CN116425707A - Tafluprost intermediate isomer impurity and preparation method thereof - Google Patents
Tafluprost intermediate isomer impurity and preparation method thereof Download PDFInfo
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- CN116425707A CN116425707A CN202310331825.0A CN202310331825A CN116425707A CN 116425707 A CN116425707 A CN 116425707A CN 202310331825 A CN202310331825 A CN 202310331825A CN 116425707 A CN116425707 A CN 116425707A
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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 22
- 229960004458 tafluprost Drugs 0.000 title claims abstract description 21
- 239000012535 impurity Substances 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims description 58
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- 239000007800 oxidant agent Substances 0.000 claims description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
- 230000008569 process Effects 0.000 claims description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- 230000001590 oxidative effect Effects 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 238000006546 Horner-Wadsworth-Emmons reaction Methods 0.000 claims description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 4
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 claims description 4
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims description 4
- 239000012312 sodium hydride Substances 0.000 claims description 4
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 4
- 230000009471 action Effects 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 238000006646 Dess-Martin oxidation reaction Methods 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 238000001308 synthesis method Methods 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- 239000002585 base Substances 0.000 claims 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 claims 1
- 238000011160 research Methods 0.000 abstract description 7
- 238000003908 quality control method Methods 0.000 abstract description 3
- 239000013558 reference substance Substances 0.000 abstract description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- 239000000243 solution Substances 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- -1 (-) -benzoyl Chemical group 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 239000007791 liquid phase Substances 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 206010030043 Ocular hypertension Diseases 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000003889 eye drop Substances 0.000 description 3
- 229940012356 eye drops Drugs 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 238000010587 phase diagram Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 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
- YRIZYWQGELRKNT-UHFFFAOYSA-N 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione Chemical compound ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O YRIZYWQGELRKNT-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 208000010412 Glaucoma Diseases 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- YLFBFPXKTIQSSY-UHFFFAOYSA-N dimethoxy(oxo)phosphanium Chemical compound CO[P+](=O)OC YLFBFPXKTIQSSY-UHFFFAOYSA-N 0.000 description 2
- QBIIIFXQVGRPLX-UHFFFAOYSA-N dimethyl (2-oxo-3-phenoxypropyl) phosphate Chemical compound COP(=O)(OC)OCC(=O)COC1=CC=CC=C1 QBIIIFXQVGRPLX-UHFFFAOYSA-N 0.000 description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 150000003180 prostaglandins Chemical class 0.000 description 2
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 229950009390 symclosene Drugs 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 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
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 238000007239 Wittig reaction Methods 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 210000000795 conjunctiva Anatomy 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 230000032798 delamination Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000004406 elevated intraocular pressure Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 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 description 1
- 230000004410 intraocular pressure Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 210000000554 iris Anatomy 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Images
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
- C07D307/935—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans
-
- 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)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention discloses a tafluprost intermediate isomer impurity (3 aS,4S,5S,6 aR) -5- (benzoyloxy) -4- [ (1E) -3-carbonyl-4-phenoxy-1-butenyl ] hexahydro-2H-cyclopenta [ b ] furan-2-one and a preparation method thereof. The method has the advantages of short synthetic route, simple steps, mild reaction conditions, high product purity and considerable yield. The invention provides a new impurity reference substance for the technological research and quality control of tafluprost, and has great significance and practical value.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a tafluprost intermediate isomer 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 tafluprost is a novel PGF2 alpha fluorinated derivative, and the eye drops are novel prostaglandin analogue eye drops without preservative, can effectively reduce ocular hypertension of patients as well as have high safety and good tolerance, and become the most promising clinical glaucoma treatment medicine like other prostaglandin eye drops with preservative. The effect of the composition is superior to the known natural PGF2α in reducing intraocular pressure, has no stimulation to eyes, has no influence to eye tissues such as cornea, iris, conjunctiva and the like, and has long-acting property.
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.
Masaaki Kageyama et al firstly disclose a synthesis method patent (US 5985920) of tafluprost, and (-) -benzoyl colialdehyde is used as a raw material to prepare a target compound through Hormer-Wadsworth-Emmons reaction, fluoro, hydrolysis, reduction, wittig reaction and esterification.
In the process of synthesizing compound 3 from compound 1 and compound 2, the inventors have found by careful investigation of the synthesis process that there are by-products shown in the following structures:
and confirm the presence of the impurity. The byproduct is enantiomer of tafluprost intermediate compound 3, and the existence and preparation method of the compound are not reported in the literature at present. The inventor further researches and finds out a method for preparing the impurity, and the method has the advantages of short synthetic route, simple steps, mild reaction conditions, high product purity and considerable yield. The impurity is used as a reference substance for controlling the quality of the intermediate 3, which is more beneficial to the process research and quality control of the tafluprost, and further improves the product quality of the tafluprost. Therefore, the compound has great significance for the technological research of tafluprost.
Disclosure of Invention
The first object of the invention is to provide a tafluprost intermediate isomer impurity, the chemical name of which is: (3 aS,4S,5S,6 aR) -5- (benzoyloxy) -4- [ (1E) -3-carbonyl-4-phenoxy-1-butenyl ] hexahydro-2H-cyclopenta [ b ] furan-2-one, having a chemical structural formula shown in formula I:
the compound I is an intermediate isomer impurity generated by the synthesis process of tafluprost.
The second purpose of the invention is to provide a preparation method of the compound shown in the formula I, wherein the compound shown in the formula II is oxidized under the action of an oxidant to obtain a compound shown in the formula III, and the compound shown in the formula III is condensed with the compound shown in the formula IV to obtain the target compound I, wherein the reaction formula is as follows:
preferably, the method specifically comprises the following steps:
a) Oxidizing a compound shown in a formula II under the action of an oxidant to obtain a compound shown in a formula III;
b) Reacting a compound shown in a formula III with a compound shown in a formula IV through a Horner-Wadsworth-Emmons reaction, and connecting a side chain to obtain a target compound I;
further, the oxidizing agent in the step a is selected from one of tempo reagent (2, 6-tetramethylpiperidine oxide), dess-Martin reagent (1, 1-triacetoxy-1, 1-dihydro-1, 2-benzylioyloxy-3 (1H) -ketone), PDC reagent (pyridinium dichromate), PCC reagent (pyridinium chlorochromate) and answer oxidizing agent.
Further, the solvent in the step a is selected from one or more of dichloromethane, dimethyl carbonate, ethyl acetate and acetonitrile.
Further, when the oxidant in the step a is selected from one of Dess-Martin, PDC, PCC, swern oxidants, the molar ratio of the oxidant to the compound shown in the formula II is 1-1.5:1.
Further, the alkali used in the Horner-Wadsworth-Emmons reaction in the step b is selected from one of sodium hydride, butyllithium, potassium tert-butoxide and sodium tert-butoxide.
Further, the solvent in the step b is selected from one or more of dichloromethane, tetrahydrofuran and toluene.
Further, in the step b, the molar ratio of the alkali to the compound shown in the formula IV is 1-1.5:1.
Further, in the step b, the molar ratio of the compound shown in the formula III to the compound shown in the formula IV is 1-1.2:1.
Compared with the prior art, the invention has the following beneficial technical effects:
the invention discloses a tafluprost intermediate isomer impurity (3 aS,4S,5S,6 aR) -5- (benzoyloxy) -4- [ (1E) -3-carbonyl-4-phenoxy-1-butenyl ] hexahydro-2H-cyclopenta [ b ] furan-2-one and a preparation method thereof. The impurity is obtained through directional synthesis, the steps are simple, the reaction conditions are mild, the purity of the product is high, and the yield is considerable. The impurity can participate in subsequent reaction, and is conducted to generate the enantiomer impurity of the tafluprost, and the enantiomer impurity of the tafluprost is not easy to remove by a conventional refining method because the tafluprost is liquid. The intermediate 3 is solid, the quality is easy to control, and the impurity is used as a reference substance for controlling the quality of the intermediate 3, so that the process research and the quality control of the tafluprost are facilitated, and the product quality of the tafluprost is improved. Therefore, the compound has great significance for the technological research of tafluprost.
Drawings
Fig. 1: liquid phase profile of the compound of formula I prepared in example 1;
fig. 2: MS profile of the compound of formula I prepared in example 1;
fig. 3: hydrogen spectrum of the compound of formula I prepared in example 1;
fig. 4: carbon spectrum of the compound of formula I prepared in example 1;
fig. 5: liquid phase profile of the compound of formula I prepared in example 2;
fig. 6: liquid phase profile of the compound of formula I 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.
Preparation of (3 aS,4S,5S,6 aR) -5- (benzoyloxy) -4- [ (1E) -3-carbonyl-4-phenoxy-1-butenyl ] hexahydro-2H-cyclopenta [ b ] furan-2-one prepared by the following technical route:
wherein the raw materials of the compound shown in the formula II and the compound shown in the formula IV are prepared by adopting the prior art, the compound shown in the formula II is (+) -benzoyl lactone, and the compound shown in the formula IV is (2-oxo-3-phenoxypropyl) dimethyl phosphonate. The compound of formula III is (+) -benzoyl-colpitan aldehyde.
The HPLC detection conditions were as follows:
example 1: preparation of (3 aS,4S,5S,6 aR) -5- (benzoyloxy) -4- [ (1E) -3-carbonyl-4-phenoxy-1-butenyl ] hexahydro-2H-cyclopenta [ b ] furan-2-one
A1L three-necked flask was charged with trichloroisocyanuric acid (32.85 g,0.14 mol), 400mL of a mixed solution of dimethyl carbonate and 100mL of ethyl acetate under nitrogen protection, TEMPO (0.22 g,1.4 mmol) was added between 0 and 5℃and (+) -benzoyl kohlide (39 g,0.14 mol) was added in portions, TLC monitoring (developing agent: ethyl acetate/petroleum ether=1/1) was carried out after the starting material had reacted completely, the reaction solution was poured into an aqueous solution of sodium thiosulfate and dipotassium hydrogen phosphate, stirred, suction filtered, layered, and the organic phase was concentrated to obtain 35.24g of an off-white solid, i.e., a compound of formula III, with a yield of 91.05%.
To a 2L three-necked flask were added 60% sodium hydride (5.35 g,0.13 mol) and 500mL tetrahydrofuran, and a solution of dimethyl (2-oxo-3-phenoxypropyl) phosphate (31.39 g,0.12 mol) and 100mL tetrahydrofuran were added dropwise at a temperature of-5℃to 5℃and, after stirring for 2 hours, a compound of the formula III (35 g,0.12 mol) and 200mL tetrahydrofuran solution were added dropwise under nitrogen protection, after TLC monitoring (developing agent: ethyl acetate/petroleum ether=1/1) the starting material was completely reacted, the reaction mixture was quenched by adding acetic acid, the reaction mixture was concentrated to desolventize, ethanol was added to the reaction mixture and stirred and beaten at a temperature of 25℃to 30℃and suction filtration was carried out to obtain (3 aS,4S,5S,6 aR) -5- (benzoyloxy) -4- [ (1E) -3-oxo-1-butenyl ] hexahydro-2H-cyclopenta [ b ] furan-2-one 32.22g, purity of 99.44% by HPLC, and yield 65.22%. The liquid phase diagram of the compound of formula I is shown in figure 1.
MS (ESI (-), 75V) m/z:405.2. the MS spectrum of the compound of formula I is shown in figure 2.
1 H-NMR (DMSO-d 6): delta 7.95-7.93 (2H, m), delta 7.69-7.65 (1H, m), delta 07.55-7.51 (2H, m), delta 17.28-7.24 (2H, m), delta 6.99-6.87 (4H, m), delta 6.43 (1H, dd), delta 5.33-5.31 (1H, m), delta 5.13-5.11 (1H, m), delta 5.09 (2H, d), delta 3.08-2.91 (3H, m), delta 2.63-2.57 (2H, m), delta 2.03 (1H, dd). The hydrogen spectrum of the compound of formula I is shown in figure 3.
13 C-NMR (DMSO-d 6): delta 195.19, delta 177.02, delta 0165.57, delta 1158.22, delta 2146.43, delta 3134.01, delta 4129.89, delta 5129.83, delta 6129.73, delta 7129.18, delta 8127.68, delta 9121.43, delta 114.98, delta 83.78, delta 79.42, delta 71.38, delta 54.11, delta 42.62, delta 37.94, delta 34.91. The carbon spectrum of the compound of formula I is shown in figure 4.
Example 2: preparation of (3 aR,4R,5R,6 aS) -2-oxo-4- ((Z) -3-oxo-5-phenylpent-1-en-1-yl) hexahydro-2H-cyclopenta [ b ] furan-5-yl benzoate
In a 1L three-necked round bottom flask, oxalyl chloride (9 mL,90 mmol) and 180mL of methylene chloride were added in sequence under nitrogen protection, and after cooling to-78℃ 4,4' -xylene sulfoxide (34.5 g,0.15 mol) was added dropwise. After stirring for 1h, a solution of Cololactone (22 g,78 mmol) and 250mL of dichloromethane was added dropwise, after stirring well, freshly distilled triethylamine (42 mL,0.30 mol) was added dropwise, after TLC (ethyl acetate/petroleum ether=1/1) monitored for completion of the reaction, 200mL of water and 15mL of acetic acid were added sequentially and then the solution was separated, the organic layer was washed with saturated sodium chloride solution (300 mL. Times.3), the organic layers were combined, dried over anhydrous sodium sulfate and concentrated to give 18.73g of an off-white solid, i.e., the compound of formula III, in 85.76% yield.
To a 2L three-necked flask were added 60% sodium hydride (2.72 g,68 mmol) and 270mL tetrahydrofuran, dimethyl (2-oxo-3-phenoxypropyl) phosphate (16 g,62 mmol) and 50mL tetrahydrofuran solution were added dropwise at-5℃to 5℃and after stirring for 2 hours, the compound of formula III (18 g,66 mmol) and 100mL tetrahydrofuran solution were added dropwise under nitrogen protection, TLC (developing reagent: ethyl acetate/petroleum ether=1/1) was monitored, the starting material was completely reacted, then acetic acid was added to quench the reaction, the reaction solution was concentrated and desolventized, ethanol was added to stir and slurry at 25℃to 30℃and suction filtration was carried out to obtain (3 aS,4S,5S,6 aR) -5- [ (1E) -3-oxo-4-phenoxy-1-butenyl ] hexahydro-2H-cyclopenta [ b ] furan-2-one at 14.65g and an HPLC purity of 99.56%, yield 58.18%. The liquid phase diagram of the compound of formula I is shown in figure 5.
Example 3: preparation of (3 aR,4R,5R,6 aS) -2-oxo-4- ((Z) -3-oxo-5-phenylpent-1-en-1-yl) hexahydro-2H-cyclopenta [ b ] furan-5-yl benzoate
A1L three-necked flask was charged with trichloroisocyanuric acid (27.89 g,0.12 mol), 340mL of a mixed solution of dimethyl carbonate and 85mL of ethyl acetate under nitrogen protection, TEMPO (0.19 g,1.2 mmol) was added between 0 and 5℃and (+) -benzoyl kohlrabide (33 g,0.12 mol) was added in portions, TLC monitoring (developing agent: ethyl acetate/petroleum ether=1/1) was carried out after the starting material had reacted completely, the reaction solution was poured into an aqueous solution of sodium thiosulfate and dipotassium hydrogen phosphate, stirred, suction filtered, layered, and the organic phase was concentrated to obtain 28.75g of an off-white solid, i.e., a compound of formula III, with a yield of 87.36%.
Under nitrogen protection, adding sodium tert-butoxide (9.6 g,0.1 mol) and 100mL of tetrahydrofuran into a 500mL reaction bottle, dropwise adding a mixed solution of (2-oxo-3-phenoxypropyl) dimethyl phosphonate (23.24 g,0.09 mol) and 70mL of tetrahydrofuran under stirring, controlling the temperature between-5 ℃ and 0 ℃, carrying out nitrogen protection stirring reaction on the system at-5 ℃ to 0 ℃ for 5-9h after dropwise adding a mixed solution of a compound (28 g,0.10 mol) of formula III and 140mL of tetrahydrofuran into the system, controlling the temperature between-5 ℃ to 0 ℃ after dropwise adding, and carrying out nitrogen protection stirring reaction on the system at-5 ℃ to 0 ℃. After the complete reaction of the starting materials, 150mL of methylene chloride and 150mL of saturated aqueous ammonium chloride solution were added to the reaction mixture under stirring, followed by stirring, delamination and concentration. Adding ethanol into the concentrate, pulping, and suction filtering. 23.65g of (3 aS,4S,5S,6 aR) -5- (benzoyloxy) -4- [ (1E) -3-carbonyl-4-phenoxy-1-butenyl ] hexahydro-2H-cyclopenta [ b ] furan-2-one are obtained in a purity of 99.65% by HPLC, yield 64.67%. The liquid phase diagram of the compound of formula I is shown in figure 6.
Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains. It will be apparent to those skilled in the art that various modifications and variations can be made to the present invention without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.
Claims (10)
1. A tafluprost intermediate isomer impurity characterized by having the structure of formula I:
2. the synthesis method of the compound I shown in the claim 1 is characterized in that the compound shown in the formula II is oxidized under the action of an oxidant to obtain a compound shown in the formula III, and the compound shown in the formula III is condensed with the compound shown in the formula IV to obtain the target compound I, wherein the reaction formula is as follows:
3. the method for synthesizing the compound I according to claim 2, which comprises the following steps:
a) Reacting a compound shown in a formula II with an oxidant in a solvent I to obtain a compound shown in a formula III;
b) And (3) reacting the compound shown in the formula III with the compound shown in the formula IV in a solvent II under alkaline conditions through a Horner-Wadsworth-Emmons reaction, and connecting a side chain to obtain the target compound I.
4. The method according to claim 3, wherein the oxidizing agent in the step a is one selected from the group consisting of tempo reagent, dess-Martin reagent, PDC reagent, PCC reagent, and swen oxidizing agent.
5. The process according to claim 4, wherein the solvent in step a is one or more selected from the group consisting of methylene chloride, dimethyl carbonate, ethyl acetate and acetonitrile.
6. The process of claim 4, wherein the molar ratio of the oxidizing agent to the compound of formula II is 1 to 1.5:1 when the oxidizing agent is selected from one of Dess-Martin, PDC, PCC, swern oxidizing agents.
7. The process according to claim 3, wherein the alkali used in the Horner-Wadsworth-Emmons reaction in the step b is one selected from sodium hydride, butyllithium, potassium tert-butoxide and sodium tert-butoxide.
8. The preparation method according to claim 7, wherein the solvent II in the step b is one or more selected from dichloromethane, tetrahydrofuran and toluene.
9. The process according to claim 7, wherein the molar ratio of the base to the compound of formula IV in step b is 1 to 1.5:1.
10. A process according to claim 2 or 3, wherein the molar ratio of the compound of formula III to the compound of formula IV is from 1 to 1.2:1.
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| US4018803A (en) * | 1976-02-13 | 1977-04-19 | The Upjohn Company | 13,14-Didehydro-PG3 compounds |
| US4086258A (en) * | 1976-02-17 | 1978-04-25 | The Upjohn Company | 13,14-Didehydro-PGA1 compounds |
| US4099015A (en) * | 1976-02-13 | 1978-07-04 | The Upjohn Company | 2,2-Difluoro-13,14-didehydro-11-deoxy-17-phenyl-18,19,20-trinor-PGE2 compounds |
| AU2133777A (en) * | 1976-02-17 | 1978-07-20 | The Upjohn Company | 13, 14-didehydro prostaglandin |
| CN1187486A (en) * | 1996-12-26 | 1998-07-15 | 旭硝子株式会社 | Difluoroprostaglundin Derivatives and their use |
| CN110522764A (en) * | 2019-10-12 | 2019-12-03 | 黄泳华 | Composition and application thereof containing derivatives of prostaglandins and inorganic salts |
| CN112209863A (en) * | 2020-07-07 | 2021-01-12 | 浙江尖峰药业有限公司 | Large-scale preparation method of tafluprost |
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2023
- 2023-03-31 CN CN202310331825.0A patent/CN116425707A/en active Pending
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| US4018803A (en) * | 1976-02-13 | 1977-04-19 | The Upjohn Company | 13,14-Didehydro-PG3 compounds |
| US4099015A (en) * | 1976-02-13 | 1978-07-04 | The Upjohn Company | 2,2-Difluoro-13,14-didehydro-11-deoxy-17-phenyl-18,19,20-trinor-PGE2 compounds |
| US4086258A (en) * | 1976-02-17 | 1978-04-25 | The Upjohn Company | 13,14-Didehydro-PGA1 compounds |
| AU2133777A (en) * | 1976-02-17 | 1978-07-20 | The Upjohn Company | 13, 14-didehydro prostaglandin |
| CN1187486A (en) * | 1996-12-26 | 1998-07-15 | 旭硝子株式会社 | Difluoroprostaglundin Derivatives and their use |
| CN110522764A (en) * | 2019-10-12 | 2019-12-03 | 黄泳华 | Composition and application thereof containing derivatives of prostaglandins and inorganic salts |
| CN112209863A (en) * | 2020-07-07 | 2021-01-12 | 浙江尖峰药业有限公司 | Large-scale preparation method of tafluprost |
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