stock solution in S1, diluting, and taking the sample stock solution as a self-control stock solution; dispersing 1- (5-hydrazino-2, 4-dinitrophenyl) -4-methylpiperazine in absolute ethyl alcohol, adding a self-control stock solution, uniformly mixing, and performing membrane filtration to obtain a control solution;
s3, preparing an impurity positioning solution: taking (4R-cis) -6-formaldehyde-2, 2 dimethyl-1, 3-dioxane-4-tert-butyl acetate isomer impurities, and respectively diluting the impurities into corresponding mixed solutions by acetonitrile to obtain positioning stock solutions of the impurities; dispersing 1- (5-hydrazino-2, 4-dinitrophenyl) -4-methylpiperazine in absolute ethyl alcohol, and respectively adding corresponding impurity positioning stock solutions; mixing uniformly, and filtering by a membrane to obtain an impurity positioning solution;
s4, high performance liquid chromatography determination: respectively carrying out high performance liquid chromatography detection on the sample solution obtained in the step S1, the control solution obtained in the step S2 and the impurity positioning solution obtained in the step S3, wherein the mobile phase is n-hexane-absolute ethyl alcohol; separating and positioning each impurity through an impurity positioning solution; and respectively collecting the peak areas of the impurities in the sample solution, comparing the peak areas of the main components in the solution, and measuring the content of the impurities by a self-comparison method.
In one embodiment of the invention, in S1, the sample concentration in the test sample stock solution is 50mg/mL.
In one embodiment of the present invention, the concentration of 1- (5-hydrazino-2, 4-dinitrophenyl) -4-methylpiperazine in the test solution in S1 is 2mg/mL relative to absolute ethanol.
In one embodiment of the present invention, in S1, the volume ratio of the sample stock solution to absolute ethanol in the sample solution is 0.3:10.
In one embodiment of the present invention, in S2, the test sample stock solution is diluted 200 times to obtain a self-control stock solution.
In one embodiment of the invention, the concentration of 1- (5-hydrazino-2, 4-dinitrophenyl) -4-methylpiperazine in the control solution in S2 is 2mg/mL relative to absolute ethanol.
In one embodiment of the invention, in S2, the volume ratio of the self-control stock solution to absolute ethanol in the control solution is 0.3:10.
In one embodiment of the invention, in S3, (4R-cis) -6-carbaldehyde-2, 2 dimethyl-1, 3-dioxane-4-acetic acid tert-butyl ester isomer impurities comprise:
in one embodiment of the present invention, in S3, the concentration of each impurity localization reservoir is 1mg/mL.
In one embodiment of the invention, the concentration of S3, 1- (5-hydrazino-2, 4-dinitrophenyl) -4-methylpiperazine in the impurity localization solution is 2mg/mL relative to absolute ethanol.
In one embodiment of the present invention, in S3, the volume ratio of the impurity localization reservoir to the absolute ethanol in the impurity localization solution is 0.3:10.
In one embodiment of the invention, in S4, the volume ratio of n-hexane to absolute ethanol in the mobile phase is 80:20.
In one embodiment of the invention, in S4, the chromatogram is recorded to 7 times the principal component peak retention time.
In one embodiment of the present invention, in S4, the flow rate in high performance liquid chromatography is 1.0mL/min.
In one embodiment of the present invention, in S4, the column temperature in high performance liquid chromatography is 35 ℃.
In one embodiment of the present invention, in S4, the sample amount in the hplc column is 20 μl.
In one embodiment of the present invention, in S4, the detection wavelength in the high performance liquid chromatography column is 350nm.
In one embodiment of the present invention, in S4, the high performance liquid chromatography column is CHIRALCEL AY-3 chiral 4.6mm.times.250 mm,5 μm.
In one embodiment of the present invention, in S4, the calculation formula of the self-collation method is as follows:
impurity% = (a Impurity(s) /A Control )*(C Control /C Test article )*100％
Wherein: a is that Impurity(s) The peak area of each isomer impurity in the sample; a is that Control Is the peak area of the main component in the control solution; c (C) Control The concentration of the control solution (the concentration of the main component in the control solution); c (C) Test article The concentration of the sample solution (the concentration of the sample (main component) in the sample solution).
In one embodiment of the present invention, the chromatographic conditions for the high performance liquid chromatography detection specifically include: chromatographic column: CHIRALCEL AY-3 (4.6 mm. Times.250 mm,5 μm); the mobile phase is normal hexane-absolute ethyl alcohol (80:20); detection wavelength: 350nm; flow rate: 1.0mL/min; column temperature: 35 ℃; sample injection amount: 20 μl; record to 7 times the main peak retention time.
The invention has the beneficial effects that:
the method can effectively separate the (4R-cis) -6-formaldehyde-2, 2 dimethyl-1, 3-dioxane-4-tert-butyl acetate from isomer impurities (the separation degree between the impurity peaks is more than or equal to 1.5), so that the content of each impurity can be accurately measured, the stability is high, the reliability is high, and a reliable basis is provided for controlling the impurities of the (4R-cis) -6-formaldehyde-2, 2 dimethyl-1, 3-dioxane-4-tert-butyl acetate, thereby being beneficial to ensuring the quality of downstream products.
Drawings
FIG. 1 is a chromatogram of a test solution.
FIG. 2 is a chromatogram of a control solution.
Fig. 3 is a chromatogram of an impurity localization solution.
Fig. 4 is a schematic diagram of the rosuvastatin calcium synthesis route.
Fig. 5 is a diagram of the impurity derivatization of rosuvastatin calcium isomer.
Detailed Description
The present invention will be described in more detail by way of examples. It is also to be understood that the following examples are given solely for the purpose of illustration and are not to be construed as limitations on the scope of the invention, since various modifications and adaptations may be made by those skilled in the art in light of the teachings herein. The specific process parameters and the like described below are also merely examples of suitable ranges, i.e., one skilled in the art can make a selection within the suitable ranges by the description herein and are not intended to be limited to the specific data described below.
The structural formula of each isomer impurity is as follows:
(4S-cis) -6-carbaldehyde-2, 2-dimethyl-1, 3-dioxane-4-acetic acid tert-butyl ester (Z1 for short)
2- [ (4R, 6R) -6-formyl-2, 2-dimethyl-1, 3-dioxan-4-yl ] acetic acid tert-butyl ester (abbreviated as Z2)
2- [ (4S, 6S) -6-formyl-2, 2-dimethyl-1, 3-dioxan-4-yl ] acetic acid tert-butyl ester (abbreviated as Z3)
Example 1 isolation detection of (4R-cis) -6-carbaldehyde-2, 2-dimethyl-1, 3-dioxane-4-acetic acid tert-butyl ester impurity
(1) Sample solution preparation: taking the product ((4R-cis) -6-formaldehyde-2, 2 dimethyl-1, 3-dioxane-4-tert-butyl acetate), adding acetonitrile to dissolve and dilute the product to prepare a solution containing 50mg of the product in each 1mL, and shaking the solution uniformly to serve as a sample stock solution; 20mg of 1- (5-hydrazino-2, 4-dinitrophenyl) -4-methylpiperazine is taken, precisely weighed, placed in a 25mL measuring flask, precisely added with 10mL of absolute ethyl alcohol, sonicated for 5 minutes, precisely added with 0.3mL of sample stock solution, strongly shaken for 10 minutes at 30-40 ℃, immediately filtered by a 0.45 mu m filter membrane, and taken as sample solution.
(2) Control solution preparation: precisely measuring 1mL of a sample stock solution, placing the sample stock solution into a 200mL measuring flask, diluting with acetonitrile to a scale, and shaking uniformly to serve as a self-control stock solution; 20mg of 1- (5-hydrazino-2, 4-dinitrophenyl) -4-methylpiperazine is precisely weighed and placed in a 25mL measuring flask, 10mL of absolute ethyl alcohol is precisely added, ultrasound is carried out for 5 minutes, 0.3mL of self-control stock solution is precisely added, strong shaking is carried out for 10 minutes at the temperature of 30-40 ℃, a filter membrane with the thickness of 0.45 mu m is immediately used for filtering, and the filtrate is taken as a control solution.
(3) Preparing an impurity positioning solution: taking proper amounts of isomer impurities Z1, Z2 and Z3, and adding acetonitrile to dilute to prepare mixed solution containing 1mg of each impurity Z1, Z2 and Z3 in each 1mL, and taking the mixed solution as an impurity positioning stock solution; 20mg of 1- (5-hydrazino-2, 4-dinitrophenyl) -4-methylpiperazine is taken and placed in a 25mL measuring flask, 10mL of absolute ethyl alcohol is precisely added, ultrasound is carried out for 5 minutes, 0.3mL of impurity positioning stock solution is precisely added, strong shaking is carried out for 10 minutes at 30-40 ℃, a 0.45 mu m filter membrane is immediately used for filtering, and filtrate is taken as impurity positioning solution.
(4) High performance liquid chromatography separation and detection:
the chromatographic conditions were as follows: chromatographic column: CHIRALCEL AY-3 (4.6 mm. Times.250 mm,5 μm); the mobile phase is normal hexane-absolute ethyl alcohol (80:20); detection wavelength: 350nm; flow rate: 1.0mL/min; column temperature: 35 ℃; sample injection amount: 20. Mu.L; record to 7 times the main peak retention time.
And (3) injecting the sample solution in the step (1) into a high performance liquid chromatograph, and recording a chromatogram (shown in figure 1).
Injecting the control solution in the step (2) into a high performance liquid chromatograph, and recording a chromatogram (as shown in fig. 2, wherein 9.420min is the retention time of the main component in the control solution).
Injecting the impurity localization solution in the step (3) into a high performance liquid chromatograph, and recording a chromatogram (as shown in fig. 3).
Comparing the peak area of the control solution with the peak area of the impurity in the sample solution (called as self-control method), and determining the content of the impurity in the sample, wherein the calculation formula is as follows:
impurity% = (a Impurity(s) /A Control )*(C Control /C Test article )*100％
Wherein: a is that Impurity(s) The peak area of each isomer impurity in the sample; a is that Control Is the peak area of the main component in the control solution; c (C) Control The concentration of the control solution (the concentration of the main component in the control solution); c (C) Test article The concentration of the sample solution (the concentration of the sample in the sample solution (main)Component(s).
And precisely measuring 20 mu L of impurity positioning solution, injecting the solution into liquid chromatograph, recording the chromatogram, and observing impurity positioning results in table 1.
Table 1 results of System suitability investigation
As can be seen from table 1: the separation degree between any adjacent peaks is larger than 1.5, which shows that (4R-cis) -6-formaldehyde-2, 2 dimethyl-1, 3-dioxane-4-tert-butyl acetate and isomer impurities are well separated, and a favorable precondition is provided for accurately testing the content of the (4R-cis) -6-formaldehyde-2, 2 dimethyl-1, 3-dioxane-4-tert-butyl acetate isomer impurities.
Example 2 precision of sample injection investigation
Preparing a solution: the impurities Z1, Z2 and Z3 are taken as reference substances, a proper amount of the reference substances is precisely weighed, acetonitrile is added for dissolution and dilution to prepare a solution containing 1.5 mug per 1mL, 20 mug of the solution is precisely measured as a sample injection precision solution, the solution is injected into a liquid chromatograph, the sample is continuously injected for 6 times, and the relative standard deviation of the retention time and the peak area is examined, and the result is shown in Table 2.
Table 2 results of sample injection precision investigation
Example 3 linear Range investigation of (4R-cis) -6-formyloxy-2, 2-dimethyl-1, 3-dioxane-4-acetic acid tert-butyl ester impurity
Preparing a solution: taking a proper amount of the reference substances of the impurities Z1, Z2 and Z3, precisely weighing, adding acetonitrile for dissolving and diluting to prepare a solution with a series of concentrations (12-2000 mug/mL, which is equivalent to 0.024% -4% of the concentration of the sample) as a linear solution.
Respectively weighing 20mg of 1- (5-hydrazino-2, 4-dinitrophenyl) -4-methylpiperazine, placing in a 25mL measuring flask, precisely adding 10mL of absolute ethyl alcohol, carrying out ultrasonic treatment for 5 minutes, precisely adding 0.3mL of each linear solution, carrying out strong shaking for 10 minutes at 30-40 ℃, immediately filtering with a 0.45 mu m filter membrane, precisely measuring 20 mu L of the subsequent filtrate, injecting into a liquid chromatograph according to the high performance liquid chromatography separation detection process in the step (4) of the example 1, and recording a chromatogram to obtain a peak area value; and (5) linearly correlating the peak area value with the corresponding concentration to obtain the quantitative detection model. Slope, Y-axis intercept and correlation coefficient are calculated.
The linear results were:
the impurity Z1 has good linear relation between concentration and peak area within the range of 12.04-1925.80 mug/mL, and the quantitative detection model is y= 292.2494x-1684.0854, R 2 =0.9998, greater than 0.9990.
The impurity Z2 is in the range of 12.51-2001.60 mug/mL, the concentration and the peak area are in good linear relation, the quantitative detection model is y= 398.8017x-8298.8876, R 2 =0.9997, greater than 0.9990.
The impurity Z3 is in the range of 12.69-2031.00 mug/mL, the concentration and the peak area are in good linear relation, the quantitative detection model is y= 351.7258x-3080.2099, R 2 =0.9998, greater than 0.9990.
Detection limit and quantitative limit:
preparing a solution: taking Z1, Z2 and Z3 reference substances, precisely weighing, adding acetonitrile for dissolution and stepwise dilution, measuring the detection limit according to the triple response value of the instrument noise, and measuring the quantitative limit according to the ten-time response value of the instrument noise. The test results are shown in Table 3.
TABLE 3 sensitivity results
Conclusion: the detection method in the embodiment 1 has higher sensitivity and meets the detection requirement.
EXAMPLE 4 solution stability
According to the detection method of the sample in the embodiment, 1 part of the solution of the sample is prepared, the sample is placed for 24 hours under the freezing condition, the impurity content and the impurity number are not obviously changed, and the solution stability is good.
Example 5 accuracy investigation
Preparing a test solution:
preparing a reference substance solution: and taking proper amounts of isomer impurities Z1, Z2 and Z3, and adding acetonitrile to dilute to prepare mixed solution containing 50 mug of the impurities Z1, Z2 and Z3 in each 1mL serving as a reference substance solution.
Preparing a recovery rate solution: taking 250mg of the product, 9 parts in parallel, precisely weighing, respectively placing into 5mL measuring flask, precisely adding three impurity Z1, Z2 and Z3 stock solutions with high, medium and low concentrations, respectively, adding acetonitrile for dilution to scale, and shaking uniformly to obtain the product.
The operation is as follows: 20mg of 1- (5-hydrazino-2, 4-dinitrophenyl) -4-methylpiperazine is taken, precisely weighed, placed in a 25mL measuring flask, precisely added with 10mL of absolute ethyl alcohol, sonicated for 5 minutes, precisely added with 0.3mL of reference substance solution and recovery rate solution, strongly shaken for 10 minutes at 30-40 ℃, immediately filtered by a 0.45 mu m filter membrane, precisely measured and added with 20 mu L of subsequent filtrate, injected into a liquid chromatograph, and the recovery rate is calculated by recording a chromatogram.
The accuracy results show that the recovery rates of the impurities Z1, Z2 and Z3 are all 80-120%, and the accuracy of the method is high.
Comparative example 1
Preparing a mixed solution: taking proper amounts of the product, the Z1 reference substance, the Z2 reference substance and the Z3 reference substance, and dissolving with dimethyl sulfoxide to prepare solutions containing 0.5mg each 1 mL.
Determination by gas chromatography, gas chiral chromatography column Agelient CYCLOSIL-B (30 m.times.0.25 mm,0.25 μm); heating to the initial column temperature of 100 ℃, heating to 200 ℃ at the speed of 5 ℃/min, and keeping for 20 minutes; the temperature of the sample inlet is 250 ℃; the detector temperature was 280 ℃; the nitrogen flow rate is 0.5mL/min; the separation ratio is 20:1; the sample injection amount was 1. Mu.L.
The results show that: the retention time of the main component and the impurity Z3 is about 20.5 minutes, and the main component and the impurity Z3 cannot be separated.
Comparative example 2
The measurement by high performance liquid chromatography was carried out with the same column, mobile phase, flow rate, column temperature, and sample introduction amount as in example 1, except that the sample and impurities were not derivatized
Preparing an impurity positioning solution: taking proper amounts of impurity Z1 reference substance, Z2 reference substance and Z3 reference substance, and respectively preparing into solutions containing 0.5mg of each 1mL by using mobile phases (n-hexane-absolute ethyl alcohol 80:20).
The results show that: when the impurity concentration was 0.5mg/mL, no peak was observed in the sample and the impurity, and it was found that 1- (5-hydrazino-2, 4-dinitrophenyl) -4-methylpiperazine was not added.
Comparative example 3
The detection procedure was the same as in example 1, except that the chiral chromatographic column was chosen differently:
measuring by high performance liquid chromatography, wherein the chromatographic column is CHIRALCEL AD-H; the mobile phase is n-hexane-absolute ethanol (80:20) detection wavelength: 350nm; flow rate: 1.0mL/min; column temperature: 35 ℃; sample injection amount: 20. Mu.L.
The results show that: the retention time of the impurities Z1 and Z2 is about 16 minutes, and the impurities are completely overlapped.
Comparative example 4
The detection procedure was the same as in example 1, except that the mobile phase conditions in the high performance liquid chromatography were different:
the chromatographic conditions were as follows: chromatographic column: CHIRALCEL AY-3 (4.6 mm. Times.250 mm,5 μm); mobile phase conditions are shown in table 4; detection wavelength: 350nm; flow rate: 1.0mL/min; column temperature: 35 ℃; sample injection amount: 20. Mu.L; record to 7 times the main peak retention time.
TABLE 4 detection results of different mobile phases
Claims (6)
1. The separation and detection method of the (4R-cis) -6-formaldehyde-2, 2 dimethyl-1, 3-dioxane-4-tert-butyl acetate isomer impurity is characterized by comprising the following steps:
(1) Sample liquid preparation: dispersing a (4R-cis) -6-formaldehyde-2, 2 dimethyl-1, 3-dioxane-4-tert-butyl acetate sample in acetonitrile, dissolving and diluting to obtain a sample stock solution; dispersing 1- (5-hydrazino-2, 4-dinitrophenyl) -4-methylpiperazine in absolute ethyl alcohol, then adding a sample stock solution, uniformly mixing, and performing membrane filtration to obtain a sample solution;
(2) Preparing an impurity positioning solution: taking (4R-cis) -6-formaldehyde-2, 2 dimethyl-1, 3-dioxane-4-tert-butyl acetate isomer impurities, and respectively diluting the impurities into corresponding mixed solutions by acetonitrile to obtain positioning stock solutions of the impurities; dispersing 1- (5-hydrazino-2, 4-dinitrophenyl) -4-methylpiperazine in absolute ethyl alcohol, and respectively adding corresponding impurity positioning stock solutions; mixing uniformly, and filtering by a membrane to obtain an impurity positioning solution;
(3) High performance liquid chromatography detection: taking n-hexane-absolute ethyl alcohol as a mobile phase, performing high performance liquid chromatography detection on the impurity positioning solution to realize impurity separation and obtain corresponding chromatographic information; then, high performance liquid chromatography detection is carried out on the sample liquid, and impurities in the sample are separated and detected by contrasting the chromatographic information of the impurity positioning solution;
the (4R-cis) -6-formyl-2, 2-dimethyl-1, 3-dioxane-4-acetic acid tert-butyl ester isomer impurities comprise:
、/>、/>；
the chromatographic conditions for high performance liquid chromatography detection specifically include: chromatographic column: CHIRALCEL AY-3, 4.6mm.times.250mm, 5 μm; the mobile phase is n-hexane-absolute ethyl alcohol 80:20 mobile phase; detection wavelength: 350nm; flow rate: 1.0ml/min; column temperature: 35 ℃; sample injection amount: 20 μl.
2. The method of claim 1, wherein in step (1), the concentration of the sample in the sample reservoir is 50mg/mL.
3. The method according to claim 1, wherein in the step (1), the concentration of 1- (5-hydrazino-2, 4-dinitrophenyl) -4-methylpiperazine in the sample solution is 2mg/mL relative to absolute ethanol.
4. The method of claim 1, wherein in step (1), the volume ratio of the sample stock solution to absolute ethanol in the sample solution is 0.3:10.
5. The method of claim 1, wherein in step (2), the concentration of each impurity localization reservoir is 1mg/mL.
6. The method for measuring the content of the (4R-cis) -6-formaldehyde-2, 2 dimethyl-1, 3-dioxane-4-tert-butyl acetate isomer impurity is characterized by comprising the following steps of:
s1, preparing a test sample solution: dispersing a (4R-cis) -6-formaldehyde-2, 2 dimethyl-1, 3-dioxane-4-tert-butyl acetate sample in acetonitrile, dissolving and diluting to prepare a sample stock solution; dispersing 1- (5-hydrazino-2, 4-dinitrophenyl) -4-methylpiperazine in absolute ethyl alcohol, adding a sample stock solution, uniformly mixing, and performing membrane filtration to obtain a sample solution;
s2, preparing a control solution: taking a sample stock solution in S1, diluting, and taking the sample stock solution as a self-control stock solution; dispersing 1- (5-hydrazino-2, 4-dinitrophenyl) -4-methylpiperazine in absolute ethyl alcohol, adding a self-control stock solution, uniformly mixing, and performing membrane filtration to obtain a control solution;
s3, preparing an impurity positioning solution: taking (4R-cis) -6-formaldehyde-2, 2 dimethyl-1, 3-dioxane-4-tert-butyl acetate isomer impurities, and respectively diluting the impurities into corresponding mixed solutions by acetonitrile to obtain positioning stock solutions of the impurities; dispersing 1- (5-hydrazino-2, 4-dinitrophenyl) -4-methylpiperazine in absolute ethyl alcohol, and respectively adding corresponding impurity positioning stock solutions; mixing uniformly, and filtering by a membrane to obtain an impurity positioning solution;
s4, high performance liquid chromatography determination: respectively carrying out high performance liquid chromatography detection on the sample solution obtained in the step S1, the control solution obtained in the step S2 and the impurity positioning solution obtained in the step S3, wherein the mobile phase is n-hexane-absolute ethyl alcohol; separating and positioning each impurity through an impurity positioning solution; respectively collecting peak areas of impurities in the sample solution, comparing the peak areas of main components in the solution, and measuring the content of the impurities by a self-comparison method;
the (4R-cis) -6-formyl-2, 2-dimethyl-1, 3-dioxane-4-acetic acid tert-butyl ester isomer impurities comprise:
、/>、/>；
the chromatographic conditions for high performance liquid chromatography detection specifically include: chromatographic column: CHIRALCEL AY-3, 4.6mm.times.250mm, 5 μm; the mobile phase is n-hexane-absolute ethyl alcohol 80:20 mobile phase; detection wavelength: 350nm; flow rate: 1.0ml/min; column temperature: 35 ℃; sample injection amount: 20 μl.
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