CN105153013A - Synthesis method of 6-bromoisoindolinyl-1-one - Google Patents
Synthesis method of 6-bromoisoindolinyl-1-one Download PDFInfo
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- CN105153013A CN105153013A CN201510586049.4A CN201510586049A CN105153013A CN 105153013 A CN105153013 A CN 105153013A CN 201510586049 A CN201510586049 A CN 201510586049A CN 105153013 A CN105153013 A CN 105153013A
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- bromine
- isoindolinone
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- SDMFCBBVHINMPW-WWOBDGNQSA-N CCCOC(C(C)/C=C/C(/Br)=C\C)=N Chemical compound CCCOC(C(C)/C=C/C(/Br)=C\C)=N SDMFCBBVHINMPW-WWOBDGNQSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
Abstract
The invention provides a synthesis method of 6-bromoisoindolinyl-1-one, which comprises the following steps: (a) carrying out substitution reaction on a compound (I) and a bromination reagent in an organic solvent to obtain a compound (IIa)-compound (IIb) mixture; (b) carrying out hydrolysis reaction on the compound (IIa)-compound (IIb) mixture under alkaline conditions, and separating a compound (IIIa) out of the obtained product; (c) carrying out cyclization reaction on the compound (IIIa) in an acidic solution to obtain the compound (IIa); (d) reacting the compound (IIa) and thionyl chloride in an organic solvent under the action of a catalyst to obtain a compound (IV); and (e) carrying out reflux reaction on the compound (IV) in ethanol, and adding ammonia water to react, thereby obtaining the compound (V) 6-bromoisoindolinyl-1-one. The method has the advantages of simple route, controllable conditions and high yield, and can easily implement industrial production. The reaction route of the method is disclosed in the specification.
Description
Technical field
The present invention relates to the field of chemical synthesis, be specifically related to isoindoline technology of preparing, relate more specifically to a kind of synthetic method of 6-bromine 1-isoindolinone.
Background technology
Isoindolinone is extensively present in natural separated product and medicinal design molecule, many separate from plant have good biological activity containing the compound of isoindolinone structure, cause the extensive concern of people in recent years.6-bromine 1-isoindolinone synthesizes the key intermediate that some have bioactive isoindoline ketone compounds; the 6-bromine 1-isoindolinone synthesis document of current report has (the JournalofPharmaceuticalScience & Technology such as WO2008023161, US20080194546, US20080019915, WO2014028968 and Kumar; 2 (12), 380-390; 2010) document delivered etc.These synthetic methods reported are all be raw material with o-methyl benzoic acid methyl ester, are obtained by reacting compound 6-bromine 1-isoindolinone through 4 steps.There is the shortcomings such as by product is many, productive rate is low in these methods, first, have two step bromination reactions in literature method synthesis, bromo quantity is wayward, and by product is more; Secondly, literature method productive rate is low, and especially second step reaction, we are only about 10% by the method productive rate of reference literature, and by product is extremely many.
Summary of the invention
For overcoming the problems referred to above of the prior art, the invention provides a kind of synthetic method of 6-bromine 1-isoindolinone, this synthetic method route is simple, and yield is high, is easy to suitability for industrialized production.
The technical solution used in the present invention is:
A synthetic method for 6-bromine 1-isoindolinone, comprises the following steps:
A there is substitution reaction in () compound (I) and bromide reagent, obtains the mixture of compound (IIa) and compound (IIb), wherein compound (IIa) about 85%, compound (IIb) about 15% in organic solvent;
B there is hydrolysis reaction in the mixture of () compound (IIa) and (IIb), recrystallization isolates the compound (IIIa) in products therefrom in the basic conditions;
There is ring closure reaction in an acidic solution in (c) compound (IIIa), obtain compound (IIa), obtain pure compound (IIa) in this step, target product 6-bromine 1-isoindolinone can be obtained after reacting further, avoid the interference of compound (IIb);
D () compound (IIa) and thionyl chloride in organic solvent, react under the effect of catalyzer, obtain compound (IV); And
E () compound (IV) is in ethanol after back flow reaction, then add ammoniacal liquor and react and obtain compound (V), 6-bromine 1-isoindolinone;
The reaction scheme of the method is schematically as follows:
。
Wherein, in step (b) after hydrolysis reaction, compound (IIa) and (IIb) are hydrolyzed to corresponding product respectively, the corresponding hydrolysate compound (IIIa) of the compound (IIa) in product can be separated by recrystallization.
Preferably, in step (a)., bromide reagent is N-bromosuccinimide.
More preferably, compound (I) and the amount of substance of N-bromosuccinimide are than being 1:1.2.
Preferably, in step (a)., organic solvent is selected from one or more in trichloromethane, acetic acid, tetracol phenixin and DMF.
Preferably, substitution reaction is carried out at a reflux temperature, and the time of substitution reaction is 4 ~ 6 hours.
More preferably, in step (a)., organic solvent is trichloromethane and acetic acid, and the temperature of reaction is 40 ~ 60 DEG C, preferably 40 ~ 50 DEG C further.
Again preferably, in step (a)., also comprise and extract crude product and the step of recrystallization after bromo-reaction, the solvent that recrystallization uses is selected from one or more in sherwood oil, ethyl acetate and isopropyl ether.
Further, in step (b), alkaline condition is aqueous sodium hydroxide solution, and the temperature of hydrolysis reaction is 20 ~ 50 DEG C.
Preferably, in step (b), the mixture of compound (IIa) and (IIb) in methyl alcohol with aqueous sodium hydroxide solution generation hydrolysis reaction.
Preferably, the amount of substance of sodium hydroxide and compound (IIa) is than being 1.2:1 ~ 1.5:1, and the time of reaction is 1 ~ 2 hour.
Preferably, in step (b), after hydrolysis reaction, first evaporated under reduced pressure solvent, then adopt recrystallization to isolate compound (IIIa) in products therefrom.
More preferably, one or more in the solvent selected from methanol of recrystallization, second alcohol and water.
Further preferably, in step (c), compound (IIIa) in a solvent with acidic solution generation ring closure reaction, more preferably, described solvent is the mixed solvent of first alcohol and water.
Preferably, in step (c), acidic solution is hydrochloric acid or sulphuric acid soln, and the temperature of reaction is 20 ~ 50 DEG C.
Preferably, the ratio of the amount of substance of hydrochloric acid and compound (IIIa) is 1.5:1 or 0.75:1.
Preferably, the ratio of the amount of substance of sulfuric acid and compound (IIIa) is 0.75:1.
Preferably, in step (c), the reaction times is 0.5 ~ 1 hour.
Preferably, in step (c), after reaction terminates, also comprise and add sodium bicarbonate adjust ph to 7 ~ 8, then add appropriate solvent extraction, through the step of washing, drying obtains compound (IIa).
Further, in step (d), catalyzer is boron trifluoride diethyl etherate and benzyltriethylammoinium chloride.
Preferably, the amount of substance of compound (IV), sulfur oxychloride, boron trifluoride diethyl etherate, benzyltriethylammoinium chloride is than being 1:1.2:0.08:0.07.
Preferably, in step (d), organic solvent is one or more in dimethylbenzene, toluene, chlorobenzene and ethylbenzene, and temperature of reaction is 80 ~ 100 DEG C, preferably 90 DEG C.
More preferably, organic solvent is dimethylbenzene, and temperature of reaction is 90 DEG C.
More preferably, in step (d), with gradient increased temperature to 80 ~ 100 DEG C of 5 DEG C, drip thionyl chloride, the reaction times is 8 ~ 10 hours simultaneously, preferably 8.5 hours.
Further, in process step (e), the massfraction of ammoniacal liquor is 25%, and compound (IV) is 1:10 with the amount of substance ratio of ammonia.
Preferably, in process step (e), compound (IV) in ethanol back flow reaction after 2 ~ 3 hours, add ammoniacal liquor back flow reaction 4 ~ 6 hours.
More preferably, compound (IV) refluxes 2.5 hours in ethanol, then adds ammoniacal liquor back flow reaction 5 hours.
The raw material that the present invention adopts directly is bought by commercial sources, also can conventionally synthesize.Such as, 2-benzofuranone (Compound I) can directly be bought, also can according to existing document (JournaloftheAmericanChemicalSociety, 136 (49), 17180-17192; 2014) synthesize easily.
Compared with prior art, the present invention has the following advantages:
1, the present invention adopts 2-benzofuranone (Compound I) to be raw material, it obtains 6-bromine 1-isoindolinone through series reaction such as bromo, hydrolysis, esterification, chloride, ammonia solutions, and synthetic route is simple, and by product is few, yield is high, and total recovery can reach 65% ~ 75%.
2, the present invention does not relate to complex reaction, easy and simple to handle, condition easily controls, and is easy to suitability for industrialized production.
Embodiment
Below in conjunction with specific embodiment, the present invention is further elaborated.
Embodiment 1
example 1-1: synthetic compound IIa and Compound II per b.
By 0.67g(5mmol, 1equiv. under room temperature) Compound I (2-benzofuranone, self-control, JournaloftheAmericanChemicalSociety, 136 (49), 17180-17192; 2014) add in the mixing solutions of 15mL chloroform and 10mL acetic acid composition, stir, under nitrogen protection, add N-bromo butyryl imines 1.067g(6mmol, 1.2equiv. again).Slowly heat up and cause backflow, after stirring 5h, some plate confirms that reaction terminates, and reaction solution is put refrigerator and cools half an hour, filter elimination solid, underpressure distillation, washing, extraction, be spin-dried for organic phase and obtain crude product 1.06g, that is, the mixture of Compound II per a and Compound II per b, treat directly to cast single step reaction.
example 1-2: synthetic compound IIa and Compound II per b.
By 0.67g(5mmol, 1equiv. under room temperature) Compound I (2-benzofuranone, self-control, JournaloftheAmericanChemicalSociety, 136 (49), 17180-17192; 2014) add in the mixing solutions of 12mL chloroform and 6mL acetic acid composition, stir, under nitrogen protection, add N-bromo butyryl imines 1.067g(6mmol, 1.2equiv. again).Slowly heat up and cause backflow, after stirring 4.5h, some plate confirms that reaction terminates, and reaction solution is put refrigerator and cools half an hour, filter elimination solid, underpressure distillation, washing, extraction, be spin-dried for organic phase and obtain white solid crude product 1g, that is, the mixture of Compound II per a and Compound II per b
treatdirectly cast single step reaction.
Embodiment 2
example 2-1: synthetic compound IIIa, i.e. 5-bromo-2-hydroxymethyl-benzoic acid sodium.
Under room temperature, crude product 0.4g obtained in the previous step is added 10mL methyl alcohol, then add the NaOH solution of 2mol/L, the amount of added sodium hydroxide and the amount of substance of Compound II per a are than being 1.5:1.Stirred at ambient temperature 2h, reaction terminates, and revolve and steam removing solvent wherein, obtain solid, then use methyl alcohol, ethanol, water or their mixed solvent recrystallization, obtain the solid product that 0.4g is pure, i.e. compound III a, and productive rate is 84%.
1HNMR(300MHz,CDCl
3+CD
3OD):δ=7.89(d,J=8.3Hz,1H),7.67(d,J=1.9Hz,1H),7.50(dd,J=8.3,1.9Hz,1H),3.99(s,2H)。
MS(EI):m/e=252。
example 2-2: synthetic compound IIIa, i.e. 5-bromo-2-hydroxymethyl-benzoic acid sodium.
Under room temperature, crude product 0.4g obtained in the previous step is added 10mL methyl alcohol, then add the NaOH solution of 2mol/L, the amount of added sodium hydroxide and the amount of substance of Compound II per a are than being 1.2:1.Stirred at ambient temperature 1.5h, reaction terminates, and revolve and steam removing solvent wherein, obtain solid, then use methyl alcohol, ethanol, water or their mixed solvent recrystallization, obtain the solid product that 0.39g is pure, i.e. compound III a, and productive rate is 82%.
1HNMR(300MHz,CDCl
3+CD
3OD):δ=7.89(d,J=8.3Hz,1H),7.67(d,J=1.9Hz,1H),7.50(dd,J=8.3,1.9Hz,1H),3.99(s,2H)。
MS(EI):m/e=252。
Embodiment 3
example 3-1: synthetic compound IIa, i.e. the bromo-2-cumarone-1 (3 of 6-
h) ketone.
Under room temperature, by 0.4g compound III a, namely 5-bromo-2-hydroxymethyl-benzoic acid sodium is dissolved in the mixed solvent of 5mL methyl alcohol and 5mL water, then drips the sulfuric acid of 6mol/L, the ratio of the amount of substance of added sulfuric acid and compound III a is 0.75:1, and some plate confirms to react completely.Slowly add sodium hydrogen carbonate solution cancellation reaction again, adjust ph is 7 ~ 8, revolves methyl alcohol, then adds appropriate solvent extraction, and after washing, drying, obtain 0.336g Compound II per a, productive rate is 99.8%.
1HNMR(300MHz,CDCl
3):δ=8.01(d,J=1.8Hz,1H),7.80(dd,J=8.4,1.8Hz,1H),7.41(d,J=7.8Hz,1H),5.29(s,2H)。
MS(EI):m/e=212/214。
example 3-2: synthetic compound IIa, i.e. the bromo-2-cumarone-1 (3 of 6-
h) ketone.
Under room temperature, by 0.4g compound III a, namely 5-bromo-2-hydroxymethyl-benzoic acid sodium is dissolved in the mixed solvent of 5mL methyl alcohol and 5mL water, drip the hydrochloric acid of 6mol/L again, the ratio of the amount of substance of added hydrochloric acid and compound III a is 1.5:1, stirring at room temperature, after reaction 0.5h, some plate confirms to react completely.Slowly add sodium hydrogen carbonate solution cancellation reaction again, adjust ph is 7 ~ 8, revolves methyl alcohol, then adds appropriate solvent extraction, and after washing, drying, obtain 0.336g Compound II per a, productive rate is 99.8%.
1HNMR(300MHz,CDCl
3):δ=8.01(d,J=1.8Hz,1H),7.80(dd,J=8.4,1.8Hz,1H),7.41(d,J=7.8Hz,1H),5.29(s,2H)。
MS(EI):m/e=212/214。
Embodiment 4
example 4-1: synthetic compound IV, i.e. the bromo-2-chloromethyl benzoic acid chlorides of 5-.
First by 0.212g(1mmol, 1equiv.) Compound II per a, i.e. 6-bromo-2-cumarone-1 (3H) ketone, 0.018g(0.08mmol, 0.08equiv.) benzyltriethylammoinium chloride, 0.010g(0.07mmol, 0.07equiv.) boron trifluoride diethyl etherate is added in dimethylbenzene, clearly not molten.Sulfur oxychloride 0.142g(1.2mmol, 1.2equiv. is dripped when being heated to 75 DEG C), slowly, limit gradient (5 DEG C) is warming up to 90 DEG C of limits and drips, time for adding 1 hour in venting, still exits slowly, and reaction solution gentle reflux.Add 90 DEG C of reactions after 2.5 hours sampling send gas-chromatography, residue 60%, continue reaction 6 hours, sampling spot plate Compound II per a primitive reaction is complete, and gas-chromatography monitoring compound IIa is almost without remaining.Reaction solution concentrated (70 DEG C) removes most of dimethylbenzene and sulfur oxychloride.Oil pump distills, and obtain 0.169g compound IV, productive rate is 63.4%.
example 4-2: synthetic compound IV, i.e. the bromo-2-chloromethyl benzoic acid chlorides of 5-.
First by 0.212g(1mmol, 1equiv.) Compound II per a, i.e. 6-bromo-2-cumarone-1 (3H) ketone, 0.018g(0.08mmol, 0.08equiv.) benzyltriethylammoinium chloride, 0.010g(0.07mmol, 0.07equiv.) boron trifluoride diethyl etherate is added in dimethylbenzene, clearly not molten.Sulfur oxychloride 0.142g(1.2mmol, 1.2equiv. is dripped when being heated to 75 DEG C), slowly, limit gradient (5 DEG C) is warming up to 90 DEG C of limits and drips, time for adding 1 hour in venting, still exits slowly, and reaction solution gentle reflux.Add 90 DEG C of reactions after 2.5 hours sampling send gas-chromatography, residue 60%, continue reaction 6 hours, sampling spot plate Compound II per a primitive reaction is complete, and gas-chromatography monitoring compound IIa is almost without remaining.Reaction solution concentrated (70 DEG C) removes most of dimethylbenzene and sulfur oxychloride.Oil pump distills, and obtain 0.179g compound IV, productive rate is 67.1%.
Embodiment 5
example 5-1: synthetic compound V, i.e. 6-bromine 1-isoindolinone.
By 0.256g(1mmol, 1equiv.) the bromo-2-chloromethyl benzoic acid chlorides of 5-joins in 10mL ethanol the 2.5h that refluxes, and drip ammoniacal liquor (massfraction 25%, 10mmol, 10equiv.) and continue back flow reaction 5 hours afterwards.Sampling spot board raw material remains on a small quantity, and reaction solution concentrated removing ethanol, has solid to separate out.Add 10mL methylene dichloride, 10mL water, aqueous phase uses 10mL dichloromethane extraction again, concentrate after merging the washing of organic phase 5mL saturated common salt, anhydrous sodium sulfate drying, filtration, to a small amount of methylene dichloride residue, existing solid is separated out, add after 5mL ethyl acetate stirs and filter, filter cake ethyl acetate washes one time, collects white solid oil pump and drains, obtain 0.074g white powdery solids, i.e. 6-bromine 1-isoindolinone, productive rate is 36.5%.
1HNMR(400MHz,DMSO-d6):δ=4.35(s,2H),7.56(d,J=8.8Hz,1H),7.77(d,J=2.0Hz,1H),7.79(s,1H),8.72(s,1H)。
MS(EI):m/e=262/264。
example 5-2: synthetic compound V, i.e. 6-bromine 1-isoindolinone.
By 0.256g(1mmol, 1equiv.) the bromo-2-chloromethyl benzoic acid chlorides of 5-joins in 10mL ethanol the 2.5h that refluxes, and drip ammoniacal liquor (massfraction 25%, 10mmol, 10equiv.) and continue back flow reaction 5 hours afterwards.Sampling spot board raw material remains on a small quantity, and reaction solution concentrated removing ethanol, has solid to separate out.Add 10mL methylene dichloride, 10mL water, aqueous phase uses 10mL dichloromethane extraction again, concentrate after merging the washing of organic phase 5mL saturated common salt, anhydrous sodium sulfate drying, filtration, to a small amount of methylene dichloride residue, existing solid is separated out, add after 5mL ethyl acetate stirs and filter, filter cake ethyl acetate washes one time, collects white solid oil pump and drains, obtain 0.078g white powdery solids, i.e. 6-bromine 1-isoindolinone, productive rate is 38.5%.
1HNMR(400MHz,DMSO-d
6):δ=4.35(s,2H),7.56(d,J=8.8Hz,1H),7.77(d,J=2.0Hz,1H),7.79(s,1H),8.72(s,1H)。
MS(EI):m/e=262/264。
In sum, the method for synthesis 6-bromine 1-isoindolinone of the present invention has the advantage that synthetic route is simple, easy and simple to handle, cost is low, productive rate is high and be easy to suitability for industrialized production.
Above specific embodiment of the present invention is illustrated; but protection content of the present invention is not only limited to above embodiment; in art of the present invention, the usual knowledge of a GPRS, just can carry out diversified change within the scope of its technology main idea
.
Claims (10)
1. a synthetic method for 6-bromine 1-isoindolinone, is characterized in that, comprises the following steps:
A there is substitution reaction in () compound (I) and bromide reagent, obtains the mixture of compound (IIa) and compound (IIb) in organic solvent;
B there is hydrolysis reaction in the mixture of () compound (IIa) and (IIb), isolates the compound (IIIa) in products therefrom in the basic conditions;
C there is ring closure reaction in () compound (IIIa), obtains compound (IIa) in an acidic solution;
D () compound (IIa) and thionyl chloride in organic solvent, react under the effect of catalyzer, obtain compound (IV); And
E () compound (IV) is in ethanol after back flow reaction, then add ammoniacal liquor and react, and obtains compound (V) 6-bromine 1-isoindolinone;
。
2. the synthetic method of 6-bromine 1-isoindolinone according to claim 1, is characterized in that: in step (a)., and described bromide reagent is N-bromosuccinimide, and compound (I) is 1:1.2 with the amount of substance ratio of N-bromosuccinimide.
3. the synthetic method of 6-bromine 1-isoindolinone according to claim 1, it is characterized in that: in step (a)., described organic solvent is selected from one or more in trichloromethane, acetic acid, tetracol phenixin and DMF.
4. the synthetic method of 6-bromine 1-isoindolinone according to claim 1, is characterized in that: in step (b), and described alkaline condition is aqueous sodium hydroxide solution, and the temperature of hydrolysis reaction is 20 ~ 50 DEG C.
5. the synthetic method of 6-bromine 1-isoindolinone according to claim 1, it is characterized in that: in step (b), after hydrolysis reaction, recrystallization isolates the compound (IIIa) in products therefrom, one or more in the solvent selected from methanol of recrystallization, second alcohol and water.
6. the synthetic method of 6-bromine 1-isoindolinone according to claim 1, it is characterized in that: in step (c), described acidic solution is hydrochloric acid or sulphuric acid soln, and the temperature of reaction is 20 ~ 50 DEG C.
7. the synthetic method of 6-bromine 1-isoindolinone according to claim 1, it is characterized in that: in step (d), described catalyzer is boron trifluoride diethyl etherate and benzyltriethylammoinium chloride, and the amount of substance of compound (IV), sulfur oxychloride, boron trifluoride diethyl etherate, benzyltriethylammoinium chloride is than being 1:1.2:0.08:0.07.
8. the synthetic method of 6-bromine 1-isoindolinone according to claim 1, is characterized in that: in step (d), and described organic solvent is one or more in dimethylbenzene, toluene, chlorobenzene and ethylbenzene, and temperature of reaction is 80 ~ 100 DEG C.
9. the synthetic method of 6-bromine 1-isoindolinone according to claim 1, is characterized in that: in process step (e), and the massfraction of ammoniacal liquor is 25%, and compound (IV) is 1:10 with the amount of substance ratio of ammonia.
10. the synthetic method of the 6-bromine 1-isoindolinone according to claim 1 or 9, is characterized in that: in process step (e), and compound (IV), in ethanol after back flow reaction 2-3 hour, adds ammoniacal liquor back flow reaction 4 ~ 6 hours.
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| CN106699716A (en) * | 2017-01-14 | 2017-05-24 | 山东理工大学 | Novel synthesis method of 6-bromo-4H-chromone |
| CN110498759A (en) * | 2019-09-12 | 2019-11-26 | 天津瑞岭化工有限公司 | The synthetic method of isoindoline ketone compound |
| US11363815B2 (en) | 2018-06-05 | 2022-06-21 | Shenyang University Of Chemical Technology | Trifluoroethyl thioether (sulfoxide) substituted benzene compound and use thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106699716A (en) * | 2017-01-14 | 2017-05-24 | 山东理工大学 | Novel synthesis method of 6-bromo-4H-chromone |
| US11363815B2 (en) | 2018-06-05 | 2022-06-21 | Shenyang University Of Chemical Technology | Trifluoroethyl thioether (sulfoxide) substituted benzene compound and use thereof |
| CN110498759A (en) * | 2019-09-12 | 2019-11-26 | 天津瑞岭化工有限公司 | The synthetic method of isoindoline ketone compound |
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