CN111978257A - Synthesis method of aldehyde group and carboxyl group-containing 1-methyl arene-1H-imidazole series compounds - Google Patents
Synthesis method of aldehyde group and carboxyl group-containing 1-methyl arene-1H-imidazole series compounds Download PDFInfo
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Abstract
The invention discloses a method for synthesizing 1-methyl arene-1H-imidazole series compounds containing aldehyde groups and carboxyl groups. Comprises the following steps: firstly, aldehyde imidazole, halomethyl aryl formate and weak base are added into a solvent to obtain a nitrogen alkylation product. After chromatographic separation, respectively obtaining intermediates, and respectively adding the intermediates into a strong alkali methanol aqueous solution to complete hydrolysis to obtain a final product. The method has wide raw material application range, wherein one raw material can be 2, 4 or 5-position aldehyde substituted imidazole, the other main raw material can be aryl formate substituted by halogenated methyl, the formate group can be in ortho position, meta position or para position with the halogenated methyl, and any carbon atom which is not substituted by other groups on a substituted aromatic ring is substituted.
Description
Technical Field
The invention belongs to the field of chemical synthesis, and particularly relates to a method for synthesizing 1-methyl aromatic hydrocarbon-1H-imidazole series compounds containing aldehyde groups and carboxyl groups.
Background
The 1-methyl arene-1H-imidazole series compound containing aldehyde group and carboxyl is a molecule with aldehyde group and carboxyl on two different aromatic rings, can further generate derivatization reaction with different groups to generate a target compound, is a medicament chemical intermediate with wide application, and is an important bifunctional synthetic building block which can be used for a DNA coding compound library.
There are few reports on the preparation method of 1-methyl arene-1H-imidazole containing aldehyde group and carboxyl group. Synth. commun.1992,22,2971, reported a synthesis of benzoate as an intermediate using an aldehyde group-containing imidazole and methyl p-benzylbromobenzoate in the presence of a basic reagent to perform the N-alkylation reaction, which has the major disadvantage of occupying the 4-position with a chlorine atom to produce a 1-position nitrogen alkylated product, followed by removal of the 4-position chlorine atom.
Journal of Medicinal Chemistry 1997(62),8449-8454 also reports the synthesis of benzoic acid, the reaction route of the raw material (E) 2-bromo-3-isopropoxy acrolein and methyl 4- [ [ N- (1-imine phenyl) amino) methyl) benzoic acid undergoing a ring closure reaction to synthesize the target product, but the similar raw materials are not easily available, so the method is not suitable for synthesizing other similar 1-benzyl-1H-imidazole containing aldehyde group and carboxyl group.
Disclosure of Invention
The invention aims to solve the technical problem of providing a synthesis method which is wide in applicable raw material range, feasible and easy to operate and is used for 1-methyl arene-1H-imidazole series compounds containing aldehyde groups and carboxyl groups.
In order to solve the technical problems, the invention adopts the following technical scheme: a synthetic method of 1-methyl arene-1H-imidazole series compounds containing aldehyde group and carboxyl group comprises the steps of firstly adding aldehyde imidazole, halomethyl aryl formate and weak base into a solvent to obtain a nitrogen alkylation product; and then carrying out chromatographic separation to respectively obtain intermediates, and respectively adding the intermediates into a strong alkali methanol aqueous solution to complete hydrolysis to obtain a final product.
As a preferential technical scheme of the invention, the method specifically comprises the following steps:
step I: and (2) carrying out nitrogen alkylation reaction, namely adding aldehyde imidazole of a compound with a structural formula 1, halomethyl aryl formate of a compound with a structural formula 2 and weak base into a solvent, heating and stirring to obtain a nitrogen alkylation product, wherein the reaction formula is as follows:
wherein X is hydrogen, chlorine, bromine, iodine or straight-chain alkane; y is CH or N; z is chlorine, bromine or iodine; r1 is methyl, ethyl, isopropyl or tert-butyl.
Step II: post-treating the reaction solution, and performing chromatographic separation to obtain intermediate products, namely a compound with a structural formula 3a and a compound with a structural formula 3b respectively;
step III: and (3) ester group hydrolysis reaction, namely adding the intermediate compound shown in the structural formula 3a and the intermediate compound shown in the structural formula 3b into a strong alkali methanol aqueous solution respectively to complete hydrolysis reaction to obtain final products shown in the structural formula 4a and the structural formula 4b, wherein the reaction formula is as follows:
wherein X is hydrogen, chlorine, bromine, iodine or straight-chain alkane; y is CH or N; z is chlorine, bromine or iodine; r1 is methyl, ethyl, isopropyl or tert-butyl.
As a preferred technical solution of the present invention, in step I, in the compound of structural formula 1, X is hydrogen, chlorine, bromine, iodine or straight-chain alkane, X may be substituted for any carbon atom on the imidazole ring that is not substituted by an aldehyde group, and the aldehyde group may be at any position of 2, 4, or 5 positions of the imidazole ring; in the compound of the structural formula 2, Y is CH or N; z is chlorine, bromine or iodine, and halomethyl can replace any carbon atom on the aromatic ring which is not replaced by other groups; r1 is methyl, ethyl, isopropyl or tert-butyl, and the formate group can be in ortho, meta or para position with the halogenated methyl on the aromatic ring to substitute any carbon atom on the aromatic ring which is not substituted by other groups.
As a preferential technical scheme of the invention, in the nitrogen alkylation reaction in the step I, the solvent is Dimethylformamide (DMF), acetonitrile or dimethyl sulfoxide (DMSO); the weak base is potassium carbonate, sodium carbonate or cesium carbonate; the reaction temperature is 20-80 ℃ and the reaction time is 1-12 hours.
As a preferential technical scheme of the invention, in the step II, the post-treatment is column separation or recrystallization separation and purification of two products with different positions of aldehyde groups substituted imidazole rings.
As a preferential technical scheme of the invention, in the step III ester group hydrolysis reaction, the strong base is sodium hydroxide or lithium hydroxide, the reaction temperature is from room temperature to 80 ℃, and the reaction time is from 1 to 12 hours.
Compared with the prior art, the invention has the beneficial effects that:
1. compared with the prior art, the reaction of the invention is simpler. In the method, the imidazole ring and the benzoate are connected, only one-step nitrogen alkylation reaction is needed, and the products of aldehyde groups at different positions for replacing the imidazole ring can be separated by adopting a column chromatographic separation or recrystallization mode;
2. compared with the prior art, the raw materials are easier to obtain, and the raw materials have wide application range. The final product is obtained by hydrolyzing benzoate, and the final product can be obtained by using easily obtained aldehyde imidazole and halomethyl aromatic carbamate as raw materials and performing two-step reaction of imidazole nitrogen alkylation and ester hydrolysis, and the method is widely applicable to raw materials. One of the raw materials can be 2, 4 or 5-position aldehyde substituted imidazole, the other main raw material is aryl formate substituted by halogenated methyl, the formate group can be in ortho position, meta position or para position with the halogenated methyl, and carbon atoms which are not substituted by other groups on a substituted aromatic ring are substituted.
Detailed Description
The above-described scheme is further illustrated below with reference to specific examples. It should be understood that these examples are for illustrative purposes and are not intended to limit the scope of the present invention. The following examples are included to aid in the understanding of the present invention, and the invention includes, but is not limited to, the following:
EXAMPLE Synthesis of 3- ((5-formyl-1H-imidazol-1-yl) methyl) benzoic acid and 3- ((4-formyl-1H-imidazol-1-yl) methyl) benzoic acid
First step Synthesis of methyl 3- ((5-formyl-1H-imidazol-1-yl) methyl) benzoate and methyl 3- ((4-formyl-1H-imidazol-1-yl) methyl) benzoate
A mixture of the compound 1H-imidazole-4-aldehyde (2.00 g, 20.8mmol,1.00 g eq) and Cs2CO3(10.2,31.2mmol,1.50eq) was stirred in 30.0mL of DMF at room temperature for 20 minutes, to which was added methyl 3- (bromomethyl) benzoate (5.24 g, 22.9mmol,1.10eq), and the mixture was stirred at 70 ℃ for 1 hour. TLC (petroleum ether: EtOAc ═ 1:1) indicated complete consumption of 1H-imidazole-4-aldehyde. The reaction mixture was filtered, washed 3 times with 20.0mL of ethyl acetate and 20.0mL of water, and the organic layer was washed with 20.0mL of saturated brine, dried over anhydrous Na2SO4, and concentrated by filtration under reduced pressure to give an oil. Column chromatography (SiO2, petroleum ether: ethyl acetate 200:1 to 0:1) gave methyl 3- ((4-formyl-1H-imidazol-1-yl) methyl) benzoate (1.90g,7.8mmol, yield 37.5%), 1H NMR (400MHz, CDCl3)9.72(d, J ═ 0.80Hz,1H),7.97-7.93(m,1H),7.84(s,1H),7.82(d, J ═ 0.80Hz,1H),7.73(s,1H),7.42-7.37(m,2H),5.54(s,2H),3.87(s, 3H). Methyl 3- ((5-formyl-1H-imidazol-1-yl) methyl) benzoate (1.67g,6.86mmol, yield 33.6%) was a yellow oil. 1H NMR (400MHz, CDCl3)9.74(d, J ═ 0.80Hz,1H),9.99(d, J ═ 2.00Hz,1H),7.97(s,1H),7.96(s,1H),7.87(s,1H),7.44-7.27(m,2H),5.56(s,2H),3.90(s,3H).
Second step Synthesis of 3- ((5-formyl-1H-imidazol-1-yl) methyl) benzoic acid and 3- ((4-formyl-1H-imidazol-1-yl) methyl) benzoic acid
To a solution of methyl 3- ((4-formyl-1H-imidazol-1-yl) methyl) benzoate (1.50g,6.14mmol,1.00eq) in 40.0mL MeOH was added an aqueous solution of LiOH · H2O (515mg,12.3mmol,2.00eq) (10.0 mL). The mixture was stirred at 25 ℃ for 12 hours. TLC showed the starting benzoate was completely consumed. The reaction mixture was adjusted to pH 7-8 with hydrochloric acid (1M), methanol was removed under reduced pressure, and then the residue was diluted with water (10.0mL), the aqueous layer was adjusted to pH 4 with citric acid (1M), and a solid precipitated, which was filtered and washed to give a pale yellow solid. 3- ((4-formyl-1H-imidazol-1-yl) methyl) benzoic acid (770mg,3.32mmol, 54.1% yield, 99.3% purity). 1H NMR (400MHz, DMSO)13.0(s,1H),9.70(s,1H),8.16(s,1H),8.04(s,1H),7.89(d, J ═ 6.40Hz,2H),7.59(d, J ═ 7.60Hz,1H), 7.52(t, J ═ 8.00Hz,1H),5.38(s, 2H). The hydrolysis process of 3- ((5-formyl-1H-imidazol-1-yl) methyl) benzoic acid is the same as for its isomer. Methyl 3- ((5-formyl-1H-imidazol-1-yl) methyl) benzoate 1.50g finally gave 823mg of product as a pale yellow solid (3.58mmol, yield 58.3%, 99.7% purity). 1H NMR (400MHz, DMSO)9.71(s,1H),8.31(s,1H),7.96(d, J ═ 0.80Hz,1H),7.86-7.83(m,1H),7.73(s,1H),7.50-7.42(m,2H),5.58(s,2H).
Example two
(6) Synthesis of (4-formyl-1H-imidazol-1-yl) methylnicotinic acid and (6) - (5-formyl-1H-imidazol-1-yl) methylnicotinic acid
First step Synthesis of methyl (6) - (4-formyl-1H-imidazol-1-yl) methylnicotinate and methyl (6) - (5-formyl-1H-imidazol-1-yl) methylnicotinate
To a solution of 1H-imidazole-4-aldehyde (4.00g,41.6mmol,1.00eq) in MeCN (100mL) was added K2CO3(11.5g,83.3mmol,2.00eq) and methyl 6- (bromomethyl) nicotinate (11.5g,50.0mmol,1.20 eq). The mixture was stirred at room temperature for 12 hours. TLC (EA: MeOH ═ 10:1) showed that 1H-imidazole-4-aldehyde was completely consumed. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to remove MeCN. The concentrated solution was purified by column chromatography (SiO2, petroleum ether: ethyl acetate 100:1 to 0:1) to obtain methyl (6) - (4-formyl-1H-imidazol-1-yl) methylnicotinate (2.02g,8.24mmol, 19.80% yield), which was confirmed by HNMR and LCMS to be a white solid, 1H NMR (400MHz, CDCl3)9.89(s,1H),9.20(s,1H),8.32(dd, J1 ═ 2.4Hz, J2 ═ 8.4Hz,1H),7.74-7.72(m,2H),7.17(d, J ═ 8.0Hz,1H),5.36(s,2H),3.97(s, 3H). (6) Methyl- (5-formyl-1H-imidazol-1-yl) methylnicotinate (2.11g,8.61mmol, 20.70% yield) was structurally confirmed by HNMR and LCMS as a white solid by 1H NMR (400MHz, CDCl3)9.89(s,1H),9.20(s,1H),8.32(dd, J1 ═ 2.4Hz, J2 ═ 8.4Hz,1H),7.74-7.72(m,2H),7.17(d, J ═ 8.0Hz,1H),5.36(s,2H),3.97(s, 3H).
Second step Synthesis of (6) - (4-formyl-1H-imidazol-1-yl) methylnicotinic acid and (6) - (5-formyl-1H-imidazol-1-yl) methylnicotinic acid
To a solution of methyl (6) - (4-formyl-1H-imidazol-1-yl) methylnicotinate (1.00g,4.08mmol,1.00eq) in MeOH (30.0mL) was added an aqueous solution of LiOH H2O (257mg,6.12mmol,1.50 eq). The mixture was stirred at 25 ℃ for 12 hours. TLC showed complete consumption of methyl nicotinate. Adjusting pH of the reaction solution to 7-8 with HCl (1M), concentrating under reduced pressure to remove solvent, adjusting pH of the water phase to 4 with hydrochloric acid, and separating out solid to obtain the product. (6) - (4-formyl-1H-imidazol-1-yl) methylnicotinic acid is a light yellow gum, 1H NMR (400MHz, DMSO)9.69(s,1H),8.88(d, J ═ 1.6Hz,1H),8.19(s,1H),8.10(dd, J1 ═ 2.0Hz, J2 ═ 8.0Hz,1H),7.94(d, J ═ 0.8Hz,1H),7.02(d, J ═ 8.0Hz,1H),5.61(s, 2H). (6) The synthesis of (5-formyl-1H-imidazol-1-yl) methylnicotinic acid was performed as isomer, the product was yellow solid, 1H NMR (400MHz, DMSO)9.69(s,1H),8.90(s,1H),8.14-8.10(m,2H),7.62(s,1H),7.23(d, J ═ 8.00Hz,1H),5.39(s, 2H).
EXAMPLE Synthesis of Tris 5- ((5-formyl-1H-imidazol-1-yl) methyl) -6-methoxynicotinic acid and 5- ((4-formyl-1H-imidazol-1-yl) methyl) -6-methoxynicotinic acid
First step Synthesis of methyl 5- ((5-formyl-1H-imidazol-1-yl) methyl) -6-methoxynicotinate and methyl 5- ((4-formyl-1H-imidazol-1-yl) methyl) -6-methoxynicotinate
To a solution of 1H-imidazole-4-aldehyde (3.00g,31.2mmol,1.00eq) in MeCN (50mL) was added methyl 5- (bromoethyl) 6-methoxynicotinate (8.12g,31.2mmol,1.00eq) K2CO3(8.63g,62.4mmol,2.00 eq). The mixture was stirred at 70 ℃ for 6 hours. TLC (petroleum ether: ethyl acetate ═ 1:1) showed that 1H-imidazole-4-aldehyde had been consumed. And filtering and concentrating the reaction mixture under reduced pressure, and separating and purifying the concentrated solution by column chromatography (SiO2, petroleum ether and ethyl acetate: 100: 1-0: 1) to respectively obtain two products. Methyl 5- ((4-formyl-1H-imidazol-1-yl) methyl) -6-methoxynicotinate (3.10g,11.3mmol, 36.1% yield) was a white solid. Methyl 5- ((5-formyl-1H-imidazol-1-yl) methyl) -6-methoxynicotinate (2.33g,8.92mmol, yield 28.6%) as a white solid. The structure is confirmed by HNMR and HSQC. 1H NMR (400MHz, DMSO)9.69(s,1H),8.68(d, J ═ 2.0Hz,1H),8.19(s,1H),7.99(d, J ═ 0.8Hz,1H),7.61(d, J ═ 2.0Hz,1H),5.47(s,2H),4.01(s,3H),3.80(s,3H).
Second step Synthesis of 5- ((5-formyl-1H-imidazol-1-yl) methyl) -6-methoxynicotinic acid and 5- ((4-formyl-1H-imidazol-1-yl) methyl) -6-methoxynicotinic acid
The hydrolysis reaction conditions and the post-treatment step of this step were the same as those of the second step of the example. 5- ((4-formyl-1H-imidazol-1-yl) methyl) -6-methoxynicotinic acid is a white solid, (yield 63.2%, purity 100%) and product structure confirmed by HNMR, LCMS 1H NMR (400MHz, DMSO)9.70(s,1H),8.69(d, J ═ 2.0Hz,1H),8.10(s,1H),7.98(d, J ═ 4.0Hz,2H),5.29(s,2H),3.99(s, 3H). 5- ((5-formyl-1H-imidazol-1-yl) methyl) -6-methoxynicotinic acid was an off-white solid, (yield 96.2%, purity 100%), product structure was confirmed by HNMR, LCMS. 1H NMR (400MHz, DMSO)9.70(s,1H),8.65(d, J ═ 2.4Hz,1H),8.18(s,1H),7.99(d, J ═ 0.4Hz,1H),7.54(d, J ═ 2.4Hz,1H),5.47(s,2H),4.00(s, 3H).
Example four
Synthesis of 4- ((4-formyl-1H-imidazol-1-yl) methyl) -3-methoxybenzoic acid and 4- ((5-formyl-1H-imidazol-1-yl) methyl) -3-methoxybenzoic acid
First step Synthesis of methyl 4- ((4-formyl-1H-imidazol-1-yl) methyl) -3-methoxybenzoate and methyl 4- ((5-formyl-1H-imidazol-1-yl) methyl) -3-methoxybenzoate
To a solution of 1H-imidazole-4-aldehyde (3.00g,31.2mmol,1.00eq) in MeCN (50mL) was added methyl 4- (bromomethyl) -3-methoxybenzoate (8.09g,31.2mmol,1.00eq) and Cs2CO3(20.4g,62.4mmol,2.00 eq). The mixture was stirred at 80 ℃ for 6 hours. TLC indicated that the starting 1H-imidazole-4-aldehyde had been consumed and the expected product was formed. The reaction mixture was concentrated by filtration under reduced pressure, and the resulting concentrate was separated and purified by column chromatography (SiO2, petroleum ether: ethyl acetate: 100:1 to 0:1) to give two products, respectively. Methyl 4- ((4-formyl-1H-imidazol-1-yl) methyl) -3-methoxybenzoate (3.40g,12.4mmol, 39.7% yield) was a yellow solid, structure confirmed by HNMR, 1H NMR (400MHz, CDCl3)9.85(s,1H),7.64(t, J ═ 4.2Hz,3H),7.58(s,1H),7.16(d, J ═ 7.6Hz,1H),5.18(s,2H),3.93(s,3H),3.92(s, 3H). Methyl 4- ((5-formyl-1H-imidazol-1-yl) methyl) -3-methoxybenzoate (3.21g,11.7mmol, 37.5% yield) was confirmed as a white solid. The structure was confirmed by HNMR and HMBC, 1H NMR (400MHz, CDCl3)9.75(s,1H),7.80(t, J ═ 3.6Hz,2H),7.61-7.55(m,2H),7.24(d, J ═ 8.0Hz,1H),5.55(s,2H),3.93(d, J ═ 6.8Hz, 6H).
Second step Synthesis of 4- ((4-formyl-1H-imidazol-1-yl) methyl) -3-methoxybenzoic acid and 4- ((5-formyl-1H-imidazol-1-yl) methyl) -3-methoxybenzoic acid
The hydrolysis reaction conditions and the post-treatment step of this step were the same as those of the second step of the example. 4- ((4-formyl-1H-imidazol-1-yl) methyl) -3-methoxybenzoic acid (78.3% yield, 99.1% purity) as a pale yellow solid. Structures were confirmed by HNMR, LCMS, 1H NMR (400MHz, DMSO)13.1(s,1H),9.69(s,1H),8.04(s,1H),7.93(s,1H),7.55-7.52(m,2H),7.21(d, J ═ 8.0Hz,1H),5.29(s,2H),3.90(s, 3H). 4- ((5-formyl-1H-imidazol-1-yl) methyl) -3-methoxybenzoic acid (yield 82.7%, purity 98.1%) as a pale yellow solid. The structure was confirmed by HNMR, LCMS, 1H NMR (400MHz, DMSO)9.70(s,1H),8.13(s,1H),7.96(s,1H),7.46(t, J ═ 4.6Hz,2H),6.76(d, J ═ 7.6Hz,1H),5.52(s,2H),3.90(s, 3H).
Claims (6)
1. A synthetic method of 1-methyl arene-1H-imidazole series compounds containing aldehyde group and carboxyl is characterized in that firstly, aldehyde imidazole, halomethyl aryl formate and weak base are added into a solvent to obtain a nitrogen alkylation product; and then carrying out chromatographic separation to respectively obtain intermediates, and respectively adding the intermediates into a strong alkali methanol aqueous solution to complete hydrolysis to obtain a final product.
2. The method of claim 1, further comprising the steps of:
step I: and (2) carrying out nitrogen alkylation reaction, namely adding aldehyde imidazole of a compound with a structural formula 1, halomethyl aryl formate of a compound with a structural formula 2 and weak base into a solvent, heating and stirring to obtain a nitrogen alkylation product, wherein the reaction formula is as follows:
wherein X is hydrogen, chlorine, bromine, iodine or straight-chain alkane; y is CH or N; z is chlorine, bromine or iodine; r1 is methyl, ethyl, isopropyl or tert-butyl.
Step II: post-treating the reaction solution, and performing chromatographic separation to obtain intermediate products, namely a compound with a structural formula 3a and a compound with a structural formula 3b respectively;
step III: and (3) ester group hydrolysis reaction, namely adding the intermediate compound shown in the structural formula 3a and the intermediate compound shown in the structural formula 3b into a strong alkali methanol aqueous solution respectively to complete hydrolysis reaction to obtain final products shown in the structural formula 4a and the structural formula 4b, wherein the reaction formula is as follows:
wherein X is hydrogen, chlorine, bromine, iodine or straight-chain alkane; y is CH or N; z is chlorine, bromine or iodine; r1 is methyl, ethyl, isopropyl or tert-butyl.
3. The method for synthesizing 1-methyl arene-1H-imidazole series compounds containing aldehyde groups and carboxyl groups according to claim 2, wherein: in the compound shown in the structural formula 1, X is hydrogen, chlorine, bromine, iodine or straight-chain alkane, X can replace any carbon atom which is not replaced by aldehyde group on an imidazole ring, and the aldehyde group can be at any position of 2, 4 or 5 positions of the imidazole ring; in the compound of the structural formula 2, Y is CH or N; z is chlorine, bromine or iodine, and halomethyl can replace any carbon atom on the aromatic ring which is not replaced by other groups; r1 is methyl, ethyl, isopropyl or tert-butyl, and the formate group can be in ortho, meta or para position with the halogenated methyl on the aromatic ring to substitute any carbon atom on the aromatic ring which is not substituted by other groups.
4. The method for synthesizing 1-methyl arene-1H-imidazole series compounds containing aldehyde groups and carboxyl groups according to claim 2, wherein: in the nitrogen alkylation reaction of the step I, the solvent is dimethyl formamide DMF, acetonitrile or dimethyl sulfoxide DMSO; the weak base is potassium carbonate, sodium carbonate or cesium carbonate; the reaction temperature is 20-80 ℃ and the reaction time is 1-12 hours.
5. The method for synthesizing 1-methyl arene-1H-imidazole series compounds containing aldehyde groups and carboxyl groups according to claim 2, wherein: in the step II, the post-treatment is column separation or recrystallization separation and purification of two products with different positions of aldehyde groups to replace imidazole rings.
6. The method for synthesizing 1-methyl arene-1H-imidazole series compounds containing aldehyde groups and carboxyl groups according to claim 2, wherein: in the step III, in the ester group hydrolysis reaction, the strong base is sodium hydroxide or lithium hydroxide, the reaction temperature is from room temperature to 80 ℃, and the reaction time is from 1 to 12 hours.
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