KR20060007924A - Process for the preparation of optically pure 2-[6-(aminoalkyl)-1,3-dioxane-4-yl] acetic acid derivatives - Google Patents

Abstract

The present invention relates to a method for preparing 2- [6- (aminoalkyl) -1,3-dioxan-4-yl] acetic acid derivative having optical activity, comprising: a) high pressure hydrogenation of a ketoester double-protected with nitrogen; Condensing the compound obtained in step a) with the lithium acetate enolate compound, c) subjecting the compound obtained in step b) to high pressure hydrogenation or stereoselective reduction under a ruthenium catalyst, and d) According to the method of the present invention comprising performing a hydroxyl group protection reaction of the compound obtained in step c), 2- [6- (aminoalkyl) having optical activity useful as a key intermediate for preparing atorvastatin, a therapeutic agent for hyperlipidemia ) -1,3-dioxan-4-yl] acetic acid derivatives can be synthesized at high yield and low cost simply under milder conditions than conventional methods.

Description

Process for preparing 2- [6- (aminoalkyl) -1,3-dioxan-4-yl] acetic acid derivative having optical activity {PROCESS FOR THE PREPARATION OF OPTICALLY PURE 2- [6- (AMINOALKYL) -1,3- DIOXANE-4-YL] ACETIC ACID DERIVATIVES}             

1 is an X-ray of 7- (benzyl, benzyloxycarbonylamino) -5 (R) -hydroxy-3-oxo-heptanoic acid-t-butyl ester prepared in Example 1-2) of the present invention. The results of X-ray crystallography are shown.

The present invention relates to an efficient process for the preparation of 2- [6- (aminoalkyl) -1,3-dioxan-4-yl] acetic acid derivatives with optical activity.

Atorvastatin (trade name: Lipitor) represented by the following formula (1) is a hyperlipidemic therapeutic agent developed by Warner Lambert Pharmaceuticals and marketed by Pfizer Pharmaceuticals. -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- (phenylcarbonyl) pyrrol-1-yl] -3,5-dihydroxyheptano acid calcium salt.

In order to prepare atorvastatin, synthesis of 2- [6- (aminoalkyl) -1,3-dioxan-4-yl] acetic acid derivative of the following general formula (2) is usually necessary as an intermediate.

Where

P and P ¹ are each independently hydrogen, benzyl, benzyloxycarbonyl, t-butyloxycarbonyl, benzoyl, acetyl, nitrobenzyloxycarbonyl, methoxybenzyloxycarbonyl or phenyloxycarbonyl,

R is C _1-6 alkyl, preferably methyl, ethyl, propyl, isopropyl or t-butyl.

Various methods for synthesizing an intermediate having a structure of Formula 2 or a compound having a structure similar thereto have been introduced in various documents. For example, a method developed by Warner Lambert Pharmaceuticals (Ref .: US 5,155,251, US 4,970,313, US 5,103,024, WO 9,932,434, US 5,998,633, US 599,521, Korean Patent 166,385 and Korean Patent 302,431), halohydroxyester or activation A metal cyanide was reacted from the dihydroxy ester, and an intermediate similar to that of Chemical Formula 2 was synthesized; The method developed by Takasago Pharmaceutical Co., Ltd. in Japan (Ref .: US 5,599,954, US4,895,979, US 5,430,171 and EP 0,573,184 A1) is a high pressure reaction of monosubstituted amino ketoesters under ruthenium catalyst to produce hydroxyketoesters. After obtaining the condensation reaction of the enolate of the acetate ester and then a high pressure hydrogenation reaction under a ruthenium catalyst to synthesize an intermediate similar to the formula (2).

A detailed analysis of the Takasago accident method described in US Pat. No. 5,599,954 is given in Scheme 1 below.

Where

R ₁ is benzyloxycarbonyl, t-butyloxycarbonyl or benzoyl,

P ² is an alcohol protecting group,

R is C _1-6 alkyl.

However, the synthesis method of such Takasago Pharmaceutical Co., Ltd. has a high stereoselectivity variation (90-97% ee) depending on the type of the amine protecting group (R ₁ ) and the alkyl group (R) of the ester. The yield of the condensation reaction (C ₄ + C ₂ ) step of the oxyketoester compound and the acetate ester enolate compound is very low as 30-40%, and in the second reduction reaction (deprotection of amine protecting group) under ruthenium catalyst Has the disadvantage of very low stereoselectivity.

Accordingly, it is an object of the present invention to readily provide, in milder conditions, higher yields of 2- [6- (aminoalkyl) -1,3-dioxan-4-yl] acetic acid derivatives with optical activity, useful as key intermediates of atorvastatin. It is to provide an improved method that can be produced.

In the present invention according to the above object,

a) high pressure hydrogenation of a compound of Formula 3 under a ruthenium catalyst to prepare a compound of Formula 4,

b) reacting a compound of Formula 4 with a compound of Formula 5 to produce a compound of Formula 6

c) preparing a compound of formula 7 by subjecting the compound of formula 6 to high pressure hydrogenation or stereosterically reducing under a ruthenium catalyst,

d) providing a method of preparing 2- [6- (aminoalkyl) -1,3-dioxan-4-yl] acetic acid derivative of the following Chemical Formula 2, comprising performing a hydroxyl group protecting reaction of a compound of Chemical Formula 7 do:

Formula 2

Where

P and P ¹ are each independently hydrogen, benzyl, benzyloxycarbonyl, t-butyloxycarbonyl, benzoyl, acetyl, nitrobenzyloxycarbonyl, methoxybenzyloxycarbonyl or phenyloxycarbonyl,

R is C _1-6 alkyl, preferably methyl, ethyl, propyl, isopropyl or t-butyl.

Hereinafter, the present invention will be described in more detail.

An example of a preparation method according to the present invention (when P = benzyl, P ¹ = -COOR ₂ , R = t-butyl) of Formula 2 is shown in Scheme 2:

Wherein R ² is benzyl, t-butyl, nitrobenzyl, methoxybenzyl or phenyl.

In the above scheme, steps a) to c) can be performed similarly to the method described in Korean Patent Application No. 2003-51360 filed by the applicant of the present application.

Specifically, in step a) according to the method of the present invention, the compound of formula 3a is hydrogenated under a ruthenium catalyst at a temperature of room temperature to 100 ° C. and a high pressure of 30 to 100 atm to prepare a compound of formula 4a. At this time, the reaction is carried out in an organic solvent, a polar or non-polar solvent is suitable as an organic solvent, for example methanol, ethanol, isopropanol, t-butanol, methylene chloride, tetrahydrofuran, acetonitrile, dimethylformamide, Diethyl ether, ethyl acetate, acetone, chloroform and the like can be used.

Examples of ruthenium catalysts used in the present invention include Ru ₂ Cl ₄ (BINAP) ₂ NEt ₃ , Ru ₂ Cl ₄ (Tol-BINAP) ₂ NEt ₃ , Ru ₂ Cl ₂ (BINAP) ₂ , Ru ₂ Br ₂ (BINAP) ₂ , RuHCl (BINAP), Ru (BINAP) CO ₂ (CH ₃ ) ₂ , Ru (Tol-BINAP) CO ₂ (CH ₃ ) ₂ , and the like, wherein Tol = toluene, BINAP = [2,2 '-Bis (diphenylphosphino) -1,1'-binafyl]), and may be used in a catalytic amount of 0.01 to 0.002 mole relative to 1 mole of the compound of Formula 3a.

The compound of formula 3 used in the method of the present invention can be easily prepared by a known method, for example, as shown in Scheme 3 below, by reacting benzylamine and ethyl acrylate 3 -Benzyl amino propionic acid ethyl ester is prepared (step (i)) and reacted with benzyl chloropermate or di-t-butoxy dicarbonate to prepare N, N-disubstituted propionic acid ethyl ester of the formula (Step (ii)), hydrolyzing it with potassium hydroxide to prepare a compound of formula 10 (step (iii)), and then reacting it with carbonyldiimidazole (CDI), potassium malonic mono ethylester and MgCl ₂ By (step (iv)), a compound of formula 3a can be prepared:

Wherein R ² is as defined above.

In step (b) according to the method of the present invention, the compound of formula 4a is reacted with a lithium acetate enolate compound of formula 5a at -60 ° C to room temperature to give 5 (R) -hydroxy- Prepare a 3-oxo-heptanoic acid derivative compound. In this case, the compound of Formula 5a may be used in an amount of 1.0 to 2.0 mole relative to 1.0 mole of Compound 4a.

Subsequently, in step (c) according to the process of the invention, the compound of formula 6a is subjected to a high pressure hydrogenation under a ruthenium catalyst under the same conditions as in step (a), or, for example, diethylmethoxyborane and sodium The dihydroxy heptanoic acid derivative of Formula 7a may be prepared by stereoselective reduction at −90 to 0 ° C. using a low hydride. According to the method according to the present invention, in the case of reducing with diethylmethoxyborane and sodium borohydride in the step (c), -20 to-unlike the conventional method performed at -80 to -70 ℃ There is an advantage that the stereoselective reduction of compound 6a can be carried out at a mild temperature of 10 ℃.

In step (d), the dioxane compound of formula 2a can be prepared by carrying out the protective reaction of 3-OH and 5-OH of compound 7a by conventional methods known in the document US 6,001,615 and the like. Specifically, the compound of formula 2a is added to an organic solvent (e.g., toluene, acetone, tetrahydrofuran and methylene chloride) by adding an acid such as p-toluenesulfonic acid, methanesulfonic acid and the like to react with dimethoxypropane. Prepare the compound. The reaction may be carried out at a temperature in the range of 0 to 50 ℃, dimethoxypropane, may be used in an amount of 1.2 to 1.5 mole per 1 mole of the compound of Formula 7a.

The process according to the invention may also further comprise the deprotection reaction step (e) of the disubstituted amino protecting group of compound 2. Specifically, in the manufacture of, the compound 2a atorvastatin by performing (P = benzyl, P ¹ = -COOR ² in the case of formula (2)) was reduced under a Pd / C catalyst under normal pressure with hydrogen, by deprotection reaction of the amino protective group Compound 2b (if P and P ¹ = H in Formula 2) can be prepared, which is an expensive reagent that is very useful. The reaction can be carried out at a temperature in the range of 0 to 50 ℃, examples of the solvent used may be methanol, ethanol, isopropanol and the like. In step (e) of the present invention, the amino protecting groups P and P ¹ of formula (2) can be removed in one reactor at a time.

According to the method of the present invention for high-pressure hydrogenation of the ketoester double-protected with nitrogen as described above, 2- [6- (aminoalkyl) -1,3-dioxane- having the optical activity of Formula 2, which is a key intermediate of atorvastatin, 4-yl] acetic acid derivatives can be synthesized easily and in high yield under mild conditions compared to conventional methods.

Hereinafter, the present invention will be described in more detail with reference to Examples, which are only intended to assist in understanding the configuration and operation of the present invention, and the scope of the present invention is not limited to these Examples.

Preparation Example 1 Preparation of 5- (benzyl, t-butyloxycarbonylamino) -3-oxo-pentanoic acid ethyl ester (Compound 3 (when P = benzyl, P ₁ = t-butyloxycarbonyl))

2 g (0.0072 mole) of 3- (benzyl, t-butyloxycarbonylamino) -propionic acid and 40 mL of acetonitrile were added to the reactor and stirred for 15 minutes under nitrogen. Add 1.3 g (0.0079 mole) of 1,1'-carbonyldiimidazole and stir for another 30 minutes, lower the temperature to 10 ° C, 1.84 g (0.0108 mole) of potassium malonate ethylester and 0.75 g (0.0079 mole) of magnesium chloride. ) Was added and stirred for 1 hour. Subsequently, the temperature of the reaction solution was 50 ° C. and further stirred for 2 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and distilled under reduced pressure to remove the solvent. The mixture was extracted with ethyl acetate and 6N hydrochloric acid, adjusted to pH 4. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2.1 g of the title compound as a yellow oil. 85%) was obtained.

¹ H-NMR (CDCl ₃ , ppm): δ 7.35-7.23 (m, 5H), 4.44 (s, 2H), 4.17 (q, 2H), 3.45-3.36 (m, 4H), 2.81-2.72 (m, 2H), 1.45 (s, 9H), 1.28 (t, 3H)

Preparation Example 2 Preparation of 5- (benzyl, benzyloxycarbonylamino) -3-oxo-pentanoic acid ethyl ester (Compound 3a)

2.8 g (0.0089 mole) of 3- (benzyl, benzyloxycarbonylamino) -propionic acid and 50 mL of acetonitrile were added to the reactor and stirred for 15 minutes under nitrogen. 1.59 g (0.0098 mole) of 1,1'-carbonyldiimidazole was added thereto, followed by further stirring for 30 minutes, and then the temperature was lowered to 10 ° C., 2.27 g (0.01335 mole) of potassium malonate and 0.94 g (0.0098 mole) of magnesium chloride. ) Was added and stirred for 1 hour. Subsequently, the temperature of the reaction solution was 50 ° C. and further stirred for 2 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and distilled under reduced pressure to remove the solvent. The mixture was extracted with ethyl acetate and 6N hydrochloric acid, adjusted to pH 4. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2.93 g of the title compound as a yellow oil (yield). 85%) was obtained.

¹ H-NMR (CDCl ₃ , ppm): δ 7.36-7.25 (m, 5H), 5.16 (s, 2H), 4.51 (s, 2H), 4.14 (q, 2H), 3.59-3.20 (m, 4H) , 2.84-2.70 (m, 2H), 1.24 (t, 3H)

Example 1 Preparation of Compound (Compound 2a) of Formula 2 (When P = benzyl, P ₁ = benzyloxycarbonyl)

1-1) Preparation of 5- (benzyl, benzyloxycarbonylamino) -3 (R) -hydroxypentanoic acid ethyl ester (Compound 4a)

5 g (0.013 mole) of 5- (benzyl, benzyloxycarbonylamino) -3-oxo-pentanoic acid ethyl ester prepared in Preparation Example 2 and 0.01 g of (R) -Ru (BINAP) Cl ₂ Et ₃ N ( 0.000011 mole) was added to 50 mL of methanol and reacted for 12 hours at 70 atm of hydrogen and 30 to 40 ° C. in a high pressure reactor. After completion of the reaction, methanol was removed by distillation under reduced pressure, extracted with ethyl acetate and water, the organic layer was dried over anhydrous magnesium sulfate, concentrated, and separated and purified by silica gel column chromatography (hexane / ethyl acetate = 2/1 (v / v)). 4.8 g (yield: 95%) of the title compound as a yellow oil were obtained (HPLC conditions-column: Chiralcel OD-H, mobile phase: hexane / isopropyl alcohol (80/20, v / v), flow rate: 0.6 mL / min, detection: 254 nm, retention time: 14.42 minutes).

¹ H-NMR (CDCl ₃ , ppm): δ 7.36-7.18 (m, 5H), 5.18 (s, 2H), 4.58-4.37 (m, 2H), 4.14 (q, 2H), 4.09-3.90 (m, 1H), 3.68 (br, 1H), 3.39-3.01 (m, 2H), 2.47-2.36 (m, 2H), 1.79-1.45 (m, 2H), 1.25 (t, 3H)

1-2) Preparation of 7- (benzyl, benzyloxycarbonylamino) -5 (R) -hydroxy-3-oxo-heptanoic acid-t-butyl ester (Compound 6a)

100 mL of anhydrous THF was added to a 250 mL reactor, and the temperature inside the reactor was lowered to −40 ° C. in the presence of nitrogen, and 62 mL (0.124 mole) of 2M LDA was added thereto. After about 10 minutes, 14.4 g (0.124 mole) of t-butyl acetate was added thereto, followed by stirring for 1 hour, followed by 5- (benzyl and benzyloxycarbonylamino) -3 (R) -hydride prepared in Example 1-1. 12 g (0.031 mole) of Roxy-pentanoic acid ethyl ester was slowly added dropwise at −40 ° C. and stirred for 2 hours. After the reaction was completed, 1N HCl was added to the reaction solution, stirred, and extracted with ethyl acetate. The organic layer was washed with saturated sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and purified by silica gel column chromatography (hexane / ethyl acetate = 2/1 (v / v)) to obtain 12.7 g (yield: 90%) of the title compound. HPLC conditions-column: Chiralcel OD-H, mobile phase: hexane / isopropyl alcohol (80/20, v / v), flow rate: 0.6 mL / min, detection: 254 nm, retention time: 21.02 min). X-ray crystallography was performed on the white solid obtained by storing the obtained compound in a refrigerator for 5 hours, and it was confirmed that the obtained compound was a compound having a crystal structure as shown in FIG.

¹ H-NMR (CDCl ₃ , ppm): δ 7.32-7.18 (m, 10H), 5.18 (s, 2H), 4.67-4.29 (m, 2H), 4.02-3.96 (m, 2H), 3.72 (br, 1H), 3.42-3.09 (m, 3H), 2.82-2.51 (m, 2H), 1.72- 1.57 (m, 2H), 1.45 (s, 9H)

1-3) Preparation of 7- (benzyl, benzyloxycarbonylamino) -3 (R), 5 (R) -dihydroxy-heptanoic acid-t-butyl ester (Compound 7a)

10 g (0.0219 mole) of 7- (benzyl, benzyloxycarbonylamino) -5 (R) -hydroxy-3-oxo-heptano-t-butyl ester prepared in Example 1-2) and anhydrous THF / MeOH = 90/10 mL was added and the temperature was lowered to −20 ° C. under argon gas, and 2.5 g (0.0250 mole) of diethylmethoxyborane was slowly added dropwise and stirred for 30 minutes. At the same temperature 1 g (0.0264 mole) of sodium borohydride were added and stirred for 5 hours. After completion of the reaction by TLC, 5 mL of acetic acid was added and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and then purified by silica gel column chromatography (hexane / ethyl acetate = 2/1 (v). / v)) to give 8.9 g (yield: 89%) of the title compound (HPLC conditions-column: Chiralcel OD-H, mobile phase: hexane / isopropyl alcohol (80/20, v / v). ), Flow rate: 0.5 mL / min, detection: 254 nm, retention time: 24.20 min).

¹ H-NMR (CDCl ₃ , ppm): δ 7.35-7.21 (m, 10H), 5.19 (s, 2H), 4.30-4.22 (m, 3H), 4.20 (br, 1H), 4.10-4.07 (m, 1H), 3.90 (br, 1H), 3.52-3.40 (m, 2H), 3.27-3.14 (m, 2H), 2.43-2.35 (m 2H), 1.70-1.47 (m, 2H), 1.44 (m, 9H )

1-4) {6- [2- (benzyl, benzyloxycarbonylamino) -ethyl] -2.2-dimethyl- [1,3] dioxan-4-yl} -acetic acid t-butyl ester (Compound 2a) Produce

5 g (0.0109) of 7- (benzyl, benzyloxycarbonylamino) -3 (R), 5 (R) -dihydroxy-heptanoic acid-t-butyl ester prepared in Example 1-3) in a 100 mL reactor mole), dissolved in 50 mL of toluene, and a small amount of p-toluenesulfonic acid and 6.2 g (0.0595 mole) of dimethoxypropane were added, followed by stirring at room temperature for 3 hours. After completion of the reaction, the organic layer was washed with sodium bicarbonate solution, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1 (v / v)) to obtain 4 g of the title compound (yield: 95). %, De 99.2%) was obtained (HPLC conditions-column: Chiralcel OD-H, mobile phase: hexane / isopropyl alcohol (80/20, v / v), flow rate: 0.6 mL / min, detection: 254 nm, retention time: 9.10 min).

¹ H-NMR (CDCl ₃ , ppm): δ 7.36-7.23 (m, 10H), 5.10 (s, 2H), 4.55-4.08 (m, 3H), 3.99-3.85 (m, 1H), 3.41-3.21 ( m, 2H), 2.43-2.27 (m, 2H), 1.75-1.52 (m, 3H), 1.45 (s, 9H), 1.41 (s, 3H), 1.36 (s, 3H), 1.27-1.16 (m, 1H)

Example 2: Preparation of Compound (Compound 2b) of Formula 2 (where P and P ₁ = hydrogen)

{6- [2- (benzyl, benzyloxycarbonylamino) -ethyl] -2,2-dimethyl- [1,3] dioxan-4-yl} -acetic acid t prepared in Example 1 in a hydrogenation reactor 5 g (0.0100 mole) of butyl ester was added and 50 mL of methanol was added thereto. Here, 100% of 5% Pd / C was added under nitrogen, hydrogen was injected using a hydrogen balloon, stirred for 30 minutes, the hydrogen balloon was replaced, and further stirred for 5 hours. After filtering the reaction solution using celite, the solvent was concentrated under reduced pressure, purified by column chromatography (ethyl acetate / methanol / ammonium hydroxide = 30/20/1 (v / v / v)) to obtain the desired product (4R-). 2.36 g of cis) -1,1-dimethylethyl 6- (2-aminoethyl) -2,2-dimethyl-1,3-dioxane-4-acetate (yield: 96%) were obtained.

¹ H-NMR (300 MHz, CDCl ₃ ,): δ 1.0-1.2 (m, 1H), 1.22 (s, 3H), 1.31 (s, 12H), 1.35-1.45 (m, 3H), 2.15 (dd, 1H J = 15.1 Hz, J = 6.2 Hz), 2.29 (dd, 1H J = 15.1 Hz J = 7.0 Hz), 2.66 (t, 2H J = 6.6 Hz), 3.82 (m, 1H), 4.12 (m, 1H) , 1.27-1.16 (m, 1 H)

Thus, according to the method of the present invention, a 2- [6- (aminoalkyl) -1,3-dioxan-4-yl] acetic acid derivative having an optical activity of the formula (2), which is useful as a key intermediate of atorvastatin, is used in a conventional method. Compared to mild conditions, it can be easily synthesized in high yield.

Claims (5)

(a) high pressure hydrogenation of a compound of formula 3 under a ruthenium catalyst to prepare a compound of formula 4 (b) reacting a compound of Formula 4 with a compound of Formula 5 to produce a compound of Formula 6 (c) preparing a compound of formula 7 by subjecting the compound of formula 6 to a high pressure hydrogenation reaction or stereosterically reducing under a ruthenium catalyst, (d) preparing a 2- [6- (aminoalkyl) -1,3-dioxan-4-yl] acetic acid derivative of the formula (II) comprising carrying out a hydroxy group protection reaction of the compound of formula: Formula 3

Formula 4

Formula 5

Formula 6

Formula 7

Formula 2

Where P and P ¹ are each independently hydrogen, benzyl, benzyloxycarbonyl, t-butyloxycarbonyl, benzoyl, acetyl, nitrobenzyloxycarbonyl, methoxybenzyloxycarbonyl or phenyloxycarbonyl, R is methyl, ethyl, propyl, isopropyl or t-butyl. The method of claim 1, If one or both of P and P ¹ of Formula 2 are not hydrogen, reducing the compound of Formula 2 to hydrogen in the presence of a Pd / C catalyst under atmospheric pressure to prepare a compound of Formula 2 wherein P and P ¹ are hydrogen; It further comprises a method. The method of claim 1, The high pressure hydrogenation reaction in steps (a) and (c) is carried out at methanol, ethanol, isopropanol, t-butanol, methylene chloride, tetrahydrofuran, acetonitrile, di And at least one organic solvent selected from methylformamide, diethyl ether, ethyl acetate, acetone, chloroform and mixtures thereof. The method of claim 1, The ruthenium catalyst used in steps (a) and (c) is Ru ₂ Cl ₄ (BINAP) ₂ NEt ₃ , Ru ₂ Cl ₄ (Tol-BINAP) ₂ NEt ₃ , Ru ₂ Cl ₂ (BINAP) ₂ , Ru ₂ Br ₂ (BINAP) ₂ , RuHCl (BINAP), Ru (BINAP) CO ₂ (CH ₃ ) ₂ and Ru (Tol-BINAP) CO ₂ (CH ₃ ) ₂ (Tol = toluene, BINAP = [2,2'-bis (Diphenylphosphino) -1,1'-binafyl]). The method of claim 1, Wherein the stereoselective reduction in step (c) is carried out at −90 to 0 ° C. using diethylmethoxyborane and sodium borohydride.

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