CN115032297B - Separation detection method of trans-1, 2-diaminomethyl cyclobutane and cis isomer thereof - Google Patents
Separation detection method of trans-1, 2-diaminomethyl cyclobutane and cis isomer thereof Download PDFInfo
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- 238000001514 detection method Methods 0.000 title claims abstract description 81
- ZBLACDIKXKCJGF-WDSKDSINSA-N [(1r,2r)-2-(aminomethyl)cyclobutyl]methanamine Chemical compound NC[C@@H]1CC[C@H]1CN ZBLACDIKXKCJGF-WDSKDSINSA-N 0.000 title claims abstract description 29
- 238000000926 separation method Methods 0.000 title abstract description 26
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 75
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims abstract description 64
- 238000000034 method Methods 0.000 claims abstract description 22
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 238000001212 derivatisation Methods 0.000 claims abstract description 16
- 239000002904 solvent Substances 0.000 claims abstract description 16
- 239000012046 mixed solvent Substances 0.000 claims abstract description 15
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 10
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 7
- 238000010521 absorption reaction Methods 0.000 claims abstract description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 45
- 239000012488 sample solution Substances 0.000 claims description 25
- YHOYYHYBFSYOSQ-UHFFFAOYSA-N 3-methylbenzoyl chloride Chemical compound CC1=CC=CC(C(Cl)=O)=C1 YHOYYHYBFSYOSQ-UHFFFAOYSA-N 0.000 claims description 23
- 239000003085 diluting agent Substances 0.000 claims description 23
- 239000000523 sample Substances 0.000 claims description 22
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 8
- 238000012360 testing method Methods 0.000 claims description 7
- 238000004090 dissolution Methods 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 238000002347 injection Methods 0.000 claims description 5
- 239000007924 injection Substances 0.000 claims description 5
- 239000002245 particle Substances 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- JXASPPWQHFOWPL-UHFFFAOYSA-N Tamarixin Natural products C1=C(O)C(OC)=CC=C1C1=C(OC2C(C(O)C(O)C(CO)O2)O)C(=O)C2=C(O)C=C(O)C=C2O1 JXASPPWQHFOWPL-UHFFFAOYSA-N 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 239000007795 chemical reaction product Substances 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- XSMVECZRZBFTIZ-UHFFFAOYSA-M [2-(aminomethyl)cyclobutyl]methanamine;2-oxidopropanoate;platinum(4+) Chemical compound [Pt+4].CC([O-])C([O-])=O.NCC1CCC1CN XSMVECZRZBFTIZ-UHFFFAOYSA-M 0.000 abstract description 23
- 229950008991 lobaplatin Drugs 0.000 abstract description 22
- 239000007858 starting material Substances 0.000 abstract description 22
- 239000000945 filler Substances 0.000 abstract description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 abstract description 8
- 239000007983 Tris buffer Substances 0.000 abstract description 8
- 239000000741 silica gel Substances 0.000 abstract description 8
- 229910002027 silica gel Inorganic materials 0.000 abstract description 8
- SBTVLCPCSXMWIQ-UHFFFAOYSA-N (3,5-dimethylphenyl) carbamate Chemical compound CC1=CC(C)=CC(OC(N)=O)=C1 SBTVLCPCSXMWIQ-UHFFFAOYSA-N 0.000 abstract description 7
- 238000004458 analytical method Methods 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 46
- -1 1, 2-diaminomethyl-cyclobutane-lactic acid platinum Chemical compound 0.000 description 20
- 238000002156 mixing Methods 0.000 description 18
- 230000000052 comparative effect Effects 0.000 description 16
- 239000007788 liquid Substances 0.000 description 16
- 239000011550 stock solution Substances 0.000 description 16
- 239000012535 impurity Substances 0.000 description 15
- 238000007865 diluting Methods 0.000 description 12
- 239000012085 test solution Substances 0.000 description 10
- 239000000047 product Substances 0.000 description 8
- 239000013558 reference substance Substances 0.000 description 7
- 238000010998 test method Methods 0.000 description 7
- 238000005303 weighing Methods 0.000 description 7
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 5
- 239000012483 derivatization solution Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000002516 radical scavenger Substances 0.000 description 5
- 238000011084 recovery Methods 0.000 description 5
- 238000003908 quality control method Methods 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000005917 acylation reaction Methods 0.000 description 3
- 238000010812 external standard method Methods 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 238000010829 isocratic elution Methods 0.000 description 3
- 238000011002 quantification Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- 101000652482 Homo sapiens TBC1 domain family member 8 Proteins 0.000 description 2
- 102100030302 TBC1 domain family member 8 Human genes 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- BLOXTRRBJWXTGT-UHFFFAOYSA-N cyclobutylmethanediamine Chemical compound NC(N)C1CCC1 BLOXTRRBJWXTGT-UHFFFAOYSA-N 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 239000012088 reference solution Substances 0.000 description 2
- KZCXMZLEEWLBFE-UHFFFAOYSA-N (3-chloro-4-methylphenyl) carbamate Chemical compound CC1=CC=C(OC(N)=O)C=C1Cl KZCXMZLEEWLBFE-UHFFFAOYSA-N 0.000 description 1
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 1
- GPZXFICWCMCQPF-UHFFFAOYSA-N 2-methylbenzoyl chloride Chemical compound CC1=CC=CC=C1C(Cl)=O GPZXFICWCMCQPF-UHFFFAOYSA-N 0.000 description 1
- 241001132374 Asta Species 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- ZBLACDIKXKCJGF-UHFFFAOYSA-N [2-(aminomethyl)cyclobutyl]methanamine Chemical compound NCC1CCC1CN ZBLACDIKXKCJGF-UHFFFAOYSA-N 0.000 description 1
- ZVQOOHYFBIDMTQ-UHFFFAOYSA-N [methyl(oxido){1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-lambda(6)-sulfanylidene]cyanamide Chemical compound N#CN=S(C)(=O)C(C)C1=CC=C(C(F)(F)F)N=C1 ZVQOOHYFBIDMTQ-UHFFFAOYSA-N 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 150000001412 amines Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012490 blank solution Substances 0.000 description 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- G—PHYSICS
- 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
-
- G—PHYSICS
- 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
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of analysis and detection, and particularly relates to a separation and detection method of trans-1, 2-diaminomethyl cyclobutane and cis-isomer thereof. The invention provides a method for detecting cis-isomer or cis-isomer salt contained in trans-1, 2-diaminomethyl cyclobutane or salt thereof, which comprises the following steps: carrying out derivatization reaction on a sample to be detected and a derivatization reagent with ultraviolet absorption, and then carrying out qualitative and/or quantitative detection on cis-isomer or salt thereof by adopting HPLC, wherein a chromatographic column filling agent is silica gel with the surface coated with amylose-tris (3, 5-dimethylphenylcarbamate), and a mobile phase solvent is a mixed solvent of n-hexane and isopropanol, wherein n-hexane: the volume ratio of the isopropanol is (88:12) - (92:8). The detection method provided by the invention can realize qualitative and quantitative detection of cis-isomer contained in the lobaplatin starting material trans-1, 2-diaminomethyl cyclobutane.
Description
Technical Field
The invention belongs to the technical field of analysis and detection, and particularly relates to a separation and detection method of trans-1, 2-diaminomethyl cyclobutane and cis-isomer thereof.
Background
Lobaplatin is a third-generation platinum anti-tumor drug originally developed by the German Aishida pharmaceutical Co (ASTA medical AG), belongs to an alkylating anti-tumor drug and is commonly applied to chronic granulocytic leukemia, advanced breast cancer and small cell lung cancer. Lobaplatin, having the chemical name 1, 2-diaminomethyl-cyclobutane-lactic acid platinum, has the chemical structure shown below:
lobaplatin is a mixture of two diastereomers according to the pharmaceutical standard:
trans-1, 2-diaminomethyl cyclobutane is a key starting material for synthesizing lobaplatin, but cis-isomer often exists in the starting material, and the cis-isomer is gradually transferred into lobaplatin bulk pharmaceutical chemicals of a final product through a synthetic route, and lobaplatin which is not a medicinal component is generated, such as lobaplatin isomer impurity C with the structure shown in the specification, so that the product quality is influenced.
Therefore, separation and detection of cis-isomer in trans-1, 2-diaminomethyl cyclobutane as starting material is necessary, and has important significance for product quality control.
To date, no relevant literature report exists on a method for separating and detecting trans-1, 2-diaminomethyl cyclobutane and cis isomer of the trans-1, 2-diaminomethyl cyclobutane, and a rapid and accurate detection method is required to be developed.
Disclosure of Invention
In order to fill the blank of the prior art, the invention provides a separation detection method of trans-1, 2-diaminomethyl cyclobutane and cis-isomer thereof.
The invention provides a method for detecting cis-isomer or cis-isomer salt contained in trans-1, 2-diaminomethyl cyclobutane or salt thereof, which comprises the steps of carrying out derivatization reaction on a sample to be detected and a derivatization reagent with ultraviolet absorption, and then carrying out qualitative and/or quantitative detection on the cis-isomer or salt thereof by adopting HPLC (high performance liquid chromatography), wherein a chromatographic column filling agent is silica gel with the surface coated with amylose-tris (3, 5-dimethylphenylcarbamate), and a mobile phase solvent is a mixed solvent of n-hexane and isopropanol, wherein n-hexane: the volume ratio of the isopropanol is (88:12) - (92:8).
The main function of the derivatizing reagent is to convert the compound without/weak ultraviolet absorption into the compound with/strong ultraviolet absorption, so that the derivatizing reagent is convenient to detect by a liquid chromatograph with an ultraviolet detector.
Further, the chromatographic column is selected from at least one of CHIRALPAK AD-3, CHIRALPAK AD-H and CHIRALPAK AD or equivalent chromatographic columns thereof. Among them, CHIRALPAK AD-3, CHIRALPAK AD-H and CHIRALPAK AD are more common chromatographic columns with amylose-tris (3, 5-dimethylphenylcarbamate) coated on the surface as filler.
Preferably, the chromatographic column is CHIRALPAK AD-H or an equivalent chromatographic column thereof.
Further, the inner diameter of the chromatographic column CHIRALPAK AD-H is 2.1-20 mm, the length is 10-250 mm, and the particle size of the filler is 5 mu m. Currently, the commercial CHIRALPAK AD-H chromatographic column has the inner diameter of 2.1-20 mm, the length of 10-250 mm and the filler particle diameter of 5 μm.
Preferably, the column CHIRALPAK AD-H has an inner diameter of 4.6mm.
Preferably, the chromatographic column CHIRALPAK AD-H has a length of 100 to 250mm. For CHIRALPAK AD-H chromatographic columns, analytical column lengths currently available for commercial use are in the range of 100 to 250mm.
More preferably, the chromatographic column CHIRALPAK AD-H has a length of 250mm.
Further, the mobile phase solvent is a mixed solvent of n-hexane and isopropanol, wherein n-hexane: the volume ratio of the isopropyl alcohol is (89:11) - (91:9).
Preferably, the mobile phase solvent is a mixed solvent of n-hexane and isopropanol, wherein n-hexane: the volume ratio of isopropanol is 90:10.
further, a tail scavenger is added in the mobile phase. The addition of the tail scavenger in the mobile phase is beneficial to improving the peak shape, so that the accuracy and precision of the detection result are higher.
Preferably, the tail scavenger is an amine tail scavenger.
More preferably, the tail scavenger is diethylamine.
Preferably, diethylamine accounting for 0.08-0.12% of the volume fraction of the mobile phase solvent is added in the mobile phase.
More preferably, diethylamine is added to the mobile phase in a volume fraction of 0.1% of the mobile phase solvent.
Further, the flow rate is 0.6-1.0 mL/min.
Preferably, the flow rate is 0.6 to 0.8mL/min.
More preferably, the flow rate is 0.6mL/min or 0.8mL/min.
Further, the column temperature is 28-32 ℃.
Preferably, the column temperature is 30 ℃.
Further, the detection wavelength is 235+ -5 nm.
Preferably, the detection wavelength is 235nm.
Further, the preparation of the test solution comprises the following derivatization steps: and (3) carrying out an acylation reaction on the sample to be detected and m-methylbenzoyl chloride to generate an amide compound.
Preferably, the acylation reaction is carried out with 40 to 160. Mu.L of m-methylbenzoyl chloride per 10mg of the sample to be tested.
More preferably, the acylation reaction is carried out with 100. Mu.L of m-methylbenzoyl chloride per 10mg of the sample to be tested.
Preferably, the concentration of the sample solution is 0.8-1.2 mg/ml. In the invention, the concentration of the sample solution is calculated according to the total amount of the sample to be measured. According to some embodiments of the invention, reducing the concentration of the test solution helps to increase the separation of SM1-a peak (cis-isomer) from its post-peak impurities.
More preferably, the concentration of the test solution is 1.0mg/ml.
Preferably, the method for preparing the test solution is as follows: adding 0.5mL of 1.0M sodium hydroxide aqueous solution into every 10mg of sample to be tested for dissolution, adding 100 mu L of M-methylbenzoyl chloride, adding a diluent to 10mL of total volume after the reaction is finished, extracting a reaction product, and collecting an upper layer to obtain the sample solution.
Preferably, the diluent for preparing the test solution is the mobile phase solvent. Namely, a mixed solvent of n-hexane and isopropyl alcohol, wherein n-hexane: isopropyl alcohol volume ratio (88:12) - (92:8), preferably n-hexane: isopropyl alcohol volume ratio (89:11) - (91:9), more preferably n-hexane: the volume ratio of isopropanol is 90:10. according to some specific embodiments of the invention, the mobile phase solvent is used as a diluent to prepare a test solution, the solution stability is better, and the ratio of the peak area of sample injection to the peak area of 0h is 95% when the solution is placed for 24h at 5 ℃ (the temperature of a sample chamber); the mobile phase solvent is used as a diluent, and the ratio of the peak area of sample injection to the peak area of 0h is 94% when the cis-isomer reference substance solution is placed for 24h at 5 ℃.
Further, the sample injection amount is 10-20 mu L. According to some embodiments of the invention, reducing the amount of sample introduced helps to increase the separation of the SM1-a peak (cis-isomer) from its post-peak impurities.
Preferably, the sample loading is 10. Mu.L.
Further, the trans-1, 2-diaminomethyl cyclobutane isOr a mixture thereof.
Further, the cis-isomer is
Wherein the salt of trans-1, 2-diaminomethyl cyclobutane and/or the salt of cis-isomer is hydrochloride.
According to some embodiments of the invention, the mobile phase elution mode employs isocratic elution.
According to some embodiments of the invention, the run time is 40 minutes.
According to some embodiments of the invention, the sample chamber temperature is 5 ℃.
According to some embodiments of the invention, the content of the cis-isomer or salt thereof is calculated as peak area using an external standard method.
According to some embodiments of the invention, the detection method comprises the steps of:
(1) Blank solution: taking 0.5mL of 1M sodium hydroxide solution and 0.1mL of M-methylbenzoyl chloride in a 10mL measuring flask, derivatizing for 1.5min, then fixing the volume by using a diluent, uniformly mixing, standing and taking the upper layer;
(2) Test solution: taking a proper amount of 10mg of trans-1, 2-diaminomethyl cyclobutane hydrochloride, adding 0.5mL of 1.0M sodium hydroxide for dissolution, diluting with a diluent after 0.1mL of m-methylbenzoyl chloride is derived for 1.5min, quantitatively preparing a solution containing about 1.0mg of trans-1, 2-diaminomethyl cyclobutane hydrochloride per 1mL, and taking the upper layer;
(3) Control solution: 10mg of cis-1, 2-diaminomethyl cyclobutane hydrochloride is taken, precisely weighed, dissolved by adding 1.0M sodium hydroxide solution and fixed in volume to prepare a stock solution containing about 0.1mg per 1 mL. Taking 0.5mL of stock solution, adding 0.1mL of m-methylbenzoyl chloride for derivatization for 1.5min, diluting with a diluent, quantitatively diluting to prepare a solution containing about 5 mug of cis-1, 2-diaminomethyl cyclobutane hydrochloride per 1mL, and taking the upper layer;
(4) System applicability solution: taking about 10mg of trans-1, 2-diaminomethyl cyclobutane hydrochloride, adding 0.5mL of 1.0M sodium hydroxide for dissolution, adding 0.5mL of cis-1, 2-diaminomethyl cyclobutane hydrochloride stock solution, uniformly mixing, finally adding 0.1mL of m-methylbenzoyl chloride for derivatization for 1.5min, diluting with a diluent, quantitatively preparing a solution containing about 1.0mg of trans-1, 2-diaminomethyl cyclobutane hydrochloride and about 5 mug of cis-1, 2-diaminomethyl cyclobutane hydrochloride per 1mL, and taking the upper layer;
(5) Setting chromatographic conditions: the chromatographic column adopts CHIRALPAK AD-H with the specification: 250mm by 4.6mm,5 μm; the detection wavelength is 235nm; the mobile phase adopts n-hexane: the mixed solvent with the volume ratio of the isopropanol being 90:10 is subjected to isocratic elution, and the mobile phase contains diethylamine, and the volume fraction of the diethylamine is equivalent to 0.1% of the total volume of the n-hexane and the isopropanol; the flow rate is 0.8mL/min; the column temperature is 30 ℃;
(6) And (3) measuring: taking 10 mu L of each solution in the steps (1), (2) and (3), respectively injecting into a high performance liquid chromatograph, and recording chromatograms;
the diluent in the steps (1) - (4) is a mixed solvent of n-hexane and isopropanol with the volume ratio of 90:10.
The invention provides a separation and detection method of trans-1, 2-diaminomethyl cyclobutane and cis-isomer thereof, which can realize qualitative and quantitative detection of cis-isomer contained in lobaplatin starting material trans-1, 2-diaminomethyl cyclobutane and has the advantages of high accuracy, high sensitivity and good specificity. The separation detection method has wide application prospect and can be used for quality control of lobaplatin and synthetic starting materials thereof.
Drawings
FIG. 1 is a HPLC detection chromatogram of a hollow Bai Yan biochemical solution of example 1 of the present invention;
FIG. 2 is a HPLC detection chromatogram of the sample solution in example 1 of the present invention;
FIG. 3 is a HPLC detection chromatogram of the control solution of example 1 of the present invention;
FIG. 4 is a HPLC detection chromatogram of the system applicability solution in example 1 of the present invention;
FIG. 5 is a chromatogram obtained by injecting the labeled sample solution into a liquid chromatograph at a chromatographic condition flow rate of 0.6mL/min in example 4 of the present invention;
FIG. 6 is a chromatogram obtained by injecting the labeled sample solution into a liquid chromatograph at a chromatographic condition flow rate of 1mL/min in example 4 of the present invention;
FIG. 7 is a chromatogram obtained by injecting a labeled sample solution into a liquid chromatograph when the chromatographic condition column in comparative example 1 of the present invention is CHIRALCEL OZ-3;
FIG. 8 is a chromatogram obtained by injecting a labeled sample solution into a liquid chromatograph when the chromatographic condition column is CHIRALPAK IA in comparative example 2;
FIG. 9 is a chromatogram obtained by injecting a labeled sample solution into a liquid chromatograph when the chromatographic condition column is CHIRALPAK IG in comparative example 3;
FIG. 10 is n-heptane of comparative example 4 with a chromatographic condition mobile phase volume ratio of 90:10: when isopropanol is added, the solution of the sample to be added with the standard is injected into a liquid chromatograph to obtain a chromatogram;
FIG. 11 is a ratio of the mobile phases of the chromatographic conditions in comparative example 5 to the volume of n-hexane of 95:5: when isopropanol is added, the solution of the sample to be added with the standard is injected into a liquid chromatograph to obtain a chromatogram;
FIG. 12 is a ratio of n-hexane with a chromatographic condition to mobile phase volume of 85:15 in comparative example 6 of the present invention: and (3) when isopropanol is added, injecting the labeled sample solution into a liquid chromatograph to obtain a chromatogram.
Detailed Description
The invention provides a method for detecting cis-isomer or cis-isomer salt contained in trans-1, 2-diaminomethyl cyclobutane or salt thereof, which comprises the following steps: carrying out derivatization reaction on a sample to be detected and a derivatization reagent with ultraviolet absorption, and then carrying out qualitative and/or quantitative detection on cis-isomer or salt thereof by adopting HPLC, wherein a chromatographic column filling agent is silica gel with the surface coated with amylose-tris (3, 5-dimethylphenylcarbamate), and a mobile phase solvent is a mixed solvent of n-hexane and isopropanol, wherein n-hexane: the volume ratio of the isopropanol is (88:12) - (92:8).
The present invention has been completed based on the following findings by the inventors: in order to avoid the effect of the cis-1, 2-diaminomethyl cyclobutane to the lobaplatin bulk pharmaceutical of the final product, which is finally transmitted to the lobaplatin bulk pharmaceutical of the final product through a synthetic route, the quality control is required to be carried out from the trans-1, 2-diaminomethyl cyclobutane as a starting material, and the content of cis-isomer is controlled to be very low (less than or equal to 0.5 percent), so that the requirement of effective separation and detection of the trans-1, 2-diaminomethyl cyclobutane and the cis-isomer thereof is raised. However, in the analytical detection process, it is found that not only the trans-isomer and the cis-isomer need to be well separated, but also the cis-isomer is difficult to separate from other impurities (possibly residues of synthetic raw materials or process impurities) in the starting raw materials, and accurate detection results are difficult to obtain. For this purpose, the inventors have thoroughly examined the detection conditions to obtain a column using a filler as a silica gel surface-coated with amylose-tris (3, 5-dimethylphenylcarbamate) and further optimizing the mobile phase composition to be n-hexane: the mixed solvent with the volume ratio of isopropanol of (88:12) - (92:8) can effectively separate trans-form and cis-form 1, 2-diaminomethyl cyclobutane, and cis-form isomers and other impurities in the initial raw materials can be well separated, so that the cis-form isomers can be accurately detected, and the quality control of the initial raw materials and the final products is facilitated.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention. The examples are not to be construed as limiting the specific techniques or conditions described in the literature in this field or as per the specifications of the product. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
The trans-1, 2-diaminomethylcyclobutane described in the examples below is a mixture of two enantiomers, i.eSometimes labeled SM1-1 and SM1-2, or SM1 in the examples. The cis-1, 2-diaminomethylcyclobutane described in the examples below is +.>Sometimes labeled SM1-a in the examples.
Example 1
1. Instrument and conditions
Chromatographic column: adopts filler as chromatographic column with amylose-tri (3, 5-dimethyl phenyl carbamate) silica gel coated on the surface, and in the embodiment, CHIRALPAK AD-H chromatographic column is specifically selected, with the specification: 250mm by 4.6mm,5 μm;
mobile phase: n-hexane: a mixed solvent with the volume ratio of isopropanol of 90:10; wherein the mobile phase contains diethylamine which is equivalent to 0.1% (V/V%) of the total volume of n-hexane and isopropanol;
column temperature: 30 ℃;
sample cell temperature: 5 ℃;
detection wavelength: 235nm;
sample injection volume: 10. Mu.L;
flow rate: 0.8mL/min;
elution mode: isocratic elution;
run time: and 40min.
A diluent: n-hexane: and uniformly mixing the isopropanol according to the volume ratio of 90:10.
Derivatizing agent: methylbenzoyl chloride (AR grade reagent) was used as such.
Blank derivatization solution: taking 0.5mL of 1M sodium hydroxide solution and 0.1mL of M-methylbenzoyl chloride in a 10mL volumetric flask, derivatizing for 1.5min, then fixing the volume by using a diluent, uniformly mixing, standing and taking the upper layer.
Test solution: about 10mg of trans-1, 2-diaminomethyl cyclobutane hydrochloride serving as a lobaplatin starting material is taken, precisely weighed, 0.5mL of 1.0M sodium hydroxide is added for dissolution, 0.1mL of M-methylbenzoyl chloride is added for derivatization for 1.5min, then the solution containing about 1.0mg of trans-1, 2-diaminomethyl cyclobutane hydrochloride per 1mL of the solution is diluted and quantitatively prepared by using a diluent, and the upper layer is taken.
SM1-a control stock solution one: taking about 10mg of cis-1, 2-diaminomethyl cyclobutane hydrochloride, precisely weighing, placing into a 100mL measuring flask, adding 1.0M sodium hydroxide to dissolve and dilute to scale, and taking the mixture as a stock solution I of a cis-1, 2-diaminomethyl cyclobutane hydrochloride reference substance;
SM1-a control stock solution two: precisely weighing 1 mL-20 mL measuring flask of SM1-A reference stock solution I, adding 1.0M sodium hydroxide to dissolve and dilute to scale, and taking as SM1-A reference stock solution II.
SM1-a control solution: precisely measuring 0.5mL of SM1-A reference stock solution, placing in a 10mL measuring flask, adding 0.1mL of m-methylbenzoyl chloride for derivatization for about 1.5min, diluting with a diluent, quantitatively preparing a solution containing about 5 mug of cis-1, 2-diaminomethyl cyclobutane hydrochloride per 1mL, uniformly mixing, standing, and taking the upper layer.
System applicability solution: taking about 10mg of trans-1, 2-diaminomethyl cyclobutane hydrochloride, precisely weighing, adding 0.5mL of 1.0M sodium hydroxide solution for dissolution, adding 0.5mL of cis-1, 2-diaminomethyl cyclobutane hydrochloride reference stock solution, uniformly mixing, finally adding about 1.5min of m-methylbenzoyl chloride derivative, diluting with a diluent and quantitatively preparing a solution containing about 1.0mg of trans-1, 2-diaminomethyl cyclobutane hydrochloride and about 5 mug of cis-1, 2-diaminomethyl cyclobutane hydrochloride per 1mL, uniformly mixing, standing, and taking the upper layer.
Adding a labeled test sample solution: taking lobaplatin starting material trans-1, 2-diaminomethyl cyclobutane hydrochloride SM1 about 10mg, placing into a 10mL measuring flask, precisely adding 0.25mL of SM1-A reference substance stock solution, adding 0.5mL of 1.0M sodium hydroxide solution to rinse the wall of the flask, uniformly mixing, finally adding 0.1mL of m-methylbenzoyl chloride to derive about 1.5min, diluting with a diluent, fixing the volume, uniformly mixing, standing, and taking the upper layer.
2. Detection method
The test method comprises the following steps: respectively precisely measuring 10 mu L of blank derivatization solution, test sample solution, reference substance solution and system applicability solution, injecting into a liquid chromatograph, recording the chromatogram, and calculating cis-isomer content of lobaplatin starting material according to external standard method and peak area, wherein the cis-isomer content is shown as
In which A X Is SM1-A area in the sample solution;
A R is the average value of the SM1-A area in the reference substance solution;
C R is the concentration of the reference substance solution, μg/ml;
C X in order to obtain the concentration of the sample solution, μg/ml.
Test results: the chromatogram obtained by recording the blank derivatization solution after being injected into the liquid chromatograph is shown in fig. 1, the chromatogram obtained by recording the sample solution SM1 after being injected into the liquid chromatograph is shown in fig. 2, the chromatogram obtained by recording the reference solution SM1-A after being injected into the liquid chromatograph is shown in fig. 3, and the chromatogram obtained by injecting the system applicability solution into the liquid chromatograph is shown in fig. 4. As can be seen from the chromatogram chart of the sample solution in FIG. 2, the method can effectively separate and detect the trans-1, 2-diaminomethyl cyclobutane (SM 1-1 and SM 1-2) and the cis-isomer (SM 1-A), and the separation degree of the cis-isomer (SM 1-A) and the adjacent impurity peaks is respectively 2.01 and 1.84, so that the separation degree is good, and the method is favorable for accurately detecting the cis-isomer content and controlling the quality of lobaplatin initial materials. The cis-isomer content of the lobaplatin starting material was 0.04% as calculated by the external standard method in terms of peak area.
Example 2
2.1 specificity
The test method comprises the following steps: taking blank derivatization solution, sample solution and reference substance solution, sampling and detecting according to the detection conditions, and recording a chromatogram.
Test results: from the detection method chromatograms 1 to 3 of example 1, it is understood that the blank derivatization solution has no chromatographic peak at the peak-out position of lobaplatin starting material SM1 and cis-isomer SM1-A thereof, and does not interfere with the detection of cis-isomer SM1-A. As can be seen from the detection method chromatogram 4 of example 1, the separation degree between the cis-isomer SM1-A and the adjacent peaks in the system applicability solution is not less than 1.2; solvents and other impurities do not interfere with the starting material SM1 and cis isomer SM1-A, indicating that the detection method of the invention is well-defined.
2.2 quantitative limit and detection limit
The test method comprises the following steps: precisely measuring 0.3mL to 10mL of second SM1-A reference stock solution, adding 0.1mL of m-methylbenzoyl chloride to derive for 1.5min, then fixing the volume of the diluent, uniformly mixing, standing and taking the upper layer, wherein the limit of quantification is made when the SM1-A peak height is 10-30 times of the baseline noise, and 6 parts of the solution are prepared by the same method and are all used as the limit of quantification solution.
Precisely measuring a second SM1-A reference stock solution from 0.1mL to 10mL of a measuring flask, adding 0.1mL of m-methylbenzoyl chloride for derivatization for 1.5min, metering the volume of the diluent, uniformly mixing, standing, taking the upper layer, and taking the detection limit when the SM1-A peak height is 3-10 times of the baseline noise as a detection limit solution.
The quantitative limit solution and the detection limit solution are detected according to the detection method and the chromatographic conditions, and chromatograms are recorded. The detection results of the detection limit and the quantitative limit and the repeated test results of the quantitative limit are shown in tables 1 and 2, respectively.
TABLE 1 limit of detection and limit of quantification results
| Name of the name | Quantitative limit (ug/ml) | Quantitative limit (%) | Detection limit (ug/ml) | Detection limit (%) |
| SM1-A | 0.1522 | 0.015 | 0.0507 | 0.005 |
Table 2 quantitative limit 6-needle repeat test results
As is clear from Table 2, the RSD of the cis isomer SM1-A of the lobaplatin starting material was 4% in terms of 6 times of peak area, which indicates that the quantitative limit reproducibility of the detection method of the present invention is good.
2.3 linearity
The test method comprises the following steps: precisely weighing cis-isomer SM1-A, diluting with solvent to different concentrations of 0.15 μg/mL, 0.5 μg/mL, 2.5 μg/mL, 5 μg/mL, 7.5 μg/mL, and 10 μg/mL, respectively adding 0.1mL of m-methylbenzoyl chloride for derivatization for 1.5min, diluting with diluent to constant volume, mixing, standing, and collecting the upper layer. The detection was performed according to the above detection method and chromatographic conditions, and the chromatograms were recorded, and the detection results are shown in table 3.
TABLE 3 Linear results
As shown in Table 3, the cis isomer SM1-A of lobaplatin starting material has good linear relationship in the range of 0.1522 mug/mL-10.1459 mug/mL, which indicates that the detection method has good linear relationship.
2.4 accuracy
The test method comprises the following steps: precisely weighing about 10mg of the product, placing into a 10L measuring flask, precisely adding 0.25mL of SM1-A reference stock solution, adding 0.5mL of 1.0M sodium hydroxide solution to rinse the wall of the flask, mixing, adding 0.1mL of m-methylbenzoyl chloride to derive for about 1.5min, diluting with a diluent, fixing the volume, mixing, standing, and taking the upper layer. Preparing 3 parts by the same method as a 50% recovery rate solution;
precisely weighing about 10mg of the product, placing into a 10mL measuring flask, precisely adding 0.5mL of SM1-A reference stock solution, adding 0.5mL of 1.0M sodium hydroxide solution to rinse the wall of the flask, mixing uniformly, finally adding about 1.5min of m-methylbenzoyl chloride derivative, diluting with a diluent, fixing the volume, mixing uniformly, standing, and taking the upper layer. Preparing 3 parts by the same method as a 100% recovery rate solution;
precisely weighing about 10mg of the product, placing into a 10ml measuring flask, precisely adding 0.75ml of SM1-A reference stock solution, adding 0.5ml of 1.0M sodium hydroxide solution to the wall of the flask, leaching the wall of the flask, uniformly mixing, finally adding about 1.5min of m-methylbenzoyl chloride derivative, diluting with a diluent (n-hexane: isopropanol=90:10), fixing the volume, uniformly mixing, standing, and taking the upper layer. Preparing 3 parts by the same method as a 150% recovery rate solution;
the detection was performed according to the above detection method and chromatographic conditions, and the chromatograms were recorded, and the detection results are shown in table 4.
TABLE 4 recovery results
As shown in Table 4, the recovery rate of cis isomer SM1-A of lobaplatin starting material is between 98.8% and 111.4%, and RSD is 4.1%, which shows that the detection method has good accuracy.
2.5 durability
The test method comprises the following steps: the mobile phase ratios (n-hexane: isopropanol: diethylamine=89:11:0.1 and n-hexane: isopropanol: diethylamine=91:9:0.1, v/v), flow rates (0.7 ml/min and 0.9 ml/min), column temperatures (28 ℃ and 32 ℃) were respectively changed, the remaining chromatographic conditions were the same as in example 1, a control solution and a system-applicable solution were respectively injected into a liquid chromatograph, and a chromatogram was recorded, and the detection results were shown in table 5.
Table 5 durability results
As shown in Table 5, the continuous 6-needle peak area of the reference solution is less than or equal to 5.5% relative to the standard deviation, and the separation degree between SM1-A and adjacent peaks in the system applicability solution is more than or equal to 1.5, which indicates that the detection method provided by the invention has good durability.
Example 3
Chromatographic conditions were the same as in example 1, except that different volumes of m-methylbenzoyl chloride was used as the derivatizing agent in the sample solutions, and the variation in the SM1 peak area was as shown in Table 6.
Table 6 examination of the amounts of derivatizing agents
| The amount of derivatizing agent (m-methylbenzoyl chloride) used (μl) | SM1 peak area |
| 40 | 62573664 |
| 80 | 62578879 |
| 100 | 68350816 |
| 140 | 61482034 |
| 160 | 61549134 |
As is clear from Table 6, when 100. Mu.L of the m-methylbenzoyl chloride derivative reagent was used, the SM1 peak area was the largest, indicating that the optimum amount of the derivative reagent was 100. Mu.L.
Example 4
The test method comprises the following steps: the flow rates were adjusted to 0.6mL/min and 1mL/min, respectively, and other instruments, detection conditions and detection methods were substantially the same as those of example 1, and the obtained chromatograms were shown in FIG. 5 and FIG. 6, respectively.
Experimental results: when the flow rate is 0.6mL/min, the trans-1, 2-diaminomethyl cyclobutane and the cis isomer thereof can still be separated and detected, and the separation degree of SM1-A and the adjacent impurity peak thereof is respectively 1.73 and 1.50, which is better than that when the flow rate is 0.8mL/min, but the peak outlet time is later. When the flow rate is 1.0mL/min, the trans-1, 2-diaminomethyl cyclobutane and the cis-isomer thereof can still be separated and detected, and the separation degree of SM1-A and the adjacent impurity peak thereof is respectively 1.39 and 1.23, so that the basic separation degree requirement of more than or equal to 1.2 is just met.
Comparative example 1
The chromatographic column filler adopted in comparative example 1 is silica gel with cellulose-tris (3-chloro-4-methylphenyl carbamate) coated on the surface, and a CHIRALCEL OZ-3 chromatographic column is specifically selected, and the specification is as follows: 150 mm. Times.4.6 mm,3 μm, other instruments, detection conditions and detection methods were substantially the same as in example 1, and the resulting chromatogram was shown in FIG. 7.
Experimental results: as can be seen from the chromatogram obtained from the sample solution, the cis-isomer peak coincides with the adjacent impurity peak, and is not separated, and the separation effect is poor. Using the detection method of comparative example 1, the two enantiomers of trans-1, 2-diaminomethylcyclobutane were not separated on the chromatographic column, and 1 peak was seen on the chromatogram.
Comparative example 2
The chromatographic column filler adopted in comparative example 2 is silica gel with amylose-tris (3, 5-dimethylphenylcarbamate) covalently bonded on the surface, and a CHIRALPAK IA chromatographic column is specifically selected, and has the specification: 250mm by 4.6mm,5 μm, other instruments, detection conditions and detection methods were substantially the same as in example 1, and the resulting chromatogram was shown in FIG. 8.
Experimental results: as can be seen from the chromatogram obtained from the sample solution, the separation degree of the cis-isomer from the adjacent impurity peak before the cis-isomer peak is only 1.06, the basic separation degree requirement of more than or equal to 1.2 is not met, and the separation effect is poor.
Comparative example 3
The chromatographic column filler adopted in comparative example 3 is silica gel with amylose-tris (3-chloro-5-methyl carbamate) covalently bonded on the surface, and a CHIRALPAK IG chromatographic column is specifically selected, and the specification is as follows: 250mm. Times.4.6 mm,5 μm, other instruments, detection conditions and detection methods were substantially the same as in example 1, and the resulting chromatogram was shown in FIG. 9.
Experimental results: from the chromatogram obtained from the test solution, the lobaplatin starting material trans-1, 2-diaminomethylcyclobutane and its cis-isomer did not show a peak during the 40min running time.
Comparative example 4
Using n-heptane with the volume ratio of 90:10: the mixed solvent of isopropyl alcohol was used in place of the mobile phase in example 1, and the other instruments, detection conditions and detection method were substantially the same as those in example 1, and the obtained chromatogram was shown in fig. 10.
Experimental results: as can be seen from the chromatogram obtained from the sample solution, the cis-isomer peak coincides with the adjacent impurity peak before the cis-isomer peak, and the cis-isomer peak and the adjacent impurity peak cannot be separated, so that the separation effect is poor.
Comparative example 5
Using n-hexane with the volume ratio of 95:5: the mixed solvent of isopropyl alcohol was used in place of the mobile phase in example 1, and the other instruments, detection conditions and detection method were substantially the same as those in example 1, and the obtained chromatogram was shown in fig. 11.
Experimental results: from the chromatogram obtained from the test solution, the lobaplatin starting material trans-1, 2-diaminomethylcyclobutane and its cis-isomer did not show a peak during the 40min running time.
Comparative example 6
Using n-hexane with a volume ratio of 85:15: the mixed solvent of isopropyl alcohol was used in place of the mobile phase in example 1, and the other instruments, detection conditions and detection method were substantially the same as those in example 1, and the obtained chromatogram was shown in fig. 12.
Experimental results: as can be seen from the chromatogram obtained from the sample solution, the separation degree of the cis-isomer from the adjacent impurity peak before the cis-isomer peak is only 1.10, the basic separation degree requirement of more than or equal to 1.2 is not met, and the separation effect is poor.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, or alternatives falling within the spirit and principles of the invention.
Claims (7)
1. A method for detecting cis-isomer or cis-isomer salt contained in trans-1, 2-diaminomethyl cyclobutane or a salt thereof, characterized by comprising the steps of: carrying out derivatization reaction on a sample to be detected and a derivatization reagent with ultraviolet absorption, and then carrying out qualitative and/or quantitative detection on cis-isomer or salt thereof by adopting HPLC, wherein the chromatographic conditions of the HPLC are as follows:
the chromatographic column is CHIRALPAK AD-H, the length of the chromatographic column is 250mm, the inner diameter of the chromatographic column is 4.6mm, and the particle size of the filling material is 5 mu m; the mobile phase solvent is a mixed solvent of n-hexane and isopropanol, wherein n-hexane: the volume ratio of the isopropanol is (88:12) - (92:8), and diethylamine accounting for 0.1% of the volume fraction of the mobile phase solvent is added into the mobile phase; the flow rate of the mobile phase is 0.6-1.0 mL/min; the column temperature is 28-32 ℃; the detection wavelength is 235+/-5 nm;
the derivatization reaction of the sample to be detected is a preparation process of a sample solution to be detected, and the preparation method comprises the following steps: adding 0.5mL of 1.0M sodium hydroxide aqueous solution into each 10mg of sample to be tested for dissolution, adding 100 mu L of M-methylbenzoyl chloride, adding a diluent to 10mL of total volume after the reaction is finished, extracting a reaction product, and collecting an upper layer to obtain a sample solution; the diluent for preparing the test sample solution is the mobile phase solvent;
the trans-1, 2-diaminomethyl cyclobutane isOr a mixture thereof;
the cis isomer is
The salt of trans-1, 2-diaminomethyl cyclobutane and/or the salt of cis-isomer is hydrochloride.
2. The method of detection according to claim 1, wherein: the mobile phase solvent is a mixed solvent of n-hexane and isopropanol, wherein n-hexane: the volume ratio of isopropanol is 90:10.
3. the method of detection according to claim 1, wherein: the flow rate of the mobile phase is 0.6-0.8 mL/min.
4. A method of detecting as claimed in claim 3, wherein: the mobile phase flow rate is 0.6mL/min or 0.8mL/min.
5. The method of detection according to claim 1, wherein: the column temperature was 30 ℃.
6. The method of detection according to claim 1, wherein: the detection wavelength is 235nm.
7. The method of detection according to claim 1, wherein: the sample injection amount is 10 mu L.
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