CN116655507A - Aidiecalcitol dehydration impurity as well as preparation method and application thereof - Google Patents
Aidiecalcitol dehydration impurity as well as preparation method and application thereof Download PDFInfo
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- CN116655507A CN116655507A CN202310522878.0A CN202310522878A CN116655507A CN 116655507 A CN116655507 A CN 116655507A CN 202310522878 A CN202310522878 A CN 202310522878A CN 116655507 A CN116655507 A CN 116655507A
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- 239000012535 impurity Substances 0.000 title claims abstract description 59
- 238000006297 dehydration reaction Methods 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 230000018044 dehydration Effects 0.000 title claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 78
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 22
- 229940125782 compound 2 Drugs 0.000 claims abstract description 20
- 238000010791 quenching Methods 0.000 claims abstract description 19
- 230000000171 quenching effect Effects 0.000 claims abstract description 18
- 238000005406 washing Methods 0.000 claims abstract description 17
- 229940125904 compound 1 Drugs 0.000 claims abstract description 15
- 238000002156 mixing Methods 0.000 claims abstract description 12
- RCBVKBFIWMOMHF-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical compound C1=CC=NC=C1.C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O RCBVKBFIWMOMHF-UHFFFAOYSA-L 0.000 claims abstract description 11
- 229940126214 compound 3 Drugs 0.000 claims abstract description 9
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 6
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 6
- 238000003032 molecular docking Methods 0.000 claims abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 28
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 25
- 150000001875 compounds Chemical class 0.000 claims description 22
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 21
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 16
- 239000000126 substance Substances 0.000 claims description 15
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 13
- 239000012043 crude product Substances 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 229940125898 compound 5 Drugs 0.000 claims description 8
- 238000004440 column chromatography Methods 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 238000000926 separation method Methods 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 239000012074 organic phase Substances 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- 238000000746 purification Methods 0.000 claims description 5
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 210000001503 joint Anatomy 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 238000007670 refining Methods 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- 239000012153 distilled water Substances 0.000 claims description 2
- 238000001704 evaporation Methods 0.000 claims description 2
- 229960000074 biopharmaceutical Drugs 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000013558 reference substance Substances 0.000 abstract description 6
- 239000007858 starting material Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 27
- 239000000047 product Substances 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 239000003814 drug Substances 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- 238000004809 thin layer chromatography Methods 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 8
- 238000001514 detection method Methods 0.000 description 8
- 229940079593 drug Drugs 0.000 description 7
- 230000035484 reaction time Effects 0.000 description 7
- 238000012360 testing method Methods 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 239000000376 reactant Substances 0.000 description 5
- 239000012488 sample solution Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 239000012295 chemical reaction liquid Substances 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 238000011403 purification operation Methods 0.000 description 3
- 238000003908 quality control method Methods 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 238000001179 sorption measurement Methods 0.000 description 3
- 102000009310 vitamin D receptors Human genes 0.000 description 3
- 108050000156 vitamin D receptors Proteins 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- 208000001132 Osteoporosis Diseases 0.000 description 2
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000003795 desorption Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- -1 hydroxypropoxy residue Chemical group 0.000 description 2
- DHRLEVQXOMLTIM-UHFFFAOYSA-N phosphoric acid;trioxomolybdenum Chemical compound O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.OP(O)(O)=O DHRLEVQXOMLTIM-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- GMRQFYUYWCNGIN-ZVUFCXRFSA-N 1,25-dihydroxy vitamin D3 Chemical compound C1([C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=CC=C1C[C@@H](O)C[C@H](O)C1=C GMRQFYUYWCNGIN-ZVUFCXRFSA-N 0.000 description 1
- JDQDSEVNMTYMOC-UHFFFAOYSA-N 3-methylbenzenesulfonic acid Chemical compound CC1=CC=CC(S(O)(=O)=O)=C1 JDQDSEVNMTYMOC-UHFFFAOYSA-N 0.000 description 1
- 241000729173 Cirsium japonicum Species 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 102000050760 Vitamin D-binding protein Human genes 0.000 description 1
- 101710179590 Vitamin D-binding protein Proteins 0.000 description 1
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- OFHCOWSQAMBJIW-AVJTYSNKSA-N alfacalcidol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C OFHCOWSQAMBJIW-AVJTYSNKSA-N 0.000 description 1
- 229960002535 alfacalcidol Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- GMRQFYUYWCNGIN-NKMMMXOESA-N calcitriol Chemical class C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C GMRQFYUYWCNGIN-NKMMMXOESA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 230000001009 osteoporotic effect Effects 0.000 description 1
- YWWARDMVSMPOLR-UHFFFAOYSA-M oxolane;tetrabutylazanium;fluoride Chemical compound [F-].C1CCOC1.CCCC[N+](CCCC)(CCCC)CCCC YWWARDMVSMPOLR-UHFFFAOYSA-M 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 description 1
- 235000005282 vitamin D3 Nutrition 0.000 description 1
- 239000011647 vitamin D3 Substances 0.000 description 1
- 150000003704 vitamin D3 derivatives Chemical class 0.000 description 1
- 229940021056 vitamin d3 Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/60—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by elimination of -OH groups, e.g. by dehydration
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
- C07C45/29—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups
- C07C45/292—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups with chromium derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/14—All rings being cycloaliphatic
- C07C2602/24—All rings being cycloaliphatic the ring system containing nine carbon atoms, e.g. perhydroindane
-
- 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
Abstract
The invention relates to the technical field of chemistry and bio-pharmacy, and discloses a dehydrated impurity of idecalcitol, a preparation method and application thereof, which takes (epsilon R,1R,3aR,4S,7 aR) -octahydro-4-hydroxy-alpha, epsilon, 7 a-tetramethyl-1H-indene-1 amyl alcohol as a starting material, and comprises the following steps: (1) dehydration reaction: mixing the compound 1 with toluene and toluene sulfonic acid, quenching, extracting, washing, concentrating and purifying after the reaction is finished to obtain a compound 2; (2) oxidation reaction: mixing the compound 2 with pyridinium dichromate and methylene dichloride, and separating, concentrating and purifying after the reaction is finished to obtain a compound 3; (3) docking reaction; (4) deprotection reaction; (5) The idicalcitol dehydration impurity can be used as a idicalcitol impurity reference substance, and the preparation method is simple to operate, and has high yield and purity of more than 97%.
Description
Technical Field
The invention relates to the technical field of chemistry and bio-pharmacy, in particular to a dehydrated impurity of idecalcitol, a preparation method and application thereof.
Background
The idecalcitol soft capsule is an osteoporosis therapeutic drug approved by the Japanese thistle in 21 st 1 st 2011. The active substance idecalcitol is a new active vitamin D3 derivative for treating osteoporosis after alfacalcidol, and the action target point is a vitamin D3 receptor. Idecalcitol is an analogue of 1a, 25-dihydroxyvitamin D3[1, 25 (OH) 2D3] with a hydroxypropoxy residue at position 2 b. It binds with low affinity to Vitamin D Receptor (VDR) but with higher affinity than 1, 25 (OH) 2D to vitamin D binding protein, showing a long half-life in plasma. Idecalcitol is effective and safe in increasing the lumbar and hip mineral density (BMD) in osteoporotic patients and also supplements vitamin D3. The structural formula is shown in formula one:
the idecalcitol has unstable property, is sensitive to light and heat, contains a plurality of active hydroxyl groups, has a longer synthetic route, is inevitably easy to generate some dehydrated impurities and other related substances in the synthetic process, and is difficult to separate and purify, so that the synthetic condition is difficult to grasp, and the synthetic process has high technical threshold and great difficulty. Meanwhile, because the content of the idecalcitol in the preparation is extremely low, the idecalcitol belongs to a low-dose medicine, and the physicochemical property of the medicine is extremely unstable, so that higher requirements are also put forward on the quality control of bulk drugs and preparation products.
Wherein, the dehydrated impurity of the idecalcitol is the dehydrated impurity of the 25-position hydroxyl of the finished idecalcitol, the structural formula is shown as follows,
。
through searching, no literature report on the synthesis of the impurity exists, so that the idecalcitol dehydration impurity, a preparation method and application thereof are provided, and the idecalcitol dehydration impurity is used for preparing an idecalcitol impurity reference substance and has important practical significance.
Disclosure of Invention
The invention aims to solve the problem of preparation of an idecalcitol impurity reference substance to a certain extent, and provides an idecalcitol dehydration impurity, a preparation method and application thereof. The method can be used for accurately positioning and qualifying the impurities in the detection and analysis process of the finished product of the idecalcitol, is beneficial to strengthening the control of the impurities, and further improves the quality of the raw materials and preparations of the idecalcitol.
In order to achieve the above object, the present invention is achieved by the following technical solutions.
The invention provides a dehydrated impurity of idecalcitol, which has the chemical structural formula:
。
the invention also provides a preparation method of the idecalcitol dehydration impurity, which comprises the following steps:
(1) Dehydration reaction: mixing the compound 1 with toluene and toluene sulfonic acid, quenching, extracting, washing, concentrating and purifying after the reaction is finished to obtain a compound 2;
it should be noted that this step is critical to the preparation process, and the reaction time and reaction temperature must be strictly controlled, and too short a reaction time results in low conversion of the reactants, while too high a reaction temperature results in a large amount of by-product compound 2'; in addition, the toluene sulfonic acid includes toluene sulfonic acid having methyl groups in ortho, meta and para positions, and among them, p-toluene sulfonic acid is preferable.
(2) Oxidation reaction: mixing the compound 2 with pyridinium dichromate and methylene dichloride, and separating, concentrating and purifying after the reaction is finished to obtain a compound 3;
(3) And (3) butt joint reaction: mixing a compound 4, anhydrous tetrahydrofuran and n-hexane solution of n-butyllithium, adding the anhydrous tetrahydrofuran solution of the compound 3 for reaction, and quenching, extracting, washing and purifying after the reaction is finished to obtain a compound 5;
(4) Deprotection reaction: mixing the compound 5 with tetrabutylammonium fluoride solution, concentrating and purifying after the reaction is finished to obtain a crude product of the compound 6;
(5) And (3) refining by recrystallization: and mixing the crude product of the compound 6 with ethyl acetate, heating and refluxing for reaction, crystallizing, filtering, and drying under reduced pressure to obtain the compound 6, namely the idecalcitol dehydrated impurity.
Further, in the step (1), the quenching is performed by adding saturated sodium bicarbonate, the extracted extractant is ethyl acetate, the organic phase is extracted at least twice, the washing comprises distilled water washing and saturated saline water washing, the concentration is heating and evaporating the solvent, and the purification is column chromatography purification.
Further, in the step (2), the reaction temperature is 20-30 ℃; the dosage ratio of the compound 2, pyridinium dichromate and methylene dichloride is 2g: (3-6) g: (75-125) ml; the separation is a filtration separation, and the concentration operation and the purification operation are the same as in step (1).
Further, the quenching in step (3) is quenching by adding water; the dosage ratio of the hexane solution of the compound 4, anhydrous tetrahydrofuran and n-butyllithium is 6.5g: (30-60) ml: (4-8) ml; the extraction operation, the washing operation and the purification operation are the same as those of the step (1), and the step (3) is performed under the protection of nitrogen.
Further, step (3) is specifically to add the compound 4 and anhydrous tetrahydrofuran, stir and keep the temperature to-75- -60 ℃, add the hexane solution of n-butyllithium, and react for (1.5-2.5) h; continuously adding anhydrous tetrahydrofuran of the compound 3, and keeping the temperature to 0-10 ℃ until the reaction is finished; quenching, extracting, washing and purifying are carried out after the reaction is finished.
Further, in the step (4), the reaction temperature is 55-65 ℃; the dosage ratio of the compound 5 to the tetrabutylammonium fluoride solution is 1g: (10-15) ml; the tetrabutylammonium fluoride solution is a tetrahydrofuran solution of 0.8-1.2M tetrabutylammonium fluoride, and the concentration operation is the same as the purification operation in the step (1).
It should be noted that, in the steps (1) - (4), the column chromatography is performed on 100-400 mesh silica gel, but preferably 100-200 mesh silica gel, and the column chromatography is performed according to the difference of adsorption forces of substances on the silica gel, and in general, substances with larger polarity are easily adsorbed by the silica gel, substances with weaker polarity are not easily adsorbed by the silica gel, and in the whole chromatography process, substances with different polarities are separated by adsorption, desorption, re-adsorption and re-desorption until being washed, and the mesh number of the silica gel affects the separation speed and the separation effect of the substances passing through the column.
Further, the volume ratio of the crude product of the compound 6 to ethyl acetate in the step (5) is (20-30) ml:1ml.
It should be noted that in the steps (2) - (4), the concentration, the purification, the extraction, the washing and the quenching are the same as the principle, but specific parameters such as time, amount and amount ratio are different, for example, the quenching operation is performed in the step (1) and the step (3), but the quenching agent in the step (1) is saturated sodium bicarbonate, and the quenching agent in the step (3) is water.
The idecalcitol dehydration impurity and the preparation method thereof can be at least applied to the related substance reference substance of idecalcitol, the impurity identification of idecalcitol or the quality control aspect of idecalcitol bulk drug and preparation.
The invention discloses a dehydrated impurity of idecalcitol and a preparation method and application thereof, which have the beneficial effects that compared with the prior art:
according to the preparation method of the idecalcitol dehydration impurity, in the preparation method, the compound 1 can generate a hydroxyl elimination reaction at a specific position under the action of the methylbenzenesulfonic acid, the reaction time is prolonged, the hydroxyl of the compound 1 can be completely dehydrated and converted, and finally, the compound 2 meeting the purity requirement can be obtained through column chromatography purification and put into subsequent reaction; meanwhile, the whole set of preparation method is simple to operate, does not need complex expensive instruments, and is safe and high in yield.
The dehydrated impurity of the idecalcitol prepared by the method can reach more than 97% purity, and can be used as a reference substance, so that the accuracy positioning and the quality of the impurity in the detection and analysis of the idecalcitol finished product are improved, the impurity control is facilitated to be enhanced, and further, a beneficial reference is provided for the improvement of the quality standard of the idecalcitol bulk drug and the preparation thereof and the quality control of the product, and a reference is also provided for the nuclear magnetism of the similar compound.
Drawings
FIG. 1 is a chemical structural formula of a dehydrated impurity of idecalcitol according to an embodiment of the present invention;
FIG. 2 is a synthetic route diagram of an embodiment of the present invention for idecalcitol dehydration impurity;
FIG. 3 is a nuclear magnetic spectrum of a dehydrated impurity of idecalcitol according to an embodiment of the present invention;
FIG. 4 is a high performance liquid chromatogram of an embodiment of the present invention of a dehydrated impurity of idecalcitol;
fig. 5 is a high performance liquid chromatogram of the impurity dehydrated by idecalcitol, the reaction solution under the acidity of the crude product of idecalcitol and the raw material medicine of idecalcitol according to the embodiment of the invention.
Detailed Description
The following description of the technical solutions in the embodiments of the present invention will be clear and complete, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
It should be noted that the reaction time of all steps is not fully specified in the present invention, because the reaction time must be changed as the amount and ratio of the reactants are changed, and the reaction can be defaulted to be performed to the end of the step for which the reaction time is not specified in the present invention, and the generation of the product is not continued.
The raw material compound 1 used in the invention is a commercial chemical, the alias of the raw material compound is idecalcitol CD ring, the CAS number is 66774-84-3, and other raw material reagents are commercially available.
The structural formula of the idecalcitol dehydration impurity to be prepared in the invention is shown in figure 1, and the synthetic route is shown in figure 2.
Example 1
(1) Dehydration reaction: about 5g of compound 1 and 50ml of toluene were charged into a reaction flask, 5g of p-toluenesulfonic acid was added, and the reaction was maintained at 40 ℃. After the reaction was started for 3 hours, the reaction condition was determined by TLC plate, and after the reaction was terminated, saturated sodium bicarbonate was added to the system to quench, and ethyl acetate was added to extract 2 times, each in an amount of 100ml, and an organic phase was taken. After completion of the extraction, the organic phase was washed with 100ml of water and 100ml of saturated brine in this order, and concentrated to dryness. Purifying by column chromatography using 200 mesh silica gel column, eluting with n-hexane: ethyl acetate = 10:1, eluting to give compound 2 and weighing about 4g.
(2) Oxidation reaction: 4g of Compound 2, 9g of pyridinium dichromate and 200ml of methylene chloride were added to a reaction flask and the reaction was maintained at 25 ℃. After the reaction is finished, filtering, concentrating the filtrate to be dry, purifying by 200-mesh silica gel column chromatography, and purifying by n-hexane: ethyl acetate=10:1 to give compound 4 and weigh approximately 4g.
(3) And (3) butt joint reaction: under the protection of nitrogen, 6.5g of compound 4 and 50ml of anhydrous tetrahydrofuran are added into a reaction bottle, the temperature is reduced to-60 ℃ under stirring, 6ml of hexane solution of n-butyllithium is dropwise added at constant temperature, the reaction is kept for 2 hours after the dropwise addition is finished, and 15ml of mixed solution of 2g of compound 4 and the rest of anhydrous tetrahydrofuran is continuously dropwise added. After the dripping is finished, the temperature is kept to 5 ℃ for reaction, after the reaction is finished, 200ml of water is added into the system for quenching, 300ml of ethyl acetate is used for extraction, the organic phase is collected, 200ml of water washing and 200ml of saturated saline washing are sequentially added, the mixture is concentrated to dryness, and the mixture is purified by 200-mesh silica gel column chromatography, wherein the eluent is n-hexane: ethyl acetate = 100:1, eluting to give compound 5 and weighing about 5g.
(4) Deprotection reaction: 4g of compound 5 is added into 50ml of 1M tetrabutylammonium fluoride tetrahydrofuran solution, the temperature is raised to 60 ℃ to start the reaction, the reaction time is 4 hours, the mixture is concentrated to be dry, and 200-mesh silica gel column chromatography is carried out, and the eluent is dichloromethane: methanol=20: 1, eluting to give about 2g of crude compound 6.
(5) And (3) refining by recrystallization: adding 500mg of the crude product of the compound 6 and 20ml of ethyl acetate into a reaction bottle, heating to reflux, filtering out insoluble substances, naturally cooling to room temperature, starting crystallization, filtering, decompressing and drying to obtain the compound 6, weighing the mass of about 400mg, and obtaining the yield: 80%.
Example 2
This embodiment differs from embodiment 1 in that: step (1) dehydration reaction, adding about 5g of compound 1 and 50ml of toluene into a reaction bottle, adding 5g of p-toluenesulfonic acid, keeping the reaction at 30 ℃ to be complete, and calculating the yield of step (1).
Example 3
This embodiment differs from embodiment 1 in that: step (1) dehydration reaction, adding about 5g of compound 1 and 50ml of toluene into a reaction bottle, adding 5g of p-toluenesulfonic acid, keeping the reaction at 50 ℃ to be complete, and calculating the yield of step (1).
Example 4
This embodiment differs from embodiment 1 in that: and (3) replacing the reactant of the dehydration reaction in the step (1) with o-toluenesulfonic acid, and calculating the yield of the step (1).
Example 5
This embodiment differs from embodiment 1 in that: and (3) replacing the reactant of the dehydration reaction in the step (1) with m-toluenesulfonic acid, and calculating the yield of the step (1).
Example 6
This embodiment differs from embodiment 1 in that: in the step (2), the reaction temperature is kept at 20 ℃, and the yield of the step (2) is calculated.
Example 7
This embodiment differs from embodiment 1 in that: in the step (2), the reaction temperature is kept at 30 ℃, and the yield of the step (2) is calculated.
Comparative example 1
Dehydration reaction: about 5g of compound 1 and 50ml of toluene were charged into a reaction flask, 5g of p-toluenesulfonic acid was added and kept at 25℃for 6 hours, then the reaction solution of the reaction system, commercially available compound 1, toluene, p-toluenesulfonic acid, compound 2 of example 1 were separately taken for TLC thin layer chromatography test, and the spot plate condition was observed and recorded, the spots of reactant compound 1, toluene, p-toluenesulfonic acid on the silica gel plate were observed clearly under development of phosphomolybdic acid/ethanol solution (5%), and the spot of product compound 2 was not observed at the height, so that it was inferred that the reaction temperature was too low and the reaction condition was not reached without starting the reaction.
Comparative example 2
Dehydration reaction: about 5g of compound 1 and 50ml of toluene were charged into a reaction flask, 5g of p-toluenesulfonic acid was added and kept at 60℃for 6 hours, then the reaction solution of the reaction system, commercially available compound 1, toluene, p-toluenesulfonic acid, compound 2 of example 1 were taken separately for TLC thin layer chromatography test, and spot plate condition was observed and recorded, and the yield of step (2) was calculated.
Comparative example 3
Oxidation reaction: 4g of Compound 2, 9g of pyridinium dichromate and 200ml of methylene chloride were added to a reaction flask, and the reaction was carried out at 10℃for 10 hours, and the reaction mixture of the reaction system, compound 2, pyridinium dichromate and Compound 3 of example 1 were each subjected to TLC thin layer chromatography, and the condition of the spot plate was observed and recorded, and the spots of Compound 2 and pyridinium dichromate on the silica gel plate were observed clearly under development of phosphomolybdic acid/ethanol solution (5%), and the spots of the product were not observed, so that it was inferred that the reaction temperature was too low, and the reaction condition was not reached without starting the reaction.
Comparative example 4
Oxidation reaction: 4g of Compound 2, 9g of pyridinium dichromate and 200ml of methylene chloride were added to a reaction flask, and the reaction was carried out at 40℃for 10 hours, and the reaction mixture of the reaction system, compound 2, pyridinium dichromate and Compound 3 of example 1 were each subjected to TLC thin-layer chromatography, and spot-plating conditions were observed and recorded, whereby the yield of step (2) was calculated.
The statistics of the yields calculated for examples 1-7 and comparative examples 1-4 are shown in Table 1.
Table 1 yield statistics table
Note that: yield 1 represents the yield of this example/comparative example step (1), and yield 2 represents the yield of this example/comparative example step (2).
As can be seen from the above examples, comparative examples and data records, the reaction temperature in the step (1) should be strictly controlled to be 30-50 ℃, the reaction cannot be carried out due to the too low temperature, and a large amount of byproducts are generated due to the too high temperature; among all the methylbenzenesulfonic acids, the methylbenzenesulfonic acid with a para-structure has the best effect; the reaction temperature in the step (2) should be controlled to be 20-30 ℃, and too low or too high temperature can lead to obvious reduction of the yield.
Next, the relevant substances in the crude drug of idecalcitol are checked by taking the idecalcitol dehydrated impurity as an impurity reference substance.
1. Nuclear magnetic testing
Nuclear magnetic detection was performed on the dehydrated impurity of idecalcitol in example 1, and the detection results are shown in FIG. 3.
2. High Performance Liquid Chromatography (HPLC) detection
2.1. Experimental principle: the liquid is used as mobile phase, a high-pressure transfusion system is adopted, the mobile phase such as single solvent with different polarities or mixed solvent with different proportions, buffer solution and the like is pumped into a chromatographic column filled with stationary phase, and after components in the column are separated, the components enter a detector for detection, so that analysis of a sample is realized.
2.2. Chromatographic conditions
Chromatographic column: octadecylsilane chemically bonded silica was used as filler (4.6 mm. Times.250 mm,5 um);
column temperature: 30 ℃;
mobile phase: water-acetonitrile (50:50);
flow rate: 1.0ml/min;
detection wavelength: 265nm;
sample injection volume: 50ul;
a diluent: acetonitrile-water (50:50).
2.3. Test reagent configuration
Control solution of idecalcitol dehydrated impurities
The control product of the embodiment 1 is taken as the control product of the dehydrated impurity of the idecalcitol, a proper amount of the control product is precisely weighed, and the control product is dissolved and diluted by a diluent to prepare a solution with about 2 mug of each 1ml of the control product of the dehydrated impurity of the idecalcitol.
Sample solution 1
Proper amount of idecalcitol is taken, precisely weighed, and dissolved and diluted by a diluent to prepare a solution containing about 1mg per 1ml.
Sample solution 2
Taking a reaction solution for preparing idecalcitol by deprotection under an acidic condition, and diluting the reaction solution by adding a diluent according to the concentration of the reaction solution to prepare a solution with the concentration of about 1mg in each 1ml, wherein the solution is used as a test sample 2.
2.4. Operation processing
Precisely measuring the above solutions, respectively injecting into high performance liquid chromatograph, and recording chromatogram. The chromatograms of the test sample solutions contain the idecalcitol dehydration impurities, and the content of the dehydration impurities is calculated according to an external standard method and the peak area.
2.5. Data recording
Fig. 4 is a purity measurement chart of a control substance of the dehydrated impurity of the idecalcitol, the chromatographic peak results are shown in table 2, fig. 5 is an HPLC detection result of the dehydrated impurity of the idecalcitol, the reaction liquid of the crude product of the idecalcitol under the acidity and the crude drug of the idecalcitol, in the figure, the sample solution 1 corresponds to the crude drug of the idecalcitol, the sample solution 2 corresponds to the reaction liquid of the crude product of the idecalcitol under the acidity, and the dehydrated impurity corresponds to the control substance solution of the dehydrated impurity of the idecalcitol.
TABLE 2 chromatographic peak results for idicalcitol dehydrated impurity control
3. Data analysis
From the data, it is known that the impurity eliminated by the 25-position hydroxyl is generated in the reaction liquid for preparing the idecalcitol by deprotection under the acidic condition, and the impurity can be effectively removed by purifying and recrystallizing the reaction liquid through column chromatography, so that the idecalcitol bulk drug is obtained.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (10)
1. The idicalcitol dehydration impurity is characterized by having a chemical structural formula as follows:
。
2. a process for the preparation of the idicalcitol dehydration impurity of claim 1, comprising the steps of:
(1) Dehydration reaction: mixing the compound 1 with toluene and toluene sulfonic acid, quenching, extracting, washing, concentrating and purifying after the reaction is finished to obtain a compound 2;
；
(2) Oxidation reaction: mixing the compound 2 with pyridinium dichromate and methylene dichloride, and separating, concentrating and purifying after the reaction is finished to obtain a compound 3;
；
(3) And (3) butt joint reaction: mixing a compound 4, anhydrous tetrahydrofuran and n-hexane solution of n-butyllithium, adding the anhydrous tetrahydrofuran solution of the compound 3 for reaction, and quenching, extracting, washing and purifying after the reaction is finished to obtain a compound 5;
；
(4) Deprotection reaction: mixing the compound 5 with tetrabutylammonium fluoride solution, concentrating and purifying after the reaction is finished to obtain a crude product of the compound 6;
；
(5) And (3) refining by recrystallization: mixing the crude product of the compound 6 with ethyl acetate, heating and refluxing for reaction, crystallizing, filtering, and drying under reduced pressure to obtain the compound 6, namely the idecalcitol dehydrated impurity;
。
3. the method for preparing the idicalcitol dehydration impurity according to claim 2, wherein in step (1), the reaction temperature is 30-50 ℃;
the dosage ratio of the compound 1 to toluene to the methylbenzenesulfonic acid is 1g: (10-15) ml: (1-3) g.
4. The method for preparing the dehydrated impurity of idecalcitol according to claim 2, wherein in the step (1), the quenching is performed by adding saturated sodium bicarbonate, the extracting agent of the extraction is ethyl acetate, and the organic phase is extracted at least twice, the washing comprises washing with distilled water and washing with saturated saline water, the concentration is performed by heating and evaporating the solvent, and the purification is performed by column chromatography.
5. The method for preparing the idicalcitol dehydration impurity according to claim 2, wherein in step (2), the reaction temperature is 20-30 ℃;
the dosage ratio of the compound 2, pyridinium dichromate and methylene dichloride is 2g: (3-6) g: (75-125) ml;
the separation is a filtration separation.
6. The method for preparing a dehydrated impurity of idecalcitol according to claim 2, wherein the quenching in step (3) is quenching by adding water;
the dosage ratio of the hexane solution of the compound 4, anhydrous tetrahydrofuran and n-butyllithium is 6.5g: (30-60) ml: (4-8) ml;
the docking reaction was carried out under nitrogen protection.
7. The method for preparing the dehydrated impurity of idecalcitol according to claim 2, wherein the step (3) is specifically that after the compound 4 and anhydrous tetrahydrofuran are added, stirring and keeping the temperature to-75 to 60 ℃, adding a hexane solution of n-butyllithium, and reacting for 1.5 to 2.5 hours; continuously adding anhydrous tetrahydrofuran of the compound 3, and keeping the temperature to 0-10 ℃ until the reaction is finished; quenching, extracting, washing and purifying are carried out after the reaction is finished.
8. The method for preparing the idicalcitol dehydration impurity according to claim 2, wherein in step (4), the reaction temperature is 55-65 ℃;
the dosage ratio of the compound 5 to the tetrabutylammonium fluoride solution is 1g: (10-15) ml;
the tetrabutylammonium fluoride solution is a tetrahydrofuran solution of 0.8-1.2M tetrabutylammonium fluoride.
9. The process for preparing a dehydrated impurity of idecalcitol according to claim 2, wherein the volume ratio of the crude product of compound 6 to ethyl acetate in step (5) is (20-30): 1.
10. use of the idicalcitol dehydration impurity of claim 1 in chemistry and biopharmaceuticals.
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