CN109897013B - Preparation method of selective PPAR delta agonist GW501516 - Google Patents
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Abstract
The invention discloses a preparation method of a selective PPAR delta agonist GW501516, belonging to the technical field of synthesis of medical intermediates. The method comprises the steps of taking o-methylphenol as a raw material, obtaining 4-iodine/bromine-2-methylphenol through an oxidant and iodine/potassium bromide, reacting the o-methylphenol with chlorine/bromine tert-butyl acetate to obtain (4-bromine/iodine-2-methylphenoxy) -acetic acid tert-butyl ester, then carrying out Grignard reagent exchange, reacting the Grignard reagent exchange with sulfur powder and 5- (bromomethyl) -4-methyl-2- [4- (trifluoromethyl) phenyl ] -1,3-thiazole in sequence to obtain 2- [ 2-methyl-4- [ [ [ 4-methyl-2- [4- (trifluoromethyl) phenyl ] -5-thiazolyl ] methyl ] thio ] phenoxy ] acetic acid tert-butyl ester, and finally hydrolyzing to obtain the selective PPAR delta agonist GW501516. The invention has simple and convenient process operation, mild condition and cheap and easily obtained raw materials, and provides reference for the synthesis and amplification of the medicament.
Description
Technical Field
The invention relates to synthesis of a medical intermediate, in particular to a preparation method of a selective PPAR delta agonist GW501516, belonging to the technical field of organic synthesis.
Background
2- (4- ((2- (4- (trifluoromethyl) phenyl) -5-methylthiazol-4-yl) methylthio) -2-methylphenoxy) acetic acid, also known as 2- [ 2-methyl-4- [ [ [ 4-methyl-2- [4- (trifluoromethyl) phenyl ] acetic acid]-5-thiazolyl]Methyl radical]Thio group]Phenoxy radical]Acetic acid, abbreviation: GW501516, CAS:317318-70-0, formula: c 21 H 18 F 3 NO 3 S 2 . GW501516 is a peroxisome proliferator-activated receptor PPAR delta agonist, can obviously improve body functions, can be synthesized by related medicines, and is widely concerned by the scientific community as an important intermediate. The product has increased market demand and good market prospect.
At present, the product presents more and more application values, however, the synthetic literature of the compound is rarely reported. Patents WO2003/106442,2003,a1 and WO2006/121223,2006,a1 and tetrahedron letters,2005,46,6683-6686, report the synthesis of 4-hydroxy-3-methylphenylthiophenol and 5- (chloromethyl) -4-methyl-2- [4- (trifluoromethyl) phenyl ] -1,3-thiazole, respectively, using 4-iodo-2-methylphenol and 4-trifluoromethylphenylacetonitrile as two-fragment starting materials, which are reacted and then subjected to hydroxyl protection and hydrolysis to obtain GW501516.
In the reaction, the potential safety hazard of synthesis exists, so that a proper synthesis method needs to be developed to solve the problems of simple, convenient and stable synthesis operation, high yield, environmental friendliness, low production cost, safe operation and suitability for industrial scale-up production.
Disclosure of Invention
In order to overcome the technical defects, the invention provides a method for preparing a selective PPAR delta agonist GW501516 by a four-step reaction method. The method comprises the steps of taking o-methylphenol as a raw material, obtaining 4-iodine/bromine-2-methylphenol through an oxidant and iodine/potassium bromide, reacting the o-methylphenol with chlorine/bromine tert-butyl acetate to obtain (4-bromine/iodine-2-methylphenoxy) -acetic acid tert-butyl ester, then carrying out Grignard reagent exchange, reacting the Grignard reagent exchange with sulfur powder and 5- (bromomethyl) -4-methyl-2- [4- (trifluoromethyl) phenyl ] -1,3-thiazole in sequence to obtain 2- [ 2-methyl-4- [ [ [ 4-methyl-2- [4- (trifluoromethyl) phenyl ] -5-thiazolyl ] methyl ] thio ] phenoxy ] acetic acid tert-butyl ester, and finally hydrolyzing to obtain the selective PPAR delta agonist GW501516.
The invention provides a preparation method of a selective PPAR delta agonist GW501516, which is characterized by comprising the following reaction equation:
a preparation method of selective PPAR delta agonist GW501516 is characterized by comprising the following steps of:
the first step is as follows: synthesis of Compound 2
Dissolving o-methylphenol 1 and bromine/potassium iodide in an organic solvent, adding an oxidant, and obtaining 4-halogen-2-methylphenol 2 in the presence of a catalyst.
The second step is that: synthesis of Compound 3
Dissolving 4-halo-2-methylphenol 2 in an organic solvent, and reacting with chloro/bromo tert-butyl acetate in the presence of an inorganic base to obtain (4-bromo/iodo-2-methylphenoxy) -acetic acid tert-butyl ester 3.
The third step: synthesis of Compound 6
(4-bromo/iodo-2-methylphenoxy) -acetic acid tert-butyl ester 3 is exchanged with grignard reagent followed by addition of sulfur powder to give intermediate 4; then reacting with 5- (bromomethyl) -4-methyl-2- [4- (trifluoromethyl) phenyl ] -1,3-thiazole 5 to obtain 2- [ 2-methyl-4- [ [ [ 4-methyl-2- [4- (trifluoromethyl) phenyl ] -5-thiazolyl ] methyl ] thio ] phenoxy ] acetic acid tert-butyl ester 6.
The fourth step: synthesis of Compound 7 (GW 501516)
Tert-butyl 2- [ 2-methyl-4- [ [ [ 4-methyl-2- [4- (trifluoromethyl) phenyl ] -5-thiazolyl ] methyl ] thio ] phenoxy ] acetate 6 is hydrolyzed to obtain 2- [ 2-methyl-4- [ [ [ 4-methyl-2- [4- (trifluoromethyl) phenyl ] -5-thiazolyl ] methyl ] thio ] phenoxy ] acetic acid 7.
Further, in the above technical solution, in the first step, the organic solvent is selected from t-butanol, acetonitrile, methanol.
Further, in the above technical solution, in the first step, the oxidizing agent is selected from oxone, peracetic acid, and hydrogen peroxide.
Further, in the above technical solution, in the first step, the catalyst is selected from acetylacetonato alum oxide.
Further, in the above technical solution, in the first step, the molar ratio of the o-methylphenol, the bromine/potassium iodide and the oxidant is: 1:1.1-1.5:1.2-1.5.
Further, in the above technical solution, in the second step, the organic solvent is selected from ethanol, tetrahydrofuran, and acetone.
Further, in the above technical solution, in the second step, the inorganic base is selected from potassium tert-butoxide, sodium hydride, and anhydrous potassium carbonate.
Further, in the above technical scheme, in the second step, the molar ratio of o-4-halo-2-methylphenol, the inorganic base and the tert-butyl chloro/bromoacetate is 1:1.1-3.0:1.05-1.1.
Further, in the above technical solution, in the second step, the product needs to be purified by recrystallization, and the recrystallization solvent is selected from dichloromethane and n-heptane, and the mass ratio of the recrystallization solvent is 1:2.1-2.4.
Further, in the above technical scheme, in the third step, the reaction is performed in tetrahydrofuran or 2-methyltetrahydrofuran.
Further, in the above technical solution, in the third step, the grignard reagent is selected from isopropyl magnesium chloride, isopropyl magnesium bromide, and isopropyl magnesium chloride-lithium chloride.
Further, in the above technical solution, in the third step, the molar ratio of compound 3, grignard reagent, sulfur powder and compound 5 is 1:1.0-1.2:2.0-2.2:1.05-1.1.
Further, in the above technical solution, in the fourth step, the hydrolysis reaction is performed in hydrochloric acid or hydrobromic acid.
Advantageous effects of the invention
The method has the advantages of short synthetic route steps, easily available raw materials, mild reaction conditions, high total reaction yield, high purity of the obtained product up to 99.5 percent and potential process amplification prospect.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The average room temperature described in the following examples of the invention is 20-25 ℃. Unless otherwise indicated, the reagents are not specifically indicated and are all used without purification. All solvents were purchased from commercial suppliers and used without treatment. The reaction was analyzed by TLC and HPLC, and the termination of the reaction was judged by the consumption of starting material.
The first step is as follows: 4-iodine/bromine-2-methylphenol.
Example 1
108.1g (1 mol) of o-methylphenol, 130.9g (1.1 eq) of potassium bromide and 2.5Kg of acetonitrile were charged into a reaction flask. Stirring at room temperature, controlling the temperature to be 25-30 ℃, adding 677g (1.1 eq) of potassium monopersulfate complex salt in batches, reacting for 6 hours at room temperature, detecting the raw material by HPLC (high performance liquid chromatography) to be less than 1.5%, filtering, concentrating the filtrate, replacing with ethyl acetate, adding saturated sodium bisulfite aqueous solution for washing, concentrating the organic layer to be a non-flowing liquid, adding n-heptane for pulping to obtain 117.6g of 4-bromo-2-methylphenol, wherein the purity is 91.2%, and the yield is 95%. 1 HNMR(400MHz,CDCl3):7.36-7.34(d,1H),6.71-6.75(d,1H),6.58-6.53(dd,1H),4.73(s,1H),2.34(s,3H)。
Example 2
108.1g (1 mol) of o-methylphenol, 183g (1.1 eq) of potassium iodide and 2Kg of methanol were charged into a reaction flask. Stirring at room temperature, adding 677g (1.1 eq) of potassium monopersulfate complex salt in batches at a temperature controlled between 25 and 30 ℃, reacting for 8 hours at room temperature, detecting by HPLC that the raw material is less than 3.5%, filtering, concentrating the filtrate, replacing with ethyl acetate, adding saturated sodium bisulfite aqueous solution for washing, concentrating the organic layer to a non-flowing liquid, adding n-heptane for pulping to obtain 204g of 4-iodine-2-methylphenol with the purity of 81.6% and the yield of 87%. 1 HNMR(400MHz,CDCl3):7.45-7.41(d,1H),7.36-7.34(d,1H),6.56-6.52(dd,1H),4.78(s,1H),2.20(s,3H).
Example 3:
108.1g (1 mol) of o-methylphenol, 183g (1.1 eq) of potassium iodide and 0.6Kg of acetonitrile were charged into a reaction flask. Under the condition of stirring at room temperature, controlling the temperature to be 25-35 ℃, dropwise adding 340g (1.25 eq) of 23% peracetic acid, reacting for 5 hours at room temperature, detecting that the raw material is less than 1.5% by HPLC, concentrating under reduced pressure at 45 ℃ until the liquid does not flow, replacing by ethyl acetate, adding saturated sodium bisulfite aqueous solution for washing, concentrating an organic layer until the liquid does not flow, adding n-heptane for pulping to obtain 210g of 4-iodine-2-methylphenol, wherein the purity is 87.7%, and the yield is 90%. 1 HNMR(400MHz,CDCl3):7.45-7.41(d,1H),
7.36-7.34(d,1H),6.56-6.52(dd,1H),4.78(s,1H),2.20(s,3H).
Example 4:
108.1g (1 mol) of o-cresol and ethyl are put into a reaction bottle0.6g (0.5%) of alum acetylacetonate, 183g (1.1 eq) of potassium iodide and 0.6Kg of tert-butanol. Under the condition of stirring at room temperature, 140g (1.15 eq) of 28% hydrogen peroxide is dropwise added at the temperature of 25-30 ℃, the reaction is carried out for 10 hours at room temperature, HPLC detection raw materials are less than 3.5%, reduced pressure concentration is carried out at 45 ℃ until no-flow liquid exists, ethyl acetate is replaced, saturated sodium bisulfite aqueous solution is added for washing, an organic layer is concentrated until no-flow liquid exists, n-heptane is added for pulping, 206g of 4-iodine-2-methylphenol is obtained, the purity is 84.7%, and the yield is 88%. 1 HNMR(400MHz,CDCl3):7.45-7.41(d,1H),7.36-7.34(d,1H),6.56-6.52(dd,1H),4.78(s,1H),2.20(s,3H).
The second step is that: synthesis and purification of (4-bromo/iodo-2-methylphenoxy) -acetic acid tert-butyl ester
Example 5:
into the reaction flask, 18.7g (0.1 mol) of 4-bromo-2-methylphenol having a purity of 91.2% and 280g of anhydrous tetrahydrofuran were charged. While stirring, 5.4g (1.3 eq) of sodium hydride (60% w/w) was added, and 16.6g (1.1 eq) of t-butyl chloroacetate was slowly added dropwise at room temperature to carry out reaction at room temperature for 2 hours, with HPLC analysis of starting material < 0.5%. Cooling to 5 deg.C, adding ethanol dropwise for quenching, concentrating the solvent, adding dichloromethane and water for dissolving, washing the organic phase with saturated saline solution, drying the organic layer with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain a non-flowing liquid. 64g of dichloromethane were added: n-heptane is 1:2.2, heating the mixed solution to 45 ℃, dissolving the materials, cooling to 0 ℃, and filtering to obtain 25g of (4-bromo-2-methylphenoxy) -tert-butyl acetate with the purity of 98.7% and the yield of 83%. 1 HNMR(400MHz,CDCl3):7.16-7.13(d,1H),7.09-7.06(d,1H),6.49-6.45(dd,1H),4.59(s,2H),2.24(s,3H),1.40(s,9H).
Example 6:
into a reaction flask, 23.4g (0.1 mol) of 4-iodo-2-methylphenol having a purity of 84.7 g, 48.4g of anhydrous potassium carbonate and300g of acetone. Under stirring at 30 ℃, 21.5g (1.1 eq) of tert-butyl bromoacetate is slowly added dropwise and reacted for 8 hours at room temperature, and HPLC detection shows that the raw material is less than 0.8 percent. Filtering, concentrating the filtrate, adding dichloromethane and water to dissolve, washing the organic phase with saturated saline, drying the organic layer with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain a non-flowing liquid. 64g of dichloromethane were added: n-heptane is 1:2.2, heating to 45 ℃, dissolving the materials, cooling to 0 ℃, and filtering to obtain 25.5g of (4-iodo-2-methylphenoxy) -tert-butyl acetate with the purity of 98.1% and the yield of 73.3%. 1 HNMR(400MHz,CDCl3):7.46-7.43(d,1H),7.40-7.37(d,1H),6.49-6.45(dd,1H),4.59(s,2H),2.24(s,3H),1.40(s,9H).
Example 7:
into the reaction flask, 23.4g (0.1 mol) of 4-iodo-2-methylphenol, 14.6g (1.3 eq) of potassium tert-butoxide and 230g of ethanol were charged, the purity was 84.7%. 16.6g (1.1 eq) of tert-butyl chloroacetate is slowly dropped into the mixture under the stirring at the temperature of 10 ℃, the mixture reacts for 3 hours at the temperature of 25-35 ℃, and the HPLC detection raw material is less than 0.8 percent. Concentrating the solvent, dissolving with dichloromethane and water, washing the organic phase with saturated saline, drying the organic layer with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure. 64g of dichloromethane were added: n-heptane is 1:2.2, heating to 45 ℃, dissolving and clearing the materials, cooling to 0 ℃, and filtering to obtain 26.6g of (4-iodo-2-methylphenoxy) -tert-butyl acetate with the purity of 98.3 percent and the yield of 76.3 percent. 1 HNMR(400MHz,CDCl3):7.46-7.43(d,1H),7.40-7.37(d,1H),6.49-6.45(dd,1H),4.59(s,2H),2.24(s,3H),1.40(s,9H).
The third step: exchange synthesis of grignard reagents
Example 8:
under the protection of nitrogen, 26.6g (76.3 mmol) of (4-iodine-2-methylphenoxy) -tert-butyl acetate and 120g of tetrahydrofuran are added into a reaction bottle, 42mL of 2mol/L isopropyl magnesium chloride tetrahydrofuran solution is dropwise added at-10-5 ℃, reaction is carried out for 2 hours at 10 ℃ after dropwise addition is finished, and sample water is taken to quench the LC detection raw material until the residual is less than 0.3%. Used directly in the next step.
Example 9:
under the protection of nitrogen, 25g (83 mmol) of (4-bromo-2-methylphenoxy) -acetic acid tert-butyl ester and 130g of 2-methyltetrahydrofuran are added into a reaction bottle, 45.6mL of 2mol/L isopropyl magnesium chloride-lithium chloride 2-methyltetrahydrofuran solution is dropwise added at-10-5 ℃, reaction is carried out at 10 ℃ for 2 hours after dropwise addition is finished, and the sample water is taken to quench LC detection raw material residue and is less than 8.3%. Was used directly in the next step. The fourth step: synthesis of tert-butyl 2- [ 2-methyl-4- [ [ [ 4-methyl-2- [4- (trifluoromethyl) phenyl ] -5-thiazolyl ] methyl ] thio ] phenoxy ] acetate by one-pot method
Example 10:
under the protection of nitrogen, 50g of the Grignard reagent of the previous example 8 and 50g of tetrahydrofuran were charged into a reaction flask, 2.44g (1.0 eq) of sulfur powder was added under the control of-65 ℃, the temperature was gradually raised to 0 ℃, after 1 hour of reaction, 5- (bromomethyl) -4-methyl-2- [4- (trifluoromethyl) phenyl ] was added dropwise at 0 DEG C]A mixed solution of 24.3g (0.95 eq) of-1,3-thiazole and 150g of tetrahydrofuran, and the purity of the product is 86.9% by sampling HPLC. Adding saturated ammonium chloride aqueous solution, quenching, standing for layering, extracting water layer with ethyl acetate, mixing organic phases, concentrating to obtain a non-flowing liquid, adding n-heptane, and pulping to obtain 2- [ 2-methyl-4- [ [ [ 4-methyl-2- [4- (trifluoromethyl) phenyl ] 2- [ 2-methyl-4- [ [ [ 4-methyl ] 4]-5-thiazolyl]Methyl radical]Thio group]Phenoxy radical]31.1g of tert-butyl acetate, the purity of 93.6 percent and the yield of 81 percent; 1 HNMR(400MHz,CDCl3):7.99-7.95(d,1H),7.67-7.63(d,2H),7.23-7.19(d,1H),6.99-6.95(d,1H),6.60-6.57(dd,1H),4.92(s,2H),4.06(s,2H),2.47(s,3H),2.35(s,3H),1.40(s,9H).
the fifth step: 2- [ 2-methyl-4- [ [ [ 4-methyl-2- [4- (trifluoromethyl) phenyl ] -5-thiazolyl ]
Synthesis and purification of methyl thio phenoxy acetic acid
Example 11:
2- [ 2-methyl-4- [ [ [ 4-methyl-2- [4- (trifluoromethyl) phenyl ] is put into a reaction bottle]-5-thiazolyl]Methyl radical]Thio group]Phenoxy radical]31.1g (61 mmol) of tert-butyl acetate and 310g of methanol, dripping 8.3g of 36% colorless hydrochloric acid aqueous solution at room temperature, heating to 50-60 ℃ for reaction for 3 hours, sampling and detecting pH =1 and the residual of the raw material is less than 0.5%, cooling and concentrating the solvent, adding 20g of methanol and 110g of deionized water, heating and refluxing to dissolve the materials, cooling to 20 ℃, and filtering to obtain 2- [ 2-methyl-4- [ [ [ 4-methyl-2- [4- (trifluoromethyl) phenyl ] ethyl]-5-thiazolyl]Methyl radical]Thio group]Phenoxy radical]24.1g of acetic acid, 99.5% of purity and 87% of yield. 1 HNMR(400MHz,CD3OD):8.02-7.97(d,2H),7.74-7.71(d,2H),7.20-7.16(d,1H),7.15-7.13(dd,1H),6.74-6.70(d,1H),4.65(s,2H),2.19(s,3H).
Example 12:
2- [ 2-methyl-4- [ [ [ 4-methyl-2- [4- (trifluoromethyl) phenyl ] is put into a reaction bottle]-5-thiazolyl]Methyl radical]Thio group]Phenoxy radical]31.1g (61 mmol) of tert-butyl acetate and 320g of dioxane, 14g of 48 percent colorless hydrobromic acid aqueous solution is dropwise added at room temperature, the temperature is increased to 50-60 ℃ for reaction for 3 hours, the pH =1 is sampled and detected, the raw material residue is less than 0.3 percent, the solvent is concentrated by cooling, 20g of methanol and 140g of deionized water are added, the temperature is increased and the reflux is carried out until the material is clear, the temperature is reduced to 15 ℃, and the filtration is carried out, thus obtaining 2- [ 2-methyl-4- [ [ [ 4-methyl-2- [4- (trifluoromethyl) phenyl ] 2]-5-thiazolyl]Methyl radical]Thio group]Phenoxy radical]23.8g of acetic acid, 99.7% purity and 86% yield. 1 HNM(400MHz,CD3OD):8.02-7.97(d,2H),7.74-7.71(d,2H),7.20-7.16(d,1H),7.15-7.13(dd,1H),6.74-6.70(d,1H),4.65(s,2H),2.19(s,3H).
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be able to cover the technical solutions and the inventive concepts of the present invention within the technical scope of the present invention.
Claims (4)
1. A preparation method of a selective PPAR delta agonist GW501516 is characterized by the following reaction equation:
the method comprises the following steps:
the first step is as follows: synthesis of Compound 2
Dissolving o-methylphenol 1 and potassium iodide in an organic solvent, adding an oxidant, and obtaining 4-iodo-2-methylphenol 2 in the presence of a catalyst; in the first step, the organic solvent is selected from tert-butyl alcohol, the oxidant is selected from hydrogen peroxide, and the catalyst is selected from acetylacetone alum; the mol ratio of the o-methyl phenol to the potassium iodide to the oxidant is 1:1.1-1.5:1.2-1.5;
the second step is that: synthesis of Compound 3
Dissolving 4-iodo-2-methylphenol 2 in an organic solvent, and reacting with tert-butyl chloro/bromoacetate in the presence of an inorganic base to obtain (4-iodo-2-methylphenoxy) -tert-butyl acetate 3; in the step, the product needs to be recrystallized and purified, and a recrystallization solvent is selected from dichloromethane and n-heptane, and the mass ratio of the recrystallization solvent is 1:2.1-2.4;
the third step: synthesis of Compound 6
(4-iodo-2-methylphenoxy) -butyl acetate 3 is subjected to exchange reaction with a Grignard reagent, followed by addition of sulfur powder to produce intermediate 4; then reacting with 5- (bromomethyl) -4-methyl-2- [4- (trifluoromethyl) phenyl ] -1,3-thiazole 5 to obtain 2- [ 2-methyl-4- [ [ [ 4-methyl-2- [4- (trifluoromethyl) phenyl ] -5-thiazolyl ] methyl ] thio ] phenoxy ] acetic acid tert-butyl ester 6; in the third step, the reaction is carried out in tetrahydrofuran or 2-methyltetrahydrofuran; the Grignard reagent is selected from isopropyl magnesium chloride, isopropyl magnesium bromide and isopropyl magnesium chloride-lithium chloride; the molar ratio of the compound 3 to the Grignard reagent to the sulfur powder to the compound 5 is 1:1.0-1.2:2.0-2.2:1.05-1.1;
the fourth step: synthesis of Compound 7, GW501516
Carrying out hydrolysis reaction on tert-butyl 2- [ 2-methyl-4- [ [ [ 4-methyl-2- [4- (trifluoromethyl) phenyl ] -5-thiazolyl ] methyl ] thio ] phenoxy ] acetate 6 to obtain 2- [ 2-methyl-4- [ [ [ 4-methyl-2- [4- (trifluoromethyl) phenyl ] -5-thiazolyl ] methyl ] thio ] phenoxy ] acetic acid 7; the hydrolysis reaction is carried out in hydrochloric acid or hydrobromic acid;
wherein, X = I in the reaction equation.
2. The process for the preparation of the selective PPAR δ agonist GW501516 of claim 1, wherein: in the second step, the organic solvent is selected from ethanol, tetrahydrofuran or acetone.
3. The process for the preparation of the selective PPAR δ agonist GW501516 of claim 1, wherein: in the second step, the inorganic base is selected from potassium tert-butoxide, sodium hydride or anhydrous potassium carbonate.
4. The process for the preparation of the selective PPAR δ agonist GW501516 of claim 1, wherein: in the second step, the mol ratio of the o-4-iodo-2-methylphenol to the inorganic base to the tert-butyl chloro/bromoacetate is 1:1.1-3.0:1.05-1.1.
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