CN103012545A - Impurity of ciclesonide and preparation method thereof - Google Patents
Impurity of ciclesonide and preparation method thereof Download PDFInfo
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- CN103012545A CN103012545A CN2011102869380A CN201110286938A CN103012545A CN 103012545 A CN103012545 A CN 103012545A CN 2011102869380 A CN2011102869380 A CN 2011102869380A CN 201110286938 A CN201110286938 A CN 201110286938A CN 103012545 A CN103012545 A CN 103012545A
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- LUKZNWIVRBCLON-GXOBDPJESA-N Ciclesonide Chemical compound C1([C@H]2O[C@@]3([C@H](O2)C[C@@H]2[C@@]3(C[C@H](O)[C@@H]3[C@@]4(C)C=CC(=O)C=C4CC[C@H]32)C)C(=O)COC(=O)C(C)C)CCCCC1 LUKZNWIVRBCLON-GXOBDPJESA-N 0.000 title claims abstract description 124
- 229960003728 ciclesonide Drugs 0.000 title claims abstract description 123
- 239000012535 impurity Substances 0.000 title claims abstract description 60
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 150000001875 compounds Chemical class 0.000 claims abstract description 244
- 238000000034 method Methods 0.000 claims description 62
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 55
- 238000012360 testing method Methods 0.000 claims description 37
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- 230000014759 maintenance of location Effects 0.000 claims description 21
- 238000012937 correction Methods 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- -1 isobutyryl Chemical group 0.000 claims description 10
- 239000003550 marker Substances 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 5
- 238000010812 external standard method Methods 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 238000013215 result calculation Methods 0.000 claims description 4
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 3
- 239000004215 Carbon black (E152) Substances 0.000 claims description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 229930195733 hydrocarbon Natural products 0.000 claims description 3
- 150000002430 hydrocarbons Chemical class 0.000 claims description 3
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 3
- 238000003908 quality control method Methods 0.000 abstract description 3
- 239000003862 glucocorticoid Substances 0.000 abstract 1
- 229940037128 systemic glucocorticoids Drugs 0.000 abstract 1
- 239000000523 sample Substances 0.000 description 34
- 239000000047 product Substances 0.000 description 29
- 239000000243 solution Substances 0.000 description 24
- 239000012088 reference solution Substances 0.000 description 15
- 230000000694 effects Effects 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- 239000012488 sample solution Substances 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 9
- 239000012071 phase Substances 0.000 description 8
- 239000000126 substance Substances 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 208000006673 asthma Diseases 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 239000000470 constituent Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000010606 normalization Methods 0.000 description 3
- 238000004237 preparative chromatography Methods 0.000 description 3
- 238000004445 quantitative analysis Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 3
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000000356 contaminant Substances 0.000 description 2
- 239000007857 degradation product Substances 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 238000004451 qualitative analysis Methods 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- XILIYVSXLSWUAI-UHFFFAOYSA-N 2-(diethylamino)ethyl n'-phenylcarbamimidothioate;dihydrobromide Chemical compound Br.Br.CCN(CC)CCSC(N)=NC1=CC=CC=C1 XILIYVSXLSWUAI-UHFFFAOYSA-N 0.000 description 1
- 206010006482 Bronchospasm Diseases 0.000 description 1
- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 description 1
- 0 C1CC*CC1 Chemical compound C1CC*CC1 0.000 description 1
- 206010014950 Eosinophilia Diseases 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- 102000003676 Glucocorticoid Receptors Human genes 0.000 description 1
- 108090000079 Glucocorticoid Receptors Proteins 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 241000337007 Oceania Species 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 239000003470 adrenal cortex hormone Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000007885 bronchoconstriction Effects 0.000 description 1
- 229960004436 budesonide Drugs 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000010954 commercial manufacturing process Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000009989 contractile response Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- KVFDZFBHBWTVID-UHFFFAOYSA-N cyclohexanecarbaldehyde Chemical compound O=CC1CCCCC1 KVFDZFBHBWTVID-UHFFFAOYSA-N 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 210000003725 endotheliocyte Anatomy 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229960002714 fluticasone Drugs 0.000 description 1
- MGNNYOODZCAHBA-GQKYHHCASA-N fluticasone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(O)[C@@]2(C)C[C@@H]1O MGNNYOODZCAHBA-GQKYHHCASA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- LSACYLWPPQLVSM-UHFFFAOYSA-N isobutyric acid anhydride Chemical compound CC(C)C(=O)OC(=O)C(C)C LSACYLWPPQLVSM-UHFFFAOYSA-N 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 210000003712 lysosome Anatomy 0.000 description 1
- 230000001868 lysosomic effect Effects 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 210000003300 oropharynx Anatomy 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 238000005220 pharmaceutical analysis Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000000053 physical method Methods 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
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- 231100000419 toxicity Toxicity 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
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Abstract
The invention relates to a impurity compound ((11beta,16alpha)-16,17-[[(R)-cyclohexyl methylene]bis(oxy)]-11-hydroxy-21-(2-methyl-1-carbonyl propoxy)-1,5-cyclopregnane-3-ene-2,20-dione) of glucocorticoids drug ciclesonide, a preparation method thereof, and an application of the impurity compound as a reference in quality control of the ciclesonide.
Description
Technical field
The invention belongs to chemistry and pharmaceutical analysis field, be specifically related to impurity compound of a kind of ciclesonide and preparation method thereof, and this impurity (11 β, 16 α)-16,17-[[(R)-the cyclohexyl methylene radical] two (oxygen)]-11-hydroxyl-21-(2-methyl isophthalic acid-carbonyl propoxy-)-1,5-encircles pregnant steroid-3-alkene-2, and the 20-diketone is as the purposes of ciclesonide quality control reference standard and the testing method of ciclesonide and impurity thereof.
Background technology
Ciclesonide (Ciclesonide) is adrenal cortex hormones drug of new generation, has efficient local anti-inflammatory effect, can strengthen the stability of endotheliocyte, smooth muscle cell nuclear lysosome membrane, the Immunosuppression reaction, reduce antibody synthetic, make release minimizing, the activity decreased of the transformation reactions active media such as histamine, and can alleviate antigen-antibody in conjunction with the time enzymic process that excites, suppress the synthetic and release of bronchoconstriction material, thereby alleviate the contractile response of unstriated muscle.This product belongs to ester prodrugs, produces active by the hydrolysis of endogenous esterase ester in the body.It has the advantage of fixed point effect in lung, and system's side effect is little, and the oropharynx effect is also little.Experiment in vitro shows, the product after this product metabolism and glucocorticoid receptor avidity are higher, and avidity own is low.In the body in the experiment, this product is better than budesonide to the supression effect of the respiratory tract eosinophilia that the antigen of a rat causes.Administration in the organ, fluticasone is stronger 7.5 times than this product, but side effect than this product large 22 times.Till now, yet there are no the clinical side effects relevant with this product occurs.According to global asthma control tissue statistics, global asthmatic patient number has exceeded 300,000,000, and this class patient number is died from this sick total number of persons every year and surpassed 180,000 just with the speed increase in per 10 years about 50%.Ciclesonide is now comprising more than 40 country's listings in European Union, America and area, Oceania, and the granted indication in Europe is to the treatment of adult persistent asthmatic patient and symptom control thereof for 〉=12 years old teenager at present.
The chemical name of ciclesonide: [11 β, 16 α (R)] 16, the 17-[(cyclohexylmethylene) two (oxygen)]-11-hydroxyl-21-(2-methyl isophthalic acid-carbonyl propoxy-) pregnant steroid-Isosorbide-5-Nitrae-diene-3, the 20-diketone, its structural formula is shown in figure below (formula III):
The preparation method that DE-4129535 disclosed ciclesonide in 1992, its synthetic route is as follows:
Take 16 α-prednisolone as starting raw material, obtain three esters with isobutyric anhydride generation esterification; Three esters are hydrolyzed in the dioxane that contains 13%HCl gas, do to react with hexahydrobenzaldehyde under the catalyzer with perchloric acid simultaneously, obtain the raceme of ciclesonide epimer, split through the HPLC post, obtain ciclesonide (III).
Known in the art for to human body administration security consideration, before the commercialization of a kind of effective pharmaceutical cpd (API) product, need to be set up by country and international management the extremely low lower limit of the evaluation of non-characteristic impurity on the toxicology.Usually, limiting the quantity of of every kind of impurity is less than approximately 0.15% weight ratio.Limiting the quantity of of unidentified and/or non-characteristic impurity is obviously lower, usually is less than 0.1% weight ratio.
Also known in this area, the impurity in ciclesonide or any effective pharmaceutical cpd (API) may from degraded (this is relevant with the stability of pure API in storage process) and the manufacturing processed of API itself, comprise chemosynthesis.Process contaminants comprises chemical derivative, synthesising by-product and the degraded product of impurity contained in unreacted starting material, the starting material.
Except stability, the purity of the commercial API that makes also obviously is business-like prerequisite.The impurity of introducing in commercial manufacturing process must be limited in indivisible, and does not preferably basically exist.For example, international conference on harmonization of technical requirements for human use (" ICH ") Q7A guide for API manufacturers requires by the raw-material quality of regulation, control processing parameter, such as temperature, pressure, time and stoichiometric ratio with in manufacturing process, add purification step, such as crystallization, distillation and extraction process contaminants is remained on and set below the limit.
The product of chemical reaction seldom has the single compound of the enough purity that meets pharmaceutical standards.Used starting material also are present in the mixture of product in byproduct of reaction and this reaction.Some stage in API such as ciclesonide preparation process, usually must analyze its purity by HPLC, TLC or GC analytical method, whether be applicable to continue processing and finally be used in the medicine to measure it.API does not need definitely pure because absolute pure be the theory target that usually can not realize.On the contrary, set purity rubric free from foreign meter as far as possible to guarantee API, and therefore safe as far as possible for clinical application.As mentioned above, recommend at the guide of U.S. FDA, the amount of some impurity only limits to be lower than 0.1%.
Usually identify impurity with spectrum and/or other physical method, then obtain a peak position, or the spot in the TLC plate.Identify afterwards impurity, for example, identify by its relative position in color atlas, the relative position in the color atlas becomes " retention time ".According to instrument working conditions and a lot of other factors, retention time every day or even among one day, all changing.In order to reduce these variable effects to the accurate identification of impurity, usually identify impurity with " relative retention time (RRT) ".The RRT of impurity is divided by the retention time of main peak with its retention time.
Reference standard known in the art can be used for the quantitative and qualitative analysis of unknown mixture reference standard compound, when the solution of the concentration known of reference standard and unknown mixture during with constructed analysis, reference standard is " external standard ", can measure by the response intensity that compares detector the amount of compound described in the mixture.
As is known to persons skilled in the art, by understanding its chemical structure and route of synthesis, and the amount that is tested and appraised the impurity of the impurity of finished product and definite finished product is come the greatly control of strengthening process impurity.
At present, existing many pieces of documents and materials have been reported preparation or the purification process of ciclesonide.US Patent No. 5482934 has been described preparation and the purification process thereof of ciclesonide, and this patent adopts the method for gel column to come purifying, and purification effect is not obvious, and yield is very low.Also there are same problem in other document WO 02/38584, WO9809982, CN1699395, WO2007056181, WO2008015696.Not yet see the report about the control method of ciclesonide impurity in the document.
Therefore, in the existing ciclesonide technology of preparing, exist product purity not high, lack the weak points such as control to single impurity.For deficiency of the prior art, we are studied the Control of Impurities in the ciclesonide product, the impurity (formula II compound) that has prepared a kind of ciclesonide of not identifying in the past, formula II compound can or form between the shelf lives in the building-up process of ciclesonide, known to the applicant, the structure of formula I compound was never reported, and this compound is also never independently prepared and separates with ciclesonide.The applicant finds that also other 3 kinds of Impurities Upon Product Qualities have considerable influence, and then has invented these 4 kinds of impurity are used for the quantitative method of ciclesonide purity check as reference standard.
Generally speaking, the high-purity medicament composition need to satisfy drug quality and the purity of standard.For example, in synthetic or storage process, usually form impurity, comprise the by product of degradation product or preparation, this may therefrom affect the curative effect of ciclesonide and/or may have toxicity in the presence of sufficiently high amount.Like this, expectation has the three-dimensional chemical configuration of mensuration ciclesonide and the ability of purity.For this reason, identification, separation and chemical characterization impurity are important, and it can be used as in chromatographic procedure and characterize thing to confirm the purity of ciclesonide.
Summary of the invention
The impurity that the purpose of this invention is to provide a kind of ciclesonide, i.e. formula I compound,
Wherein: R
1And R
2Represent independently of one another H, C
1-12Straight chain, branched-chain hydrocarbon, C
2-C
8Thiazolinyl, C
2-C
8Alkynyl, C
3-C
8Cycloalkyl or C
5-C
20Aryl, R
3Expression H, ethanoyl and isobutyryl [COCH (CH
3)
2].
In some embodiments, R
1And R
2Represent independently of one another H, normal-butyl, isobutyl-, cyclohexyl or phenyl; R
3Hydrogen or isobutyryl.In a specific embodiment, R
1The expression cyclohexyl, R
2Expression H, R
3It is isobutyryl.
The invention provides a kind of impurity of ciclesonide, i.e. the compound of formula II,
。
Above-mentioned formula II compound is separated in some embodiments has at least 50% purity, perhaps at least 60% purity, perhaps at least 70% purity, perhaps at least 80% purity, perhaps at least 90% purity is perhaps to 95% purity, perhaps at least 96% purity, perhaps at least 97% purity, perhaps at least 98% purity, perhaps at least 99% purity.This purity is generally the purity of HPLC area normalization method.
The invention provides a kind of method of preparation formula II compound, comprising: at least a organic solvent, with at least a rayed ciclesonide, obtain formula II compound.Wherein, described organic solvent comprises methyl alcohol, ethanol or acetonitrile etc.; Wherein, light comprises natural light or UV-light.The scope of UV-light is 4 ~ 400nm, preferred 254nm.The method also comprises the step by any known way purifying in this area, and for example organic solvent is as the method for moving phase purifying.
In a specific embodiment, the method for preparation formula II compound of the present invention also further comprises purification procedures, and its process is as follows:
(1) the illumination reaction mixture with aforesaid method concentrates;
(2) the concentrating residues thing is dissolved with a kind of or mixed solvent;
(3) the concentrating residues thing after utilizing the preparative chromatography post to dissolve, by separating as moving phase with single solvent or mixed solvent, the formula II compound that obtains.
In the above-mentioned purification step, wherein the solvent in the step (2) comprises methyl alcohol, ethanol, acetonitrile or their mixture etc.; Described preparative chromatography post in the step (3), its moving phase are acetonitrile and water or first alcohol and water etc.
The applicant finds, second major impurity of ciclesonide is: (11 β, 16 α) 16,17-[[(R)-the ethyl methylene radical] two (oxygen)]-11-hydroxyl-21-(2-methyl isophthalic acid-carbonyl propoxy-) pregnant steroid-1,4-diene-3,20-diketone (formula IV compound) is the intermediate of reaction, in the ciclesonide sample, may have residually, may considerable influence be arranged to quality product.
The 3rd major impurity of ciclesonide is: (11 β, 16 α) 16,17-[[(S)-cyclohexylmethylene] two (oxygen)]-11-hydroxyl-21-(methyl isophthalic acid-hydroxyl propoxy-) pregnant steroid-1,4-diene-3,20-diketone (formula V compound), be the epimer of ciclesonide, may form in the building-up process of ciclesonide sample, quality product is had considerable influence.
The 4th major impurity of ciclesonide is: (11 β, 16 α) 16,17-[[(R)-cyclohexylmethylene] two (oxygen)]-11,12-dimonohydric pregnant-1,4-diene-3,20-diketone (formula VI compound) is the degradation impurity of ciclesonide, may or form between the shelf lives in the building-up process of ciclesonide sample, quality product is had considerable influence.
This impurity is the degradation impurity of ciclesonide, and the production process of this impurity is:
A further object of the present invention is, with formula II compound, formula IV compound, formula V compound or/and formula VI compound as the purposes of ciclesonide quality control reference substance.
The present invention also provides a kind of method of measuring ciclesonide and impurity thereof, and the method comprises:
(1) provides a kind of ciclesonide sample;
(2) provide a kind of known quantity and/or characteristic formula II compound, formula IV compound, formula V compound or/and formula VI compound do with reference to sample;
(3) with II compound in the chromatography determination ciclesonide sample, formula IV compound, formula V compound or/and the existence of formula VI compound or/and the amount of amount and ciclesonide.
In the said determination method, the preferred high performance liquid chromatography of described chromatography (HPLC) method.Measure and definite ciclesonide sample Chinese style II compound, formula IV compound, formula V compound or/and the existence of formula VI compound or/and the high performance liquid chromatography (HPLC) of amount generally comprises the principal constituent Self-control method of external standard method, marker method, the correction up factor etc., the specific operation process of these methods is the knowledge of this area routine.Described determine to comprise according to the ciclesonide sample and with reference to the test result calculations of sample or contrast II compound, formula IV compound, formula V compound or/and existence and/or the amount of formula VI compound in the ciclesonide sample.Described calculating is knowledge and the calculation formula of this area routine.The formula II compound that detects in the ciclesonide sample of actual production, formula IV compound, formula V compound namely are not more than 0.1% or/and the content of formula VI compound is limited the quantity of followingly at conventional impurity.
Realize the method for said determination ciclesonide and impurity thereof, specifically can comprise following scheme:
Scheme a
The method of mensuration ciclesonide of the present invention and impurity thereof comprises: provide a kind of II compound, formula IV compound, formula V compound of containing or/and formula VI compound is done with reference to sample, test with HPLC; Provide a kind of sample that contains ciclesonide, with the HPLC test of the same terms; According to test result calculations formula II compound, formula IV compound, formula V compound or/and existence and/or the amount of formula VI compound in the ciclesonide sample.
In a specific embodiments, the method comprises: quantitatively preparation contains formula II compound, formula IV compound, formula V compound or/and the reference solution of formula VI compound, under a set condition, inject high performance liquid chromatograph, (this collection of illustrative plates can be one to obtain a HPLC collection of illustrative plates, also can be one group), wherein reference solution Chinese style II compound, formula IV compound, formula V compound are or/and the amount of formula VI compound and/or characteristic are known; Quantitatively preparation contains the need testing solution of ciclesonide, injects high performance liquid chromatograph under identical set condition, obtains the 2nd HPLC collection of illustrative plates (this collection of illustrative plates can be, also can be a group); Retention time by contrasting chromatographic peak on the first and second HPLC collection of illustrative plates or relative retention time and/or calculated by peak area go out formula II compound, formula IV compound, formula V compound or/and existence and/or the amount of formula VI compound in the ciclesonide trial-product.
Scheme b
The method of mensuration ciclesonide of the present invention and impurity thereof, comprise: provide a kind of formula II compound, formula IV compound, formula V compound or/and formula VI compound is done with reference to sample, draw relative retention time and correction factor with ciclesonide by HPLC method contrast test; Provide a kind of ciclesonide sample, with the HPLC test of the same terms; According to test result and relative retention time and correction factor calculating formula II compound, formula IV compound, formula V compound or/and existence and/or the amount of formula VI compound in the ciclesonide sample.
In a specific embodiments, the method comprises: quantitatively preparation contains formula II compound, formula IV compound, formula V compound is or/and the reference solution of formula VI compound and the reference solution that contains ciclesonide, these two kinds of reference solution can mixed preparing (namely contain the II compound, formula IV compound, formula V compound is or/and formula VI compound and the reference solution that contains ciclesonide), it also can be respectively separately preparation, under a set condition, inject high high performance liquid chromatograph, (this collection of illustrative plates can be one to obtain a HPLC collection of illustrative plates, also can be one group), reference solution Chinese style II compound wherein, formula IV compound, formula V compound is or/and the amount of formula VI compound and ciclesonide and/or characteristic are known; Quantitatively preparation contains the need testing solution of ciclesonide, injects high performance liquid chromatograph under identical set condition, obtains the 2nd HPLC collection of illustrative plates (this collection of illustrative plates can be, also can be a group); Calculate relative retention time and the correction factor of chromatographic peak by a HPLC collection of illustrative plates, the relative retention time and/or the calculated by peak area that contrast chromatographic peak on the 2nd HPLC collection of illustrative plates go out formula II compound, formula IV compound, formula V compound or/and existence and/or the amount of formula VI compound in the ciclesonide trial-product.
Scheme c
The method of mensuration ciclesonide of the present invention and impurity thereof comprises: provide a kind of formula II compound, formula IV compound, formula V compound or/and formula VI compound is done with reference to sample, draw correction factor by the contrast test with ciclesonide HPLC; Provide a kind of ciclesonide sample, with the HPLC test of the same terms; With formula II compound, formula IV compound, formula V compound or/and formula VI compound the corresponding impurity in the ciclesonide sample is positioned; According to test result and correction factor calculating formula II compound, formula IV compound, formula V compound or/and existence and/or the amount of formula VI compound in the ciclesonide sample.
In a specific embodiments, the method comprises: quantitatively preparation contains formula II compound, formula IV compound, formula V compound is or/and the reference solution of formula VI compound and the reference solution that contains ciclesonide, these two kinds of reference solution can mixed preparing (be formula II compound, formula IV compound, formula V compound is or/and formula VI compound and the reference solution that contains ciclesonide), it also can be respectively separately preparation, under a set condition, inject high performance liquid chromatograph, (this collection of illustrative plates can be one to obtain a HPLC collection of illustrative plates, also can be one group), reference solution Chinese style II compound wherein, formula IV compound, formula V compound is or/and the amount of formula VI compound and ciclesonide and/or characteristic are known; Quantitatively preparation contains the need testing solution of ciclesonide, injects high performance liquid chromatograph under identical set condition, obtains the 2nd HPLC collection of illustrative plates (this collection of illustrative plates can be, also can be a group); In the test solution that contains ciclesonide, add a certain amount of formula II compound, formula IV compound, formula V compound of containing or/and the solution of formula VI compound, under identical set condition, inject high performance liquid chromatograph, obtain the 3rd HPLC collection of illustrative plates (this collection of illustrative plates is used for formula II compound, formula IV compound, formula V compound or/and the location of formula VI compound); Calculate the correction factor of chromatographic peak by a HPLC collection of illustrative plates, by the 3rd HPLC collection of illustrative plates contrast location, by the 2nd HPLC collection of illustrative plates following formula II compound, formula IV compound, formula V compound or/and the calculated by peak area of formula VI compound chromatographic peak goes out formula II compound, formula IV compound, formula V compound or/and existence and/or the amount of formula VI compound in the ciclesonide trial-product.
Scheme d
The method of mensuration ciclesonide of the present invention and impurity thereof comprises: provide a kind of formula II compound, formula IV compound, formula V compound or/and formula VI compound is done with reference to sample, test with HPLC; Provide a kind of ciclesonide sample, with the HPLC test of the same terms; Quantitative adding formula II compound, formula IV compound, formula V compound are or/and formula VI compound is used the HPLC test of the same terms in the ciclesonide sample; According to test result calculations formula II compound, formula IV compound, formula V compound or/and existence and/or the amount of formula VI compound in the ciclesonide sample.
In a specific embodiments, the method comprises: quantitatively preparation contains formula II compound, formula IV compound, formula V compound or/and the reference solution of formula VI compound, under a set condition, inject high performance liquid chromatograph, (this collection of illustrative plates can be one to obtain a HPLC collection of illustrative plates, also can be one group), wherein reference solution Chinese style II compound, formula IV compound, formula V compound are or/and the amount of formula VI compound and/or characteristic are known; Quantitatively preparation contains the need testing solution of ciclesonide, injects high performance liquid chromatograph under identical set condition, obtains the 2nd HPLC collection of illustrative plates (this collection of illustrative plates can be, also can be a group); Add in the test solution that contains ciclesonide and quantitative contain formula II compound, formula IV compound, formula V compound or/and the reference solution of formula VI compound, under identical set condition, inject high performance liquid chromatograph, obtain the 3rd HPLC collection of illustrative plates (this collection of illustrative plates can be, also can be a group); Go out formula II compound, formula IV compound, formula V compound or/and existence and/or the amount of formula VI compound in the ciclesonide trial-product by the retention time on the HPLC collection of illustrative plates and/or calculated by peak area.
The method further also can comprise, the described formula II compound of putting on record in writing, formula IV compound, formula V compound or/and the chemical property of formula VI compound or/and it is as existence and/or the amount of impurity in the ciclesonide trial-product.
Aforesaid method described " one group " collection of illustrative plates comprises the collection of illustrative plates group of parallel sample introduction survey formula, the collection of illustrative plates group of dense rare contrast test etc.
Above-mentioned by reference (photograph) solution and need testing solution the HPLC test and calculate the existence of impurity in trial-product (sample) solution and/or the method for amount is ordinary method in the art.As will further improving the accuracy of test, can carry out necessary methodology checking to testing method.
The present invention also provides a kind of method of measuring ciclesonide and impurity thereof, and the method comprises:
(1) provide a kind of ciclesonide solution to make specimen;
(2) provide a kind of formula II compound that contains known quantity and/or characteristic, IV compound, V formula compound or/and the solution of formula VI compound is done with reference to sample;
(3) with HPLC measure the specimen of (1) and/or (2) with reference to the product sample, determine ciclesonide product Chinese style II compound, IV compound, V formula compound or/and the existence of formula VI compound or/and amount.
In the aforesaid method, describedly determine to refer to adopt the principal constituent Self-control method of external standard method, marker method or the correction up factor to calculate or judge that formula II compound is or/and existence and/or the amount of formula VI compound in the ciclesonide sample according to the ciclesonide specimen with reference to the test result of sample.
In all testing method of the invention described above, the HPLC detection method can adopt: octadecylsilane chemically bonded silica is weighting agent, and the detection wavelength is 242nm, selects the suitable mutual-assistance test of flowing to satisfy conventional requirement, and the record color atlas is used the area normalization method calculated purity.
The invention provides ciclesonide impurity of a kind of separation and preparation method thereof, and as the purposes of ciclesonide reference standard.The structure of major impurity in the ciclesonide is provided simultaneously, has been conducive to the control of Product Safety and quality.Therefore the present invention efficiently solves shortage of the prior art to the control weak point of single impurity.
Description of drawings
Fig. 1 is the typical HPLC color atlas of marker solution of the formula IV compound of embodiment 3.
Fig. 2 is the typical HPLC color atlas of marker solution of the formula VI compound of embodiment 3.
Fig. 3 is the typical HPLC color atlas of marker solution of the formula II compound of embodiment 3.
Fig. 4 is the typical HPLC color atlas of marker solution of the formula V compound of embodiment 3.
Fig. 5 is the typical HPLC color atlas of marker solution of the ciclesonide of embodiment 3.
Fig. 6 is the typical HPLC color atlas of the ciclesonide sample solution of embodiment 3.
Fig. 7 is the typical HPLC color atlas of ciclesonide 1% sample solution of embodiment 3.
Embodiment
The following examples are used for further understanding and explanation the present invention, and do not limit the scope of the invention.
General operation
The preparation of ciclesonide (compound III) for example, according to the described method of Chinese patent CN1626546, is all included it in the reference of this paper.
The instrument that mass spectroscopy is used is Agilent 1200 highly effective liquid phase chromatographic systems, the G6410A of Agilent company series connection triple quadrupole bar mass spectrograph, and ion source adopts electric spray ion source, positive ion mode.The HPLC elutriant of shunting allows to be approximately 1 μ g/ml and enters mass spectrometric ion source.
It is at CDCl that the NMR of formula II compound analyzes
3In carry out, the instrument of use is Bruker Avance500 nuclear magnetic resonance spectrometer.Resonance (the δ that is used as a proton of TMS
1H 0.00) and the solvent internal reference, CDCl
3As mark (δ in the carbon resonance
1C 77.00).
Use following contracting word, and have following implication:
| Abbreviation | Represent implication |
| δ | Chemical shift |
| CDCl 3 | Deuterochloroform |
| TMS | Tetramethylsilane |
Embodiment
Embodiment 1: the HPLC analytical procedure of ciclesonide
Get this product an amount of, add dissolve with methanol, make the solution that approximately contains 0.4mg among every 1ml with the methyl alcohol dilution, as need testing solution, measure according to high performance liquid chromatography (two appendix V of Chinese Pharmacopoeia version in 2010 D).Be weighting agent with octadecylsilane chemically bonded silica, take acetonitrile-water (90:10) as moving phase, the detection wavelength is 242nm.Number of theoretical plate calculates by ciclesonide should be not less than 5000.Precision measures need testing solution 20 μ l, the injection liquid chromatography, and the record color atlas calculates ciclesonide purity to 6 times of the main peak retention time with area normalization method.In case of necessity, can deduct system's peak area or solvent peak area by blank.
Embodiment 2: the preparation of formula II compound
5g ciclesonide (formula III compound) is dissolved among the methyl alcohol 200ml, is placed on illumination under the 254nm ultraviolet lamp, follow the tracks of reaction process with HPLC, until the raw material primitive reaction is complete, solution becomes faint yellow.Behind the reaction solution concentrating under reduced pressure, use dilution in acetonitrile, separate (chromatographic column: Agilent ZORBAX SB-C through preparative chromatography
1821.2 * 250mm), and moving phase: acetonitrile: water=80:20, flow velocity 10ml/min collects target component, and concentrating under reduced pressure gets target compound ciclesonide light degradation product (formula II compound).HPLC purity is 99.0%.
M+H in the mass spectrum [ESI-MS, m/z]
+The peak is 541.
13C NMR(500MHz, CDCl
3) δ (ppm)：207.2，203.5，176.7，165.8，132.0，107.4，97.6，81.8，67.9，67.2，54.6，54.0，49.3，46.2，40.8，40.3，39.1，38.6，33.8，33.1，29.8，27.4，27.2，26.4，25.8，24.6，19.1，17.2，14.1；
DEPT (500MHz, CDCl
3) δ (ppm): CH or CH
3Proton carbon have 165.7,132.0,107.4,81.8,67.9,54.6,49.3,40.8,40.3,33.8,29.8,19.1,17.2,14.1, CH
2Proton carbon has 67.2,39.0,33.1,27.3,27.2,26.4,25.8,24.6.
1H NMR(500MHz, CDCl
3) δ (ppm)：7.260-7.249 (1H,d)，5.891-5.878(1H,d)，4.862-4.850(1H,d)，4.713-4.984(2H,q)，4.458(1H,s)，4.392-4.383(1H,d)，2.709-2.653(1H,m)，2.340-2.301(2H,m)，2.080-1.995(3H,m)，1.53-1.83(11H,m)，
1.314-1.341(1H,m)，1.272(3H,s)，1.256-1.007(13H,m)，0.880(3H,s)。
Embodiment 3
The HPLC qualitative and quantitative analysis of ciclesonide, formula II compound, formula IV compound, formula V compound and formula VI compound
A. chromatographic condition
Se Puzhu ﹠amp; Weighting material: Agilent ZORBAX SB-C18 5 μ m, 250 * 4.6mm
Mobile phase A: acetonitrile
Mobile phase B: water
Moving phase: acetonitrile-water (90:10)
Flow velocity: 1.0ml/min
Detector: 242nm
Volume of sample: 20 μ l
B. the marker solution for preparing duscriminant ciclesonide, II compound, formula IV compound, formula V compound and formula VI compound
Get respectively ciclesonide, formula II compound, formula IV compound, formula V compound, formula VI compound an amount of, respectively with dissolve with methanol and make the solution of 0.4mg/ml, namely get each marker solution separately.Inject respectively the chromatographic column instrument and measure, obtain retention time separately.Under above-mentioned chromatographic condition, formula IV compound retention time approximately 6.2min(color atlas is seen Fig. 1), formula VI compound retention time approximately 7.2min(color atlas is seen Fig. 2), formula II compound retention time approximately 9min(color atlas is seen Fig. 3), formula V compound retention time approximately 11.5min(is seen Fig. 4), ciclesonide retention time approximately 14.5min(color atlas is seen Fig. 5), knowledge according to this area, be appreciated that, ciclesonide, formula II compound, formula IV compound, all can reach effective separation between formula V compound and formula VI compound, therefore this chromatographic condition can be with ciclesonide, formula II compound, formula IV compound, formula V compound and formula VI compound are accurately differentiated.
C. prepare sample solution
The ciclesonide sample solution of usefulness is analyzed in preparation, obtains approximately 0.4mg/ml of concentration with the dissolve with methanol ciclesonide.
D. prepare 1% sample solution
With sample solution among the methyl alcohol dilution C, obtaining concentration is 1%(4 μ g/ml) sample solution.
E. method
In the 1% sample solution injecting chromatograph with the sample solution of C and D, the record color atlas.The sample color atlas of C is seen Fig. 6, and the 1% sample color atlas of D is seen Fig. 7.
With external standard method impurity is located, calculate the amount of impurity by the principal constituent Self-control method of the correction up factor.
A i Be impurity
iPeak area,
A 1 Be the main peak area of impurity 1% sample solution ciclesonide,
f i Be impurity
iCorrection factor.
Claims (14)
1. formula I compound,
Wherein: R
1And R
2Expression H, C
1-12Straight chain, branched-chain hydrocarbon, C
2-C
8Thiazolinyl, C
2-C
8Alkynyl, C
3-C
8Cycloalkyl or C
5-C
20Aryl, R
3Expression H, ethanoyl and isobutyryl [COCH (CH
3)
2].
2. according to claim 1 compound, wherein R
1And R
2Represent independently of one another H, C
1-12Straight chain, branched-chain hydrocarbon, or C
3-C
8Cycloalkyl.
3. according to claim 2 compound, wherein R
1Expression cyclohexyl, and R
2Expression H.
4. according to claim 1 compound, wherein R
3The expression isobutyryl.
5. according to claim 1 compound, described compound is compound shown in the formula II
6. the method for a preparation formula II compound comprises: at least a organic solvent, with at least a rayed ciclesonide (formula III), obtain formula II compound,
7. method as claimed in claim 6, wherein organic solvent is acetonitrile, ethanol or methyl alcohol.
8. method as claimed in claim 6, wherein, described light is natural light or UV-light.
The arbitrary compound of claim 1-5 in measuring ciclesonide and impurity thereof as the purposes with reference to product.
10. a method of measuring ciclesonide and impurity thereof comprises
(a) provide a kind of ciclesonide sample;
(b) provide a kind of known quantity and/or characteristic formula II compound, formula IV compound, formula V compound or/and formula VI compound do with reference to sample;
(c) with the HPLC method measure respectively the ciclesonide sample of (a) and/or (b) with reference to product, determine ciclesonide sample Chinese style II compound, formula IV compound, formula V compound or/and the existence of formula VI compound or/and the amount of amount and/or ciclesonide
11. method as claimed in claim 10, described HPLC method comprises external standard method or marker method.
12. method as claimed in claim 10, described determine to comprise according to the ciclesonide sample and with reference to the test result contrast of sample or calculating formula II compound, formula IV compound, formula V compound or/and existence and/or the amount of formula VI compound in the ciclesonide sample.
13. method as claimed in claim 12, the method is: provide a kind of formula II compound, formula IV compound, formula V compound or/and formula VI compound is done with reference to sample, draw relative retention time and correction factor with ciclesonide by HPLC method contrast test; Provide a kind of ciclesonide sample, with the HPLC test of the same terms; According to test result and relative retention time and correction factor calculating formula II compound, formula IV compound, formula V compound or/and existence and/or the amount of formula VI compound in the ciclesonide sample.
Provide a kind of formula II compound, formula IV compound, formula V compound or/and formula VI compound is done with reference to sample 14. method as claimed in claim 10, the method further comprise, test with HPLC; Provide a kind of ciclesonide sample, with the HPLC test of the same terms; Quantitative adding formula II compound, formula IV compound, formula V compound are or/and formula VI compound is used the HPLC test of the same terms in the ciclesonide sample; According to test result calculations formula II compound, formula IV compound, formula V compound or/and existence and/or the amount of formula VI compound in the ciclesonide sample.
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| CN108267531A (en) * | 2016-12-31 | 2018-07-10 | 天津金耀集团有限公司 | A kind of related substance HPLC assay methods of ciclesonide |
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| CN102079769A (en) * | 2009-11-26 | 2011-06-01 | 天津金耀集团有限公司 | Cyclopropyl pregnene compound and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108267531A (en) * | 2016-12-31 | 2018-07-10 | 天津金耀集团有限公司 | A kind of related substance HPLC assay methods of ciclesonide |
| CN108267531B (en) * | 2016-12-31 | 2022-01-11 | 天津金耀集团有限公司 | HPLC (high performance liquid chromatography) determination method for ciclesonide related substances |
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