CN116217521A - Tafluprost degradation impurity and preparation method thereof - Google Patents
Tafluprost degradation impurity and preparation method thereof Download PDFInfo
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- CN116217521A CN116217521A CN202310204046.4A CN202310204046A CN116217521A CN 116217521 A CN116217521 A CN 116217521A CN 202310204046 A CN202310204046 A CN 202310204046A CN 116217521 A CN116217521 A CN 116217521A
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- WSNODXPBBALQOF-VEJSHDCNSA-N tafluprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\C(F)(F)COC1=CC=CC=C1 WSNODXPBBALQOF-VEJSHDCNSA-N 0.000 title claims abstract description 34
- 229960004458 tafluprost Drugs 0.000 title claims abstract description 32
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 239000012535 impurity Substances 0.000 title claims abstract description 17
- 230000015556 catabolic process Effects 0.000 title claims abstract description 7
- 238000006731 degradation reaction Methods 0.000 title claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 39
- 238000006243 chemical reaction Methods 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- 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 claims description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 12
- 239000007800 oxidant agent Substances 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 8
- 230000001590 oxidative effect Effects 0.000 claims description 7
- 238000010898 silica gel chromatography Methods 0.000 claims description 7
- 239000000243 solution Substances 0.000 claims description 6
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 239000012295 chemical reaction liquid Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 230000000593 degrading effect Effects 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- 238000001308 synthesis method Methods 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 17
- 229940079593 drug Drugs 0.000 abstract description 14
- 238000011160 research Methods 0.000 abstract description 5
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- 238000003908 quality control method Methods 0.000 abstract description 2
- 239000013558 reference substance Substances 0.000 abstract description 2
- 239000007791 liquid phase Substances 0.000 description 13
- 238000010587 phase diagram Methods 0.000 description 13
- 238000001228 spectrum Methods 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000012071 phase Substances 0.000 description 5
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 4
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 125000004269 oxiran-2-yl group Chemical group [H]C1([H])OC1([H])* 0.000 description 4
- 208000007950 Ocular Hypotension Diseases 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 150000003180 prostaglandins Chemical class 0.000 description 3
- PXGPLTODNUVGFL-BRIYLRKRSA-N (E,Z)-(1R,2R,3R,5S)-7-(3,5-Dihydroxy-2-((3S)-(3-hydroxy-1-octenyl))cyclopentyl)-5-heptenoic acid Chemical compound CCCCC[C@H](O)C=C[C@H]1[C@H](O)C[C@H](O)[C@@H]1CC=CCCCC(O)=O PXGPLTODNUVGFL-BRIYLRKRSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 206010064571 Gene mutation Diseases 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 206010030043 Ocular hypertension Diseases 0.000 description 2
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 2
- 102000000471 Prostaglandin F receptors Human genes 0.000 description 2
- 108050008995 Prostaglandin F receptors Proteins 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 231100000024 genotoxic Toxicity 0.000 description 2
- 230000001738 genotoxic effect Effects 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 208000010412 Glaucoma Diseases 0.000 description 1
- 206010022941 Iridocyclitis Diseases 0.000 description 1
- 235000005769 Japanese ginseng Nutrition 0.000 description 1
- 206010030348 Open-Angle Glaucoma Diseases 0.000 description 1
- 241000168720 Panax japonicus Species 0.000 description 1
- 235000003174 Panax japonicus Nutrition 0.000 description 1
- 201000004612 anterior uveitis Diseases 0.000 description 1
- 210000001742 aqueous humor Anatomy 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000002060 circadian Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 210000000795 conjunctiva Anatomy 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000004406 elevated intraocular pressure Effects 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 210000000554 iris Anatomy 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 229960001160 latanoprost Drugs 0.000 description 1
- GGXICVAJURFBLW-CEYXHVGTSA-N latanoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CC[C@@H](O)CCC1=CC=CC=C1 GGXICVAJURFBLW-CEYXHVGTSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000003061 melanogenesis Effects 0.000 description 1
- 210000001328 optic nerve Anatomy 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 150000003169 prostaglandin F2α derivatives Chemical class 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 210000001585 trabecular meshwork Anatomy 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
Images
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/38—Compounds containing oxirane rings with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D303/40—Compounds containing oxirane rings with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals by ester radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D301/00—Preparation of oxiranes
- C07D301/02—Synthesis of the oxirane ring
- C07D301/03—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds
- C07D301/12—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds with hydrogen peroxide or inorganic peroxides or peracids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D301/00—Preparation of oxiranes
- C07D301/02—Synthesis of the oxirane ring
- C07D301/03—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds
- C07D301/14—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds with organic peracids, or salts, anhydrides or esters thereof
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Steroid Compounds (AREA)
Abstract
The invention discloses two degradation impurity compounds of formula I and formula II of tafluprost, and discloses a preparation method of the two impurities. The preparation method has the advantages of short synthetic route, convenient operation, mild and controllable reaction conditions and considerable yield. The two can be used as reference substances for controlling the purity and quality of the tafluprost bulk drug and related preparations so as to ensure the quality of the drug, thereby ensuring the clinical medication safety and the life health of patients and being more beneficial to process research and quality control.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a tafluprost degradation impurity and a preparation method thereof.
Background
Hefluprost (Taflupirist) is named (5Z) -7- [ (1R, 2R,3R, 5S) -2- [ (1E) -3, 3-difluoro-4-phenoxy-1-buten-1-yl ] -3, 5-dihydroxycyclopentyl ] -5-heptenoic acid isopropyl ester, colorless to pale yellow viscous liquid, with molecular formula of C25H34F2O5 and molecular weight of 452.53.
The prostaglandin PGF2α is currently considered to have the most potential and effective ocular partial ocular hypotension drug, the ocular hypotension effect is mainly realized by improving aqueous humor drainage of the uveoscleral pathway instead of the classical trabecular meshwork pathway, and meanwhile, the prostaglandin PGF2α has good night ocular hypotension effect, can reduce circadian ocular pressure fluctuation and lighten damage of ocular pressure fluctuation to visual field and optic nerve.
Tafluprost, a novel PGF2α derivative and selective FP receptor agonist, is the first preservative-free prostaglandin analog eye drop, is substantially free of irritation to the eye, is substantially free of effects on ocular tissues such as the cornea, iris, conjunctiva, etc., has an affinity for the iridocyclitis FP receptor of about 12 times stronger than the carboxylic acid product of latanoprost, and is long-acting. They are characterized by much less melanogenesis and longer efficacy than other drugs. The medicine is developed by the Japanese ginseng pharmacy, is approved by FDA in Japan in 10 months of 2008 and is obtained in 2 months of 2012, enters China in 7 months of 2015, and has the trade name of Taprios. The medicine is used for reducing the elevated intraocular pressure of patients with open angle glaucoma or ocular hypertension, and recent researches show that the medicine can effectively reduce the ocular hypertension of patients with glaucoma, and has high safety and good tolerance. CFDA approved clinical trial was obtained 5 months 2015.
In the research of stability of the tafluprost, the inventor detects that the tafluprost can be degraded into a compound of the formula I and a compound of the formula II which are mutually isomers under the oxidation condition, wherein the compound of the formula I and the formula II is shown in the following structure:
at present, no literature reports that the two compounds exist, and the two compounds have a propylene oxide warning structure, so that DAN is possibly damaged, gene mutation is induced, cancer is further induced, the compounds are potential genotoxic impurities, the quality of the bulk drug is greatly influenced, the compounds are used as a reference substance for controlling the purity and the quality of the tafluprost bulk drug and related preparations, and the quality of the medicines can be further ensured, so that the clinical medication safety and the life health of patients are ensured. Therefore, the two compounds have great significance for the quality study of the tafluprost.
Disclosure of Invention
It is a first object of the present invention to provide a tafluprost degrading impurity comprising isopropyl 4- ((2 r,3 s) -3- (((1 r,2r,3r,5 s) -2- ((E) -3, 3-difluoro-4-phenoxy-1-buten-1-yl) -3, 5-dihydroxycyclopentyl) methyl) oxiran-2-yl) butyrate of formula I,
and isopropyl 4- ((2 s,3 r) -3- (((1 r,2r,3r,5 s) -2- ((E) -3, 3-difluoro-4-phenoxy-1-buten-1-yl) -3, 5-dihydroxycyclopentyl) methyl) oxiran-2-yl) butyrate shown in formula II
A second object of the present invention is to provide a process for the preparation of a compound of formula I and a compound of formula II, comprising the specific steps of:
a) Taking tafluprost as a starting material, dissolving tafluprost and an oxidant in a solvent, and uniformly mixing;
b) Stirring the mixture obtained in the step a at a certain temperature to react until the tafluprost is degraded;
c) And c, separating and purifying the reaction liquid obtained in the step b to obtain target products of the formulas I and II.
Further, the solvent in the step a is selected from one or more of methanol, acetonitrile and dichloromethane, preferably acetonitrile, because other impurities in the reaction liquid have less interference.
Further, the oxidant in the step a is selected from one or more of hydrogen peroxide aqueous solution and m-chloroperoxybenzoic acid.
Further, the oxidant is hydrogen peroxide (30% aqueous solution), and the molar ratio of the oxidant to the tafluprost is 10-30:1, preferably 20:1. The reaction temperature in step b is 40 to 55℃and preferably 45 to 50 ℃.
Further, when the oxidizing agent is m-chloroperoxybenzoic acid, the molar ratio of the oxidizing agent to the tafluprost is 1-1.5:1, preferably 1.2:1.
Further, the purification method in the step c comprises the steps of extracting and concentrating the reaction liquid, and then performing silica gel column chromatography. The mobile phase of the silica gel column chromatography is a mixed solution of dichloromethane and methanol, and the volume ratio of the dichloromethane to the methanol is 100-60:1, preferably 80:1.
Compared with the prior art, the invention has the following beneficial technical effects:
the invention discloses two degradation impurities of tafluprost and discloses a method for preparing the two impurities simultaneously. The inventor discovers and confirms the existence of the two impurities through careful research of the synthesis process, completes the structure confirmation of the two impurities, and discovers a synthesis method with simple and convenient operation. The method has the advantages of short synthetic route, convenient operation, mild and controllable reaction conditions and considerable yield. The two impurities are isomers and have a propylene oxide warning structure, so that DAN is possibly damaged, gene mutation is induced, cancer is further induced, and the impurity is used as a potential genotoxic impurity and used as a control product for controlling the purity and quality of the tafluprost bulk drug and related preparations, so that the drug quality is more strongly ensured, thereby ensuring the clinical medication safety and the life health of patients, and being more beneficial to process research and quality control. Has great significance and practical value.
Drawings
FIG. 1 is a liquid phase diagram of the compound of formula I prepared in example 1;
FIG. 2 is an MS spectrum of the compound of formula I prepared in example 1;
FIG. 3 is a hydrogen spectrum of the compound of formula I prepared in example 1;
FIG. 4 is a carbon spectrum of the compound of formula I prepared in example 1;
FIG. 5 is a liquid phase diagram of the compound of formula II prepared in example 1;
FIG. 6 is an MS spectrum of the compound of formula II prepared in example 1;
FIG. 7 is a hydrogen spectrum of the compound of formula II prepared in example 1;
FIG. 8 is a carbon spectrum of the compound of formula II prepared in example 1;
FIG. 9 is a liquid phase diagram of the compound of formula I prepared in example 2;
FIG. 10 is a liquid phase diagram of the compound of formula II prepared in example 2;
FIG. 11 is a liquid phase diagram of the compound of formula I prepared in example 3;
FIG. 12 is a liquid phase diagram of the compound of formula II prepared in example 3.
Detailed Description
The foregoing aspects of the invention are explained in further detail by the following description of embodiments. It should not be construed that the scope of the above subject matter of the present invention is limited to the following examples.
The preparation of the compounds of formula I and formula II is prepared by the following technical routes:
wherein the crude drug tafluprost ((5Z) -7- [ (1R, 2R,3R, 5S) -2- [ (1E) -3, 3-difluoro-4-phenoxy-1-buten-1-yl ] -3, 5-dihydroxycyclopentyl ] -5-heptenoic acid isopropyl ester) is prepared by adopting the prior art.
The chemical name of the compound of formula I is: isopropyl 4- ((2 r,3 s) -3- (((1 r,2r,3r,5 s) -2- ((E) -3, 3-difluoro-4-phenoxy-1-buten-1-yl) -3, 5-dihydroxycyclopentyl) methyl) oxiran-2-yl) butyrate.
The chemical name of the compound of formula II is: isopropyl 4- ((2 s,3 r) -3- (((1 r,2r,3r,5 s) -2- ((E) -3, 3-difluoro-4-phenoxy-1-buten-1-yl) -3, 5-dihydroxycyclopentyl) methyl) oxiran-2-yl) butyrate. The HPLC detection conditions were as follows:
example 1: preparation of Compounds of formula I and formula II
Taking tafluprost (4.97 g,0.01 mol) and adding 200mL of acetonitrile solution, adding 30% hydrogen peroxide aqueous solution (25 g,0.22 mol), stirring at 45-50 ℃ to react, stopping the reaction when HPLC monitors the complete degradation of tafluprost, adding 15g of sodium chloride into the system, stirring to dissolve the solution, standing for layering, adding ethyl acetate into the aqueous phase to extract, merging organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating to obtain crude products, separating and purifying by a silica gel column chromatography (dichloromethane/methanol=80:1 (V/V is taken as a mobile phase), collecting eluent of different compounds, decompressing and desolventizing to obtain 1.12g of the compound of the formula I, wherein the HPLC purity is 97.454%, the liquid phase diagram of the compound of the formula I is shown in figure 1, the liquid phase diagram of the compound of the formula II is 1.04g, the HPLC purity 97.345%, and the liquid phase diagram of the compound of the formula II is shown in figure 5. Total yield 42.18%.
MS (ESI (+), 75V) m/z:469.2. the MS spectrum of the compound of formula I is shown in figure 2.
1 H-NMR (DMSO-d 6): delta 7.33-7.29 (2H, m), delta 7.02-6.97 (3H, m), delta 06.20-6.14 (1H, m), delta 15.81-5.77 (1H, m), delta 24.94-4.84 (2H, m), delta 34.55 (1H, d), delta 44.35 (2H, t), delta 54.10-4.06 (1H, m), delta 63.77-3.74 (1H, m), delta 3.62-3.59 (1H, m), delta 3.38-3.35 (1H, m), delta 2.27-2.22 (5H, m), delta 1.99-1.91 (1H, m), delta 1.68-1.66 (1H, m), delta 1.58-1.51 (2H, m), delta 1.37-1.31 (3H, m), delta 1.16 (6H, d). The hydrogen spectrum of the compound of formula I is shown in figure 3.
13 C-NMR (DMSO-d 6): delta 172.91, delta 158.22, delta 0139.38, delta 1139.30, delta 2139.21, delta 3130.03, delta 4123.16, delta 5122.92, delta 6122.68, delta 7121.90, delta 8121.79, delta 9119.39, delta 117.03, delta 0115.30, delta 185.07, delta 280.91, delta 377.06, delta 471.75, delta 569.26, delta 668.95, delta 768.63, delta 867.25, delta 956.18, delta 45.95, delta 40.56, delta 34.29, delta 33.39, delta 32.81, delta 22.09, delta 21.58. The carbon spectrum of the compound of formula I is shown in figure 4.
MS (ESI (+), 75V) m/z:468.9. the MS spectrum of the compound of formula II is shown in figure 6.
1 H-NMR (DMSO-d 6): delta 7.32-7.28 (2H, m), delta 7.04-6.96 (3H, m), delta 06.22-6.16 (1H, m), delta 15.89-5.82 (1H, m), delta 24.91-4.85 (2H, m), delta 34.47 (1H, d), delta 44.39-4.28 (3H, m), delta 53.78-3.75 (1H, m), delta 3.66-3.61 (1H, m), delta 3.31-3.28 (1H, m), delta 2.34-2.32 (4H, m), delta 2.07 (1H, q), delta 1.74-1.72 (1H, m), delta 1.71-1.57 (3H, m), delta 1.55-1.30 (3H, m), delta 1.01 (6H, d). The hydrogen spectrum of the compound of formula II is shown in figure 7.
13 C-NMR(DMSO-d6)：δ172.90，δ158.22，δ139.60，δ139.51，δ139.42，δ130.08，δ123.59，δ123.35，δ123.11，δ121.91，δ121.77，δ119.39，δ117.01，δ115.31，δ80.95，δ79.65，δ75.15，δ71.93, delta 69.28, delta 68.97, delta 068.65, delta 167.25, delta 54.83, delta 46.23, delta 42.08, delta 34.34, delta 32.98, delta 32.42, delta 22.09, delta 21.65. The carbon spectrum of the compound of formula II is shown in figure 8.
Example 2: preparation of Compounds of formula I and formula II
Taking tafluprost (3.62 g,0.008 mol) and adding 150mL of methanol solution, adding 30% hydrogen peroxide aqueous solution (18.14 g,0.18 mol), stirring at 45-50 ℃ to react, stopping the reaction when the tafluprost is completely degraded by HPLC, adding 13.6g of sodium chloride into the system, stirring to dissolve the solution, standing for layering, adding ethyl acetate into the aqueous phase to extract, merging organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, separating and purifying the crude product obtained after concentration by silica gel column chromatography (with dichloromethane/methanol=80:1 (V/V being the mobile phase), collecting eluent of different compounds, decompressing and desolventizing to obtain 0.87g of the compound of the formula I, 94.775% of the HPLC purity, wherein the liquid phase diagram of the compound of the formula I is shown in figure 9, and 0.78g of the compound of the formula II, 96.49% of the HPLC purity and the liquid phase diagram of the compound of the formula II is shown in figure 10. Total yield 44.12%.
Example 3: preparation of Compounds of formula I and formula II
Taking tafluprost (3.00 g,6.6 mmol) and adding 125mL of dichloromethane to dissolve, adding m-chloroperoxybenzoic acid (1.37 g,7.9 mmol), stirring at 40-45 ℃ to react, stopping the reaction when the tafluprost is completely degraded, adding 125mL of water into the system, stirring, standing for layering, adding dichloromethane into the water phase to extract, combining organic phases, drying with anhydrous sodium sulfate, concentrating to obtain crude products, separating and purifying by silica gel column chromatography (dichloromethane/methanol= (100-60): 1 (V/V is used as mobile phase), collecting eluent of different compounds, decompressing and desolventizing to respectively obtain 0.96g of compound of formula I, 96.891% of HPLC purity, wherein the liquid phase diagram of the compound of formula I is shown in figure 11, 0.89g of compound of formula II, 97.461% of HPLC purity and the liquid phase diagram of the compound of formula II is shown in figure 12, and the total yield is 59.87%.
Claims (9)
1. Tafluprost degrading impurities comprising
Compounds of formula I
And a compound of formula II
2. The synthesis method of the tafluprost degradation impurity according to claim 1, wherein the synthesis step comprises:
a) Taking tafluprost as a starting material, dissolving tafluprost and an oxidant in a solvent, and uniformly mixing;
b) Stirring the mixture obtained in the step a at a certain reaction temperature to react until the tafluprost is degraded;
c) And c, separating and purifying the reaction liquid obtained in the step b to obtain the target compounds of the formula I and the formula II.
3. The preparation method according to claim 2, wherein the solvent in the step a is one or more selected from methanol, acetonitrile and dichloromethane.
4. The preparation method according to claim 2, wherein the oxidizing agent in the step a is selected from one or more of hydrogen peroxide and m-chloroperoxybenzoic acid.
5. The preparation method according to claim 4, wherein the oxidant is 30% hydrogen peroxide aqueous solution, and the molar ratio of the oxidant to the tafluprost is 10-30:1, preferably 20:1.
6. The preparation process according to claim 2, characterized in that the reaction temperature in step b is 40-55 ℃, preferably 45-50 ℃.
7. The process according to claim 4, wherein the oxidizing agent is m-chloroperoxybenzoic acid and the molar ratio of oxidizing agent to tafluprost is 1-1.5:1, preferably 1.2:1.
8. The method according to claim 2, wherein the purification method in step c comprises concentrating the reaction solution and then subjecting the concentrated reaction solution to silica gel column chromatography.
9. The preparation method according to claim 8, wherein the mobile phase of the silica gel column chromatography is a mixed solution of dichloromethane and methanol, and the volume ratio of the dichloromethane to the methanol is 100-60:1.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111763185A (en) * | 2020-07-16 | 2020-10-13 | 中山万远新药研发有限公司 | Prostaglandin derivative with epoxidized side chain, composition and use thereof |
| RU2021103400A (en) * | 2021-02-11 | 2021-04-16 | Общество с ограниченной ответственностью "Гротекс" (ООО "Гротекс") | PHARMACEUTICAL COMPOSITION OF TAFLUPROST |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111763185A (en) * | 2020-07-16 | 2020-10-13 | 中山万远新药研发有限公司 | Prostaglandin derivative with epoxidized side chain, composition and use thereof |
| RU2021103400A (en) * | 2021-02-11 | 2021-04-16 | Общество с ограниченной ответственностью "Гротекс" (ООО "Гротекс") | PHARMACEUTICAL COMPOSITION OF TAFLUPROST |
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