CN116120268A - Tafluprost intermediate impurity and preparation method thereof - Google Patents
Tafluprost intermediate impurity and preparation method thereof Download PDFInfo
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- CN116120268A CN116120268A CN202310204049.8A CN202310204049A CN116120268A CN 116120268 A CN116120268 A CN 116120268A CN 202310204049 A CN202310204049 A CN 202310204049A CN 116120268 A CN116120268 A CN 116120268A
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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 20
- 229960004458 tafluprost Drugs 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 239000012535 impurity Substances 0.000 title claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 37
- 150000001875 compounds Chemical class 0.000 claims description 42
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 38
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- 238000003756 stirring Methods 0.000 claims description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 24
- 229910052757 nitrogen Inorganic materials 0.000 claims description 19
- 239000000243 solution Substances 0.000 claims description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 239000012141 concentrate Substances 0.000 claims description 14
- 239000011259 mixed solution Substances 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 10
- 239000003208 petroleum Substances 0.000 claims description 9
- 230000008569 process Effects 0.000 claims description 8
- 239000000706 filtrate Substances 0.000 claims description 7
- 238000000926 separation method Methods 0.000 claims description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 5
- 238000007670 refining Methods 0.000 claims description 5
- 239000012312 sodium hydride Substances 0.000 claims description 5
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 5
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- 239000000047 product Substances 0.000 claims description 4
- 238000010898 silica gel chromatography Methods 0.000 claims description 4
- 239000012295 chemical reaction liquid Substances 0.000 claims description 3
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- 230000009471 action Effects 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 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
- 238000010791 quenching Methods 0.000 claims description 2
- 230000000171 quenching effect Effects 0.000 claims description 2
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 238000001308 synthesis method Methods 0.000 claims 1
- 230000002194 synthesizing effect Effects 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
- HMUXGYCCWIHXMK-UHFFFAOYSA-N furan-2-yl benzoate Chemical compound C=1C=CC=CC=1C(=O)OC1=CC=CO1 HMUXGYCCWIHXMK-UHFFFAOYSA-N 0.000 abstract description 7
- 238000011160 research Methods 0.000 abstract description 7
- 239000013558 reference substance Substances 0.000 abstract description 2
- 238000003908 quality control method Methods 0.000 abstract 1
- -1 hexahydro-2H-cyclopenta [ b ] furan-5-yl benzoate Chemical compound 0.000 description 12
- 239000007791 liquid phase Substances 0.000 description 10
- 239000000543 intermediate Substances 0.000 description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 150000001299 aldehydes Chemical class 0.000 description 5
- 238000010009 beating Methods 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 238000010587 phase diagram Methods 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- 238000000967 suction filtration Methods 0.000 description 5
- NQTSTBMCCAVWOS-UHFFFAOYSA-N 1-dimethoxyphosphoryl-3-phenoxypropan-2-one Chemical compound COP(=O)(OC)CC(=O)COC1=CC=CC=C1 NQTSTBMCCAVWOS-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 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 3
- 208000007950 Ocular Hypotension Diseases 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 3
- 150000003180 prostaglandins Chemical class 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 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
- 206010030043 Ocular hypertension Diseases 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 210000004087 cornea Anatomy 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- YLFBFPXKTIQSSY-UHFFFAOYSA-N dimethoxy(oxo)phosphanium Chemical compound CO[P+](=O)OC YLFBFPXKTIQSSY-UHFFFAOYSA-N 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 230000004410 intraocular pressure Effects 0.000 description 2
- 230000007794 irritation Effects 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010061218 Inflammation 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
- 206010046914 Vaginal infection Diseases 0.000 description 1
- 238000007239 Wittig reaction Methods 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 210000001742 aqueous humor Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000002060 circadian Effects 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 210000000795 conjunctiva Anatomy 0.000 description 1
- 230000032798 delamination Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 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
- 239000012467 final product Substances 0.000 description 1
- 238000003682 fluorination reaction Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 210000000554 iris Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 230000003061 melanogenesis Effects 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
- 210000001328 optic nerve Anatomy 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 150000003169 prostaglandin F2α derivatives Chemical class 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- DMHSCCFHYJAXNG-UHFFFAOYSA-N sodium;bis(trimethylsilyl)azanide;oxolane Chemical compound [Na+].C1CCOC1.C[Si](C)(C)[N-][Si](C)(C)C DMHSCCFHYJAXNG-UHFFFAOYSA-N 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
- 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)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a tafluprost intermediate impurity (3 aR,4R,5R,6 aS) -2-oxo-4- ((Z) -3-oxo-5-phenylpent-1-en-1-yl) hexahydro-2H-cyclopentane [ b ] furan-5-yl benzoate and a preparation method thereof. Simple steps, mild reaction conditions and higher product purity. The invention provides a new impurity reference substance for the technological research and quality control of the tafluprost, thereby controlling the product quality of the tafluprost and having great significance and practical value.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a tafluprost intermediate 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.
Natural Prostaglandins (PGs) are bioactive substances that are synthesized in the body and function as local hormones with various biological activities in various tissues of the body. PGFs are a group of natural prostaglandins that are known to reduce intraocular pressure when topically applied to the eye and are promising as drugs for the treatment of intraocular hypertension or glaucoma. The PGF2α ocular hypotension is mainly realized by improving aqueous humor drainage of a uveoscleral pathway instead of a classical trabecular meshwork pathway, and meanwhile, the PGF2α ocular hypotension has good night ocular hypotension effect, can reduce circadian ocular fluctuations, and can reduce the damage of ocular fluctuations to visual fields and optic nerves. However, they have a problem of irritation to eyes and side effects of inflammation caused by congestion, injury to the cornea, and the like, and thus, development and research on PGF derivatives having no such side effects have been widely conducted at home and abroad.
Tafluprost is a novel PGF2α derivative, is superior to the known natural PGF2α in the effect of lowering intraocular pressure, is substantially free from irritation to the eye, is substantially free from influence on ocular tissues such as cornea, iris, conjunctiva and the like, and has long-lasting effect. 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.
The synthesis of tafluprost generally uses Corey aldehyde as a starting material, and the final product, such as Tetrahedron Letters (2004) 1527-1529, is obtained by linking the omega chain, fluorination, DIBAL-H reduction, wittig reaction, esterification and corresponding protection and deprotection steps.
In the course of the synthesis of compound 3 from compound 1 and compound 2, the inventors have found by-products of the following structure:
the byproduct is cis isomer of tafluprost intermediate compound 3, and the existence and preparation method of the compound are not reported in the literature at present. By-products in the synthesis process of raw materials, particularly isomer impurities of intermediates directly influence the quality of medicines and the research of related preparations. Therefore, the compound has great significance for the technological research of tafluprost.
Disclosure of Invention
A first object of the present invention is to provide a tafluprost intermediate impurity having the chemical name: (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, the chemical structural formula is shown in formula I:
the compound I is an intermediate 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, which is to react the compound shown in the formula III with the compound shown in the formula II under the protection of nitrogen and the action of organic base and solvent, wherein the reaction formula is as follows:
preferably, the method specifically comprises the following steps:
a) Under the protection of nitrogen, uniformly mixing organic alkali and a solvent;
b) And c, adding a solution of the compound shown in the formula III into the reaction solution obtained in the step a.
c) Stirring the reaction solution obtained in the step b at a certain temperature for reaction;
d) C, adding a solution of a compound shown in a formula II into the reaction solution obtained in the step c;
e) Stirring the reaction solution obtained in the step d at a certain temperature for reaction;
f) And e, separating and purifying the reaction liquid obtained in the step e to obtain a target product.
Further, the organic base in the step a is selected from one of sodium hydride, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide and lithium bis (trimethylsilyl) amide;
further, the solvent in the step a is selected from one or more of tetrahydrofuran, dichloromethane, toluene, diethyl ether and MTBE.
Further, in the step b, the molar ratio of the organic base to the compound shown in the formula III is 1-1.5:1.
Further, the reaction temperature in step c and step e is-5 ℃ to 5 ℃, preferably-5 ℃ to 0 ℃.
Further, the molar ratio of the compound shown in the formula II to the compound shown in the formula III is 1-1.2:1, preferably 1.05:1.
Further, the separation method in the step f comprises the steps of quenching, extracting and concentrating the reaction liquid, adding a solvent into the concentrate, stirring and refining, filtering, concentrating the filtrate, and performing silica gel column chromatography on the concentrate to obtain the target compound.
Further, the refining solvent is selected from one or more of ethanol and ethyl acetate, preferably ethanol, and the refining effect is better. The mobile phase of the silica gel column chromatography is a mixed solution of ethyl acetate and petroleum ether, and the volume ratio of petroleum ether to ethyl acetate is (3-1): 1.
Compared with the prior art, the invention has the following beneficial technical effects:
the invention discloses a tafluprost intermediate impurity (3 aR,4R,5R,6 aS) -2-oxo-4- ((Z) -3-oxo-5-phenylpent-1-en-1-yl) hexahydro-2H-cyclopentane [ b ] furan-5-yl benzoate and a preparation method thereof. Simple steps, mild reaction conditions and higher product purity. The invention provides a new impurity reference substance for the process research of the tafluprost, the double bond configuration of the 3 branched chain of the intermediate compound can be further determined through the structure confirmation of the impurity, the configuration of the fluorine-containing branched chain double bond of the tafluprost can be indirectly determined, and a new research basis is provided for the three-dimensional configuration of the tafluprost. And the product quality of the tafluprost can be further controlled by controlling the content of the impurities, so that the tafluprost has great significance and practical value.
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;
fig. 7: liquid phase profile of the compound of formula I prepared in example 4;
fig. 8: liquid phase pattern of the compound of formula I prepared in example 5.
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 ar,4r,5r,6 as) -2-oxo-4- ((Z) -3-oxo-5-phenylpent-1-en-1-yl) hexahydro-2H-cyclopenta [ b ] furan-5-ylbenzoate prepared by the following technical route:
wherein the raw materials shown in the formula III and the compound shown in the formula II are prepared by adopting the prior art, the compound shown in the formula II is (-) -benzoyl Keli lactone aldehyde, and the compound shown in the formula III is (2-oxo-3-phenoxypropyl) dimethyl phosphonate.
The HPLC detection conditions were as follows:
example 1: 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
Under nitrogen protection, 60% sodium hydride (1.75 g,44 mmol) and 100mL tetrahydrofuran are added into a 500mL reaction bottle, a mixed solution of (2-oxo-3-phenoxypropyl) phosphonic acid dimethyl ester (10.30 g,40 mmol) and 30mL THF is dropwise added under stirring, the temperature is controlled between-5 ℃ and 0 ℃, the dropwise addition is completed, the system is subjected to nitrogen protection stirring reaction for 5-9h at the temperature between-5 ℃ and 0 ℃, a mixed solution of (-) -benzoyl-colpitis aldehyde (11.50 g,42 mmol) and 60mL tetrahydrofuran is dropwise added into the system, the temperature is controlled between-5 ℃ and 0 ℃, and the dropwise addition is completed under nitrogen protection stirring reaction between-5 ℃ and 0 ℃. After the raw materials are completely reacted, 100mL of methylene chloride and 100mL of saturated ammonium chloride aqueous solution are added under stirring, and stirring, layering, drying and concentration are carried out. The concentrate is added with ethanol for beating, suction filtration, the filtrate is concentrated under reduced pressure at 40 ℃ to 45 ℃, and the concentrate is subjected to column chromatography separation and purification (eluent: petroleum ether/ethyl acetate= (3 to 1): 1 (V/V)) to obtain (3 aR,4R,5R,6 aS) -2-oxo-4- ((Z) -3-oxo-5-phenyl pent-1-en-1-yl) hexahydro-2H-cyclopentane [ b ] furan-5-yl benzoate 0.43g with HPLC purity of 97.401 percent. The liquid phase diagram of the compound of formula I is shown in figure 1.
MS (ESI (+), 75V) m/z:424.2, 429.1. The MS spectrum of the compound of formula I is shown in figure 2.
1 H-NMR (DMSO-d 6): delta 7.92-7.89 (2H, m), delta 7.66-7.64 (1H, m), delta 07.52-7.48 (2H, m), delta 17.24 (2H, dd), delta 26.95-6.93 (1H, m), delta 36.87-6.85 (2H, m), delta 46.48 (1H, dd), delta 56.26 (1H, dd), delta 65.24 (1H, dd), delta 5.07 (1H, dt), delta 4.86 (2H, s), delta 3.86-3.84 (1H, m), delta 2.94 (1H, dd), delta 2.84-2.81 (1H, m), delta 2.63 (1H, dt), delta 2.51 (1H, dd), delta 2.10 (1H, dd). The hydrogen spectrum of the compound of formula I is shown in figure 3.
13 C-NMR (DMSO-d 6): delta 197.12, delta 176.95, delta 0165.52, delta 1158.10, delta 2147.45, delta 3133.97, delta 4129.93, delta 5129.80, delta 6129.67, delta 7129.17, delta 8125.08, delta 9121.47, delta 114.87, delta 83.72, delta 80.19, delta 72.99, delta 50.76, delta 44.48, delta 38.12, delta 35.09. 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
Under nitrogen protection, 60% sodium hydride (1.32 g,33 mmol) and 75mL tetrahydrofuran are added into a 500mL reaction bottle, a mixed solution of (2-oxo-3-phenoxypropyl) phosphonic acid dimethyl ester (7.75 g,30 mmol) and 25mL THF is dropwise added under stirring, the temperature is controlled between minus 5 ℃ and 0 ℃, the dropwise addition is completed, the system is subjected to nitrogen protection stirring reaction between minus 5 ℃ and 0 ℃ for 5-9h, a mixed solution of (-) -benzoyl-corionolide aldehyde (8.64 g,31.5 mmol) and 45mL tetrahydrofuran is dropwise added into the system, the temperature is controlled between minus 5 ℃ and 0 ℃, and the dropwise addition is completed, and the system is subjected to nitrogen protection stirring reaction between minus 5 ℃ and 0 ℃. After the complete reaction of the starting materials, 75mL of methylene chloride and 75mL of saturated aqueous ammonium chloride solution were added with stirring to the reaction solution, followed by stirring, delamination, drying and concentration. Ethyl acetate is added into the concentrate for beating, suction filtration is carried out, the filtrate is concentrated under reduced pressure at 40-45 ℃, and the concentrate is subjected to column chromatography separation and purification (eluent: petroleum ether/ethyl acetate= (3-1): 1 (V/V)) to obtain (3 aR,4R,5R,6 aS) -2-oxo-4- ((Z) -3-oxo-5-phenyl pent-1-en-1-yl) hexahydro-2H-cyclopentane [ b ] furan-5-yl benzoate 0.31g and HPLC purity 96.574 percent. 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
Under nitrogen protection, 60% sodium hydride (1.68 g,42 mmol) and 95mL of dichloromethane are added into a 500mL reaction bottle, a mixed solution of (2-oxo-3-phenoxypropyl) phosphonic acid dimethyl ester (9.03 g,35 mmol) and 30mL of dichloromethane is dropwise added under stirring, the temperature is controlled between 0 ℃ and 5 ℃, the dropwise adding is completed, the system is subjected to nitrogen protection stirring reaction for 5-9h at the temperature of 0 ℃ to 5 ℃, a mixed solution of (-) -benzoyl lactone aldehyde (10.15 g,37 mmol) and 50mL of dichloromethane is dropwise added into the system, the temperature is controlled between 0 ℃ to 5 ℃, and the dropwise adding is completed, and the system is subjected to nitrogen protection stirring reaction at the temperature of 0 ℃ to 5 ℃. After the complete reaction of the starting materials, 95mL of methylene chloride and 95mL of saturated aqueous ammonium chloride solution are added under stirring, and the mixture is stirred, layered, dried and concentrated. The concentrate is added with ethanol for beating, suction filtration, the filtrate is concentrated under reduced pressure at 40-45 ℃, and the concentrate is subjected to column chromatography separation and purification (eluent: petroleum ether/ethyl acetate= (3-1): 1 (V/V)) to obtain (3 aR,4R,5R,6 aS) -2-oxo-4- ((Z) -3-oxo-5-phenyl pent-1-en-1-yl) hexahydro-2H-cyclopentane [ b ] furan-5-yl benzoate 0.35g with HPLC purity of 97.238 percent. The liquid phase diagram of the compound of formula I is shown in figure 6.
Example 4: 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
Under nitrogen protection, adding sodium tert-butoxide (4.62 g,48 mmol) and 90mL of tetrahydrofuran into a 500mL reaction bottle, dropwise adding a mixed solution of (2-oxo-3-phenoxypropyl) phosphonic acid dimethyl ester (10.33 g,40 mmol) and 30mL of tetrahydrofuran under stirring, controlling the temperature between-5 ℃ and 0 ℃, carrying out nitrogen protection stirring reaction on the system between-5 ℃ and 0 ℃ for 5-9h, dropwise adding a mixed solution of (-) -benzoyl-corionolide aldehyde (11.50 g,42 mmol) and 60mL of tetrahydrofuran into the system, controlling the temperature between-5 ℃ and 0 ℃ and carrying out nitrogen protection stirring reaction on the system between-5 ℃ and 0 ℃. After the raw materials are completely reacted, 100mL of methylene chloride and 100mL of saturated ammonium chloride aqueous solution are added under stirring, and stirring, layering, drying and concentration are carried out. The concentrate is added with ethanol for beating, suction filtration, the filtrate is concentrated under reduced pressure at 40-45 ℃, and the concentrate is subjected to column chromatography separation and purification (eluent: petroleum ether/ethyl acetate= (3-1): 1 (V/V)) to obtain (3 aR,4R,5R,6 aS) -2-oxo-4- ((Z) -3-oxo-5-phenyl pent-1-en-1-yl) hexahydro-2H-cyclopentane [ b ] furan-5-yl benzoate 0.36g with HPLC purity of 97.546 percent. The liquid phase diagram of the compound of formula I is shown in figure 7.
Example 5: 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
Under nitrogen protection, 50mL of 1mol/L sodium bis (trimethylsilyl) amide tetrahydrofuran solution (50 mmol) is added into a 500mL reaction bottle, a mixed solution of (2-oxo-3-phenoxypropyl) dimethyl phosphonate (9.30 g,36 mmol) and 30mL tetrahydrofuran is dropwise added under stirring, the temperature is controlled between minus 5 ℃ and 0 ℃, the dropwise addition is completed, the system is subjected to nitrogen protection stirring reaction between minus 5 ℃ and 0 ℃ for 5-9h, a mixed solution of (-) -benzoyl-colpitide aldehyde (11.50 g,42 mmol) and 60mL tetrahydrofuran is dropwise added into the system, the temperature is controlled between minus 5 ℃ and 0 ℃, and the dropwise addition is completed, and the system is subjected to nitrogen protection stirring reaction between minus 5 ℃ and 0 ℃. After the raw materials are completely reacted, 100mL of methylene chloride and 100mL of saturated ammonium chloride aqueous solution are added under stirring, and stirring, layering, drying and concentration are carried out. The concentrate is added with ethanol for beating, suction filtration, the filtrate is concentrated under reduced pressure at 40 ℃ to 45 ℃, and the concentrate is subjected to column chromatography separation and purification (eluent: petroleum ether/ethyl acetate= (3 to 1): 1 (V/V)) to obtain (3 aR,4R,5R,6 aS) -2-oxo-4- ((Z) -3-oxo-5-phenyl pent-1-en-1-yl) hexahydro-2H-cyclopentane [ b ] furan-5-yl benzoate 0.38g with HPLC purity of 97.800 percent. The liquid phase diagram of the compound of formula I is shown in figure 8.
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 compound of formula I which is a tafluprost intermediate impurity:
2. the synthesis method of the compound I shown in the claim 1, which is characterized in that the compound shown in the formula III is reacted with the compound shown in the formula II under the protection of nitrogen and the action of organic base and solvent, and the reaction formula is as follows:
3. the method for synthesizing the compound I according to claim 2, which comprises the following steps:
a) Under the protection of nitrogen, uniformly mixing organic alkali and a solvent;
b) Adding a solution of a compound shown in a formula III into the reaction solution obtained in the step a;
c) Stirring the reaction solution obtained in the step b at a certain temperature for reaction;
d) C, adding a solution of a compound shown in a formula II into the reaction solution obtained in the step c;
e) Stirring the reaction solution obtained in the step d at a certain temperature for reaction;
f) And e, separating and purifying the reaction liquid obtained in the step e to obtain a target product.
4. A process according to claim 2 or 3, wherein the organic base in step a is selected from one of sodium hydride, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide and lithium bis (trimethylsilyl) amide.
5. A process according to claim 2 or 3, wherein the solvent in step a is selected from one or more of tetrahydrofuran, dichloromethane, toluene, diethyl ether and MTBE.
6. A process according to claim 2 or 3, wherein the molar ratio of the organic base to the compound of formula III is from 1 to 1.5:1.
7. A process according to claim 3, wherein the reaction temperature in steps c and e is-5 ℃ to 5 ℃, preferably-5 ℃ to 0 ℃.
8. A process according to claim 2 or 3, wherein the molar ratio of the compound of formula II to the compound of formula III is from 1 to 1.2:1, preferably 1.05:1.
9. The method according to claim 3, wherein the separation method in step f comprises quenching the reaction solution, extracting, concentrating, adding a solvent into the concentrate, stirring and refining, filtering, concentrating the filtrate, and subjecting the concentrate to silica gel column chromatography to obtain the target compound.
10. The preparation method according to claim 9, wherein the refining solvent is one or more selected from ethanol and ethyl acetate, preferably ethanol, and the mobile phase of the silica gel column chromatography is a mixed solution of ethyl acetate and petroleum ether, and the volume ratio of petroleum ether to ethyl acetate is 3-1:1.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2434133A1 (en) * | 1974-07-12 | 1976-01-22 | Schering Ag | NEW PROSTANIC ACID DERIVATIVES AND METHOD FOR THEIR PRODUCTION |
| US4018803A (en) * | 1976-02-13 | 1977-04-19 | The Upjohn Company | 13,14-Didehydro-PG3 compounds |
| US4029681A (en) * | 1976-02-13 | 1977-06-14 | The Upjohn Company | 13,14-Didehydro-PG analogs |
| CN1187486A (en) * | 1996-12-26 | 1998-07-15 | 旭硝子株式会社 | Difluoroprostaglundin Derivatives and their use |
| CN112209863A (en) * | 2020-07-07 | 2021-01-12 | 浙江尖峰药业有限公司 | Large-scale preparation method of tafluprost |
-
2023
- 2023-03-06 CN CN202310204049.8A patent/CN116120268A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2434133A1 (en) * | 1974-07-12 | 1976-01-22 | Schering Ag | NEW PROSTANIC ACID DERIVATIVES AND METHOD FOR THEIR PRODUCTION |
| US4018803A (en) * | 1976-02-13 | 1977-04-19 | The Upjohn Company | 13,14-Didehydro-PG3 compounds |
| US4029681A (en) * | 1976-02-13 | 1977-06-14 | The Upjohn Company | 13,14-Didehydro-PG analogs |
| CN1187486A (en) * | 1996-12-26 | 1998-07-15 | 旭硝子株式会社 | Difluoroprostaglundin Derivatives and their use |
| 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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| 陈刚 等: "他氟前列素的合成工艺改进", 化学研究与应用, vol. 26, pages 722 - 727 * |
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