CN103073613B - A kind of synthetic method of fluticasone derivative - Google Patents
A kind of synthetic method of fluticasone derivative Download PDFInfo
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- MGNNYOODZCAHBA-GQKYHHCASA-N fluticasone Chemical class C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(O)[C@@]2(C)C[C@@H]1O MGNNYOODZCAHBA-GQKYHHCASA-N 0.000 title claims abstract description 21
- 238000010189 synthetic method Methods 0.000 title claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 23
- 238000003682 fluorination reaction Methods 0.000 claims abstract description 21
- 150000001875 compounds Chemical class 0.000 claims abstract description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 28
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 16
- 238000001514 detection method Methods 0.000 claims description 13
- 239000012046 mixed solvent Substances 0.000 claims description 11
- 239000007810 chemical reaction solvent Substances 0.000 claims description 9
- 238000000605 extraction Methods 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 7
- 239000012363 selectfluor Substances 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 7
- 101710134784 Agnoprotein Proteins 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-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
- 238000001914 filtration Methods 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 3
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 claims description 3
- 239000012065 filter cake Substances 0.000 claims description 3
- QWVGKYWNOKOFNN-UHFFFAOYSA-N o-cresol Chemical compound CC1=CC=CC=C1O QWVGKYWNOKOFNN-UHFFFAOYSA-N 0.000 claims description 3
- 238000001556 precipitation Methods 0.000 claims description 3
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 claims description 2
- 239000000706 filtrate Substances 0.000 claims description 2
- 238000002386 leaching Methods 0.000 claims description 2
- 239000012044 organic layer Substances 0.000 claims description 2
- 238000000638 solvent extraction Methods 0.000 claims description 2
- 238000010025 steaming Methods 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 abstract description 8
- VPJVZUREKATUEU-UHFFFAOYSA-N C(C)Br.[F] Chemical compound C(C)Br.[F] VPJVZUREKATUEU-UHFFFAOYSA-N 0.000 abstract description 6
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 abstract description 6
- 239000003054 catalyst Substances 0.000 abstract description 6
- 238000009833 condensation Methods 0.000 abstract description 6
- 230000005494 condensation Effects 0.000 abstract description 6
- 229910052731 fluorine Inorganic materials 0.000 abstract description 6
- 229960002714 fluticasone Drugs 0.000 abstract description 6
- 229910052751 metal Inorganic materials 0.000 abstract description 6
- 239000002184 metal Substances 0.000 abstract description 6
- 229910052709 silver Inorganic materials 0.000 abstract description 6
- 239000004332 silver Substances 0.000 abstract description 6
- 239000011737 fluorine Substances 0.000 abstract description 5
- WZYRHMVOCDVECK-UHFFFAOYSA-N O1C(=CC=C1)C(=O)O.C(CC)(=O)O Chemical compound O1C(=CC=C1)C(=O)O.C(CC)(=O)O WZYRHMVOCDVECK-UHFFFAOYSA-N 0.000 abstract description 4
- 238000006114 decarboxylation reaction Methods 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 4
- 230000001988 toxicity Effects 0.000 abstract description 4
- 231100000419 toxicity Toxicity 0.000 abstract description 4
- 230000007613 environmental effect Effects 0.000 abstract description 3
- 238000003912 environmental pollution Methods 0.000 abstract description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 abstract 1
- 238000006467 substitution reaction Methods 0.000 abstract 1
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 16
- 238000005352 clarification Methods 0.000 description 10
- 238000004090 dissolution Methods 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 229910001961 silver nitrate Inorganic materials 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- XTULMSXFIHGYFS-VLSRWLAYSA-N fluticasone furoate Chemical compound O([C@]1([C@@]2(C)C[C@H](O)[C@]3(F)[C@@]4(C)C=CC(=O)C=C4[C@@H](F)C[C@H]3[C@@H]2C[C@H]1C)C(=O)SCF)C(=O)C1=CC=CO1 XTULMSXFIHGYFS-VLSRWLAYSA-N 0.000 description 6
- 229960000289 fluticasone propionate Drugs 0.000 description 6
- WMWTYOKRWGGJOA-CENSZEJFSA-N fluticasone propionate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(OC(=O)CC)[C@@]2(C)C[C@@H]1O WMWTYOKRWGGJOA-CENSZEJFSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 5
- 229960001469 fluticasone furoate Drugs 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- SMNDYUVBFMFKNZ-UHFFFAOYSA-N 2-furoic acid Chemical compound OC(=O)C1=CC=CO1 SMNDYUVBFMFKNZ-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- WFAZPFMRGKDDKI-IKARREQDSA-N CC(CC(C(C[C@@H](C(C1(C)C=C2)=CC2=N)F)[C@@]11F)C2(C)C[C@@H]1O)[C@@]2(C(SCC(O)=O)=O)OC(C1=CC=CC1)=O Chemical compound CC(CC(C(C[C@@H](C(C1(C)C=C2)=CC2=N)F)[C@@]11F)C2(C)C[C@@H]1O)[C@@]2(C(SCC(O)=O)=O)OC(C1=CC=CC1)=O WFAZPFMRGKDDKI-IKARREQDSA-N 0.000 description 1
- QGDRIKZDFYXNCC-OEYIFCJTSA-N CC(CC(C(C[C@@H](C(C1(C)C=C2)=CC2=O)F)[C@@]11F)C2(C)CC1=O)[C@@]2(C(S)=O)OC(c1ccc[o]1)=O Chemical compound CC(CC(C(C[C@@H](C(C1(C)C=C2)=CC2=O)F)[C@@]11F)C2(C)CC1=O)[C@@]2(C(S)=O)OC(c1ccc[o]1)=O QGDRIKZDFYXNCC-OEYIFCJTSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- CZKMPDNXOGQMFW-UHFFFAOYSA-N chloro(triethyl)germane Chemical compound CC[Ge](Cl)(CC)CC CZKMPDNXOGQMFW-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- -1 filter Substances 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 239000002608 ionic liquid Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical compound [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 229940110854 veramyst Drugs 0.000 description 1
Landscapes
- Steroid Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention discloses a kind of synthetic method of fluticasone derivative as shown in the formula (I), by the compound shown in formula II under the effect of the agent of monovalent metal silver catalyst and selective fluorination reagent, obtain fluticasone derivative as shown in the formula (I) through the substitution reaction of decarboxylation fluorine.It is generally obtain from (III) through the condensation of fluorine monobromethane that tradition prepares propionic acid (furancarboxylic acid) fluticasone (I), but fluorine monobromethane cost is high, and toxicity is large, and environmental hazard is serious.The present invention's reagent used is relatively cheap to be easy to get, and environmental pollution is little, and reaction conditions is gentle, and selectivity is good, and reaction yield is higher.
Description
(1) technical field
The present invention relates to a kind of synthetic method of fluticasone derivative.
(2) background technology
The novel glucocorticoid medicine of one that fluticasone propionate (Fluticasonepropionate) is developed for German Glaxo Wellcome company, this medicine has very strong curative effect and more weak untoward reaction compared with other glucocorticosteroids, fluticasone furoate (fluticasonefuroate), researched and developed by GlaxoSmithKline PLC company, the new drug nasal spray that in April, 2007 goes on the market in the U.S., commodity are called Veramyst.Compared with fluticasone propionate, the receptor affinity of fluticasone furoate is higher, and effective drug duration extends.
Tradition is prepared propionic acid (furancarboxylic acid) fluticasone (I) method and is generally obtained through the condensation of fluorine monobromethane by formula III, the method yield is more satisfactory, but fluorine monobromethane is expensive, toxicity is larger, international convention restriction is seriously subject to ozone layer destroying, another route uses inexpensive and affects relatively little BrCHC1 and (III) condensation to ozone, and then adopt AgF, KI/KF to carry out halogen exchange, but yield is lower.
At present for how also many from the research report of (III) propionic acid synthesized (furancarboxylic acid) fluticasone (I): world patent (WO2004/052912) utilizes novel fluorizating agent to prepare FLUTICASONE PROPIONATE, fluorine in new method is have employed in this method, first by (III) and formaldehyde condensation, and then carry out hydroxyl fluoro, comparatively fluorine halomethane is convenient to feed in raw material, but temperature requirement is very low, and expensive, yield is lower; Chinese patent (CN100549022C) reports the exchange adopting ionic liquid to carry out fluorine atom, and yield is more satisfactory; World patent (WO2011/151625A1) reports and adopts XeF
2or BrF
3carry out decarboxylation fluoro and prepare propionic acid (furancarboxylic acid) fluticasone, but XeF
2very expensive, substantially without productive value, BrF
3activity is very strong, and toxicity is comparatively large, operational hazards; World patent (WO2011/151624A1), adopts the organic salt carrier containing S, N, P directly to go up CH
2f group, yield has no report, but synthesizes this organic carrier more complicated.
(3) summary of the invention
It is gentle that the object of the invention is to provide a kind of reaction conditions, environmental friendliness, very easily operate, and there is the method for good chemical selectivity synthesis fluticasone propionate and fluticasone furoate, prepared (II) through bromoacetic acid condensation by the raw material shown in (III), (II) under the agent of monovalent metal silver catalyst and the effect of selective fluorination reagent, propionic acid synthesized (furancarboxylic acid) fluticasone (I) is replaced through decarboxylation fluorine.
The technical solution used in the present invention is:
A kind of synthetic method such as formula the fluticasone derivative shown in (I), described method, for: the compound shown in formula II is under the effect of the agent of monovalent metal silver catalyst and selective fluorination reagent, replaces synthesis through decarboxylation fluorine obtained such as formula the fluticasone derivative shown in (I);
In formula (I) or formula (II), R is the C shown in formula (a)
2h
5cO-or the C shown in formula (b)
4h
3o-CO-
Described selective fluorination reagent is for such as formula the compound shown in (IV);
In formula (IV), X is BF
4, PF
6, or CF
3sO
3.
In formula (I), R is the C shown in formula (a)
2h
5during CO-, shown in formula (I), compound is fluticasone propionate, and R is the C shown in formula (b)
4h
3during O-CO-, shown in formula (I), compound is fluticasone furoate.
Further, the method of the invention is: the compound shown in formula II, the agent of monovalent metal silver catalyst and such as formula the selective fluorination reagent shown in (IV) in reaction solvent, react at 0 ~ 80 DEG C of temperature, TLC tracing detection is to reacting end, and reaction solution aftertreatment is obtained described such as formula the fluticasone derivative shown in (I);
The agent of described monovalent metal silver catalyst is AgBF
4, AgNO
3, Silver monoacetate or silver trifluoromethanesulfonate, preferred AgNO
3;
The ratio of the amount of substance of the compound shown in described formula II, the agent of monovalent metal silver catalyst, selective fluorination reagent is 1:0.1 ~ 1.5:1 ~ 5, preferred 1:0.3 ~ 1:2.2 ~ 4.4;
Described reaction solvent is that following one or more mix in any proportion: methyl alcohol, ethanol, Virahol, the trimethyl carbinol, glycol dimethyl ether, ethylene glycol diethyl ether, ether, propyl ether, isopropyl ether, butyl ether, methyl-phenoxide, tetrahydrofuran (THF), 2-methyltetrahydrofuran, Isosorbide-5-Nitrae-dioxane, methylene dichloride, acetone, acetonitrile, DMF, water.
Selective fluorination reagent of the present invention is for such as formula the compound shown in (IV), and in formula (IV), X is preferably BF
4, be business-like selective fluorination reagent Selectfluor, can acquisition be bought.
The volumetric usage of reaction solvent of the present invention counts 30 ~ 100mL/g with the quality of the compound shown in formula II, is preferably 40 ~ 60mL/g.
Reaction solvent of the present invention is preferably the mixed solvent of water and acetone or the mixed solvent of water and acetonitrile, further, and the mixed solvent of the mixed solvent of preferred described reaction solvent acetone, water volume ratio 2 ~ 2.5:1 or acetonitrile, water volume ratio 1.67 ~ 2:1.
Reaction solution post-treating method of the present invention is one of following: after (1) reaction terminates, extraction solvent extraction is added in reaction solution, get organic layer washing, dry rear filtration, filtrate steaming removal solvent is obtained described such as formula the fluticasone derivative shown in (I); Described extraction solvent is methylene dichloride, ethyl acetate, toluene, chlorobenzene, ether, propyl ether, isopropyl ether, butyl ether or methyl-phenoxide, is preferably methylene dichloride;
(2) after reaction terminates, add water in reaction solution, separate out precipitation, cross leaching filter cake, drying is obtained described such as formula the fluticasone derivative shown in (I).
Temperature of reaction of the present invention preferably 25 ~ 55 DEG C, is more preferably 45 ~ 55 DEG C.
The described reaction times is generally 0.5 ~ 24 hour.
Comparatively concrete, recommend the method for the invention to operate according to the following steps: the compound shown in formula II, AgNO
3with selective fluorination reagent Selectfluor in reaction solvent, react at 25 ~ 55 DEG C of temperature, TLC tracing detection is to reacting end, and reaction solution aftertreatment is obtained described such as formula the fluticasone derivative shown in (I);
Compound shown in described formula II, AgNO
3, selective fluorination reagent Selectfluor the ratio of amount of substance be 1:0.3 ~ 1:2.2 ~ 4.4; Described reaction solvent is the mixed solvent of water and acetone or the mixed solvent of water and acetonitrile.
In the inventive method, compound shown in formula II can obtain by the following method: the compound shown in formula III, alkaline matter and bromoacetic acid are in the mixed solvent of water and organic solvent, at 0 ~ 50 DEG C of temperature (preferably 20 ~ 25 DEG C), TLC tracking monitor is to reacting end, usually stirring reaction is needed 1 ~ 24 hour, after reaction terminates, acid adding adjust pH is 2 ~ 3, add water precipitation solid, filter, filter cake dries to obtain the compound shown in white products formula II; Described alkaline matter is mineral alkali or organic bases, and described mineral alkali is sodium carbonate, salt of wormwood, sodium hydroxide or potassium hydroxide; Described organic bases is triethylamine, pyridine or DMAP; Described organic solvent is acetonitrile, acetone, DMF, THF or Isosorbide-5-Nitrae-dioxane; The ratio of the amount of substance of the compound shown in described formula (III), bromoacetic acid, alkaline matter is 1:1.1 ~ 1.5:1.0 ~ 2.0;
The preparation method of the compound shown in formula II well known to a person skilled in the art.
In the mixed solvent of described water and organic solvent, the volume ratio of organic solvent, water is generally 3 ~ 8:1, preferred 5:1.The volumetric usage of described mixed solvent counts 10 ~ 20mL/g usually with the quality of the compound shown in formula II.
Beneficial effect of the present invention is: it is generally obtain from (III) through the condensation of fluorine monobromethane that tradition prepares propionic acid (furancarboxylic acid) fluticasone (I), but fluorine monobromethane cost is high, and toxicity is large, and environmental hazard is serious.Instant invention overcomes the shortcoming of above-mentioned traditional method, have the following advantages:
(1) agents useful for same is relatively cheap is easy to get, and environmental pollution is little; (2) reaction conditions is gentle, and simple to operate, the reaction times is short; (3) good reaction selectivity, yield is high, and aftertreatment is simple, and product is easily separated.
(4) embodiment
Below in conjunction with specific embodiment, the present invention is described further, but protection scope of the present invention is not limited in this:
Formula III-A in the embodiment of the present invention prepares according to the method in (WO2004/001369A2), and formula III-B prepares according to the method in (WO2012029077A2).
Embodiment 1
Formula (III-A) 1.0g (2.1mmol) is added in the there-necked flask of 100ml that thermometer is housed, triethylamine 0.45ml (3.15mmol), bromoacetic acid 0.32g (2.31mmol), adds 10ml acetone and the clarification of 2ml water dissolution, at room temperature reacts, TLC tracing detection is to reacting end, regulate PH to 2 ~ 3 with hydrochloric acid, add 30ml elutriation and go out white solid, filter, dry to obtain 1.05g (II-A), yield 95%.
1HNMR(400MHz,CDCl
3),δ：0.99(d,J＝7.2Hz,3H),1.10(s,3H),1.13(t,J＝7.4Hz,3H),1.32-1.38(m,1H),1.52(s,3H),1.73-1.91(m,3H),2.17-2.39(m,7H),3.34(m,1H),3.76(s,2H),4.36(d,J＝9.2Hz,1H),5.31-5.44(m,1H),6.36(dd,J
1＝10.0Hz,J
2＝1.6Hz,1H),6.42(s,1H),7.10(d,J＝10.0Hz,1H)；MS(ESI-)m/z525(M-H)
+.
Embodiment 2
(II-A) 1.0g (1.9mmol) is added in the there-necked flask of 100ml that thermometer is housed, Silver Nitrate 0.1g (0.58mmol), selective fluorination reagent Selectfluor (Aladdin chemical reagent company limited, lower same) 1.5g (4.2mmol), add 30ml acetone and the clarification of 15ml water dissolution, react at 45 DEG C, TLC tracing detection, react reaction in 10 hours to terminate, add dichloromethane extraction, get organic phase washing, anhydrous sodium sulfate drying, be spin-dried for and obtain target product (I-A) 0.4g, yield 42%.
1HNMR(400MHz,CDCl
3),δ：0.98(d,J＝7.0Hz,3H),1.12(s,3H),1.12(t,J＝7.4Hz,3H),1.32-1.37(m,1H),1.52(s,3H),1.76-1.91(m,3H),2.25-2.44(m,7H),3.39(m,1H),4.42(d,J＝8.8Hz,1H),5.31-5.44(m,1H),5.73-5.96(m,2H),6.36(dd,J
1＝10.0Hz,J
2＝1.6Hz,1H),6.42(s,1H),7.10(d,J＝10.0Hz,1H)；MS(ESI-)m/z500(M)
+.
Embodiment 3
(II-A) 1.0g (1.9mmol) is added in the there-necked flask of 100ml that thermometer is housed, Silver Nitrate 0.1g (0.58mmol), selective fluorination reagent Selectfluor3.0g (8.4mmol), add 40ml acetone and the clarification of 20ml water dissolution, react at 45 DEG C, TLC tracing detection, react reaction in 8 hours to terminate, add dichloromethane extraction, get organic phase washing, anhydrous sodium sulfate drying, is spin-dried for and obtains target product 0.81g, yield 85%.
Embodiment 4
(II-A) 1.0g (1.9mmol) is added in the there-necked flask of 100ml that thermometer is housed, Silver Nitrate 0.1g (0.58mmol), selective fluorination reagent Selectfluor3.0g (8.4mmol), add 40ml acetone and the clarification of 20ml water dissolution, react at 25 DEG C, TLC tracing detection, react reaction in 15 hours to terminate, add dichloromethane extraction, get organic phase washing, anhydrous sodium sulfate drying, is spin-dried for and obtains target product 0.6g, yield 63%.
Embodiment 5
(II-A) 1.0g (1.9mmol) is added in the there-necked flask of 100ml that thermometer is housed, Silver Nitrate 0.1g (0.58mmol), selective fluorination reagent Selectfluor3.0g (8.4mmol), add 40ml acetone and the clarification of 20ml water dissolution, react at 55 DEG C, TLC tracing detection, react reaction in 6 hours to terminate, add dichloromethane extraction, get organic phase washing, anhydrous sodium sulfate drying, is spin-dried for and obtains target product 0.80g, yield 84%.
Embodiment 6
(II-A) 1.0g (1.9mmol) is added in the there-necked flask of 100ml that thermometer is housed, Silver Nitrate 0.32g (1.9mmol), selective fluorination reagent Selectfluor3.0g (8.4mmol), add 40ml acetone and the clarification of 20ml water dissolution, react at 45 DEG C, TLC tracing detection, react reaction in 8 hours to terminate, add dichloromethane extraction, get organic phase washing, anhydrous sodium sulfate drying, is spin-dried for and obtains target product 0.81g, yield 85%.
Embodiment 7
(II-A) 1.0g (1.9mmol) is added in the there-necked flask of 100ml that thermometer is housed, Silver Nitrate 0.1g (0.58mmol), selective fluorination reagent Selectfluor3.0g (8.4mmol), adds 25ml acetonitrile and the clarification of 15ml water dissolution, reacts at 45 DEG C, TLC tracing detection, react reaction in 12 hours to terminate, add 25ml water, filter, filtration cakes torrefaction obtains target product 0.71g, yield 75%.
Embodiment 8
(II-A) 1.0g (1.9mmol) is added in the there-necked flask of 100ml that thermometer is housed, Silver Nitrate 0.1g (0.58mmol), selective fluorination reagent Selectfluor3.0g (8.4mmol), adds 25ml acetonitrile and the clarification of 15ml water dissolution, reacts at 55 DEG C, TLC tracing detection, react reaction in 10 hours to terminate, add 25ml water, filter, filtration cakes torrefaction obtains target product 0.82g, yield 86%.
Embodiment 9
Formula (III-B) 1.0g (1.97mmol) is added in the there-necked flask of 100ml that thermometer is housed, triethylamine 0.41ml (2.9mmol), bromoacetic acid 0.30g (2.17mmol), adds 10ml acetone and the clarification of 2ml water dissolution, at room temperature reacts, TLC tracing detection is to reacting end, regulate PH to 2 ~ 3 with hydrochloric acid, add 30ml elutriation and go out white solid, filter, dry to obtain 1.00g (II-A), yield 95%.
1HNMR(400MHz,CDCl
3),δ：1.05(d,J＝7.0Hz,3H),1.17(s,3H),1.52(s,3H),1.70-1.92(m,2H),2.03-2.06(m,1H),2.26-2.48(m,4H),3.42-3.46(m,1H),3.67(d,J＝15.8Hz,1H),3.75(d,J＝15.8Hz1H),4.36(d,J＝9.2Hz,1H),5.31-5.44(m,1H),6.36(dd,J
1＝10.0Hz,J
2＝1.1Hz,1H),6.42(s,1H),6.48-6.49(m,1H),7.09(d,J＝3.4Hz,1H),7.21(d,J＝10.0Hz,1H),7.55(s,1H)；MS(ESI-)m/z563(M-H)
+.
Embodiment 10
(II-B) 1.0g (1.8mmol) is added in the there-necked flask of 100ml that thermometer is housed, Silver Nitrate 0.1g (0.58mmol), selective fluorination reagent Selectfluor3.0g (8.4mmol), adds 25ml acetonitrile and the clarification of 15ml water dissolution, reacts at 55 DEG C, TLC tracing detection, react reaction in 10 hours to terminate, add 25ml water, filter, filtration cakes torrefaction obtains target product 0.80g, yield 83%.
1HNMR(400MHz,CDCl
3),δ：1.06(d,J＝7.0Hz,3H),1.16(s,3H),1.55(s,3H),3.48(m,1H),4.48(s,1H),5.35-5.48(m,1H),5.82-5.95(m,2H),6.40(dd,J
1＝10.0Hz,J
2＝1.6Hz,1H),6.46(s,1H),6.52(dd,J＝4.2Hz,1H),7.11-7.18(m,2H),7.60(m,1H)；MS(ESI-)m/z539(M)
+.
Claims (1)
1., such as formula a synthetic method for the fluticasone derivative shown in (I), it is characterized in that described method is:
Compound shown in formula II, AgNO
3with selective fluorination reagent Selectfluor in reaction solvent, react at 25 ~ 55 DEG C of temperature, TLC tracing detection is to reacting end, and reaction solution aftertreatment is obtained described such as formula the fluticasone derivative shown in (I);
Compound shown in described formula II, AgNO
3, selective fluorination reagent Selectfluor the ratio of amount of substance be 1:0.3 ~ 1:2.2 ~ 4.4; Described reaction solvent is the mixed solvent of water and acetone or the mixed solvent of water and acetonitrile;
In formula (I) or formula (II), R is the C shown in formula (a)
2h
5cO-or the C shown in formula (b)
4h
3o-CO-
Described selective fluorination reagent Selectfluor is for such as formula the compound shown in (IV);
In formula (IV), X is BF
4
Described reaction solution post-treating method is one of following: after (1) reaction terminates, extraction solvent extraction is added in reaction solution, get organic layer washing, dry rear filtration, filtrate steaming removal solvent is obtained described such as formula the fluticasone derivative shown in (I); Described extraction solvent is methylene dichloride, ethyl acetate, toluene, chlorobenzene, ether, propyl ether, isopropyl ether, butyl ether or methyl-phenoxide;
(2) after reaction terminates, add water in reaction solution, separate out precipitation, cross leaching filter cake, drying is obtained described such as formula the fluticasone derivative shown in (I).
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