CN109574998A - A kind of synthetic method of Pitavastatin Calcium intermediate - Google Patents
A kind of synthetic method of Pitavastatin Calcium intermediate Download PDFInfo
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
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Abstract
The invention discloses a kind of synthetic method of Pitavastatin Calcium intermediate, include the following steps: that 2- cyclopropyl -4- (4- fluorophenyl) quinoline -3- bromomethyl reacts to obtain substance A under sodium hydroxide catalyzed with tri-thiol s-triazine;Then substance B is obtained through oxidant oxidation;It reacts to obtain Pitavastatin Calcium intermediate under sodium hydride catalysis with (4R-Cis) -6- aldehyde radical -2,2- dimethyl -1,3- dioxane -4- tert-butyl acetate again.Raw material of the present invention is cheap and easy to get, and route is novel, and Atom economy is good, environmentally protective, reaction condition is mildly controllable, and easy to operate simple, purification process is simple, is suitble to industrialized production, stereoselectivity is good, high income, and the Pitavastatin Calcium intermediate purity being prepared is good.
Description
Technical field
The present invention relates to chemical substance preparation technical field more particularly to a kind of synthesis sides of Pitavastatin Calcium intermediate
Method.
Background technique
The maniflest function of Pitavastatin Calcium be blood lipid-lowering medicine (HMG-CoA reductase inhibitor), be by Nissan Chemical with
First fully synthetic HMG-CoA reductase inhibitor of two company's joint development of Kowa company Ltd, belongs to statins
Object, the ability for mainly manufacturing cholesterol by reducing liver to a kind of inhibition of liver enzyme for being called HMG-CoA reductase, with
This improves the blood cholesterol levels after increasing, and is mainly used for treating hypercholesterolemia and Familial HypercholesterolemicPatients Patients,
Its lipid-lowering effect is very good, is fat-reducing medicament most potent so far.Therefore the synthetic route of research Pitavastatin Calcium has
Significance.
6- [[(1E) -2- cyclopropyl -4- (4- fluorophenyl) -3- quinolyl]-vinyl] -2,2- dimethyl -1,3- dioxy
Six ring -4- tert-butyl acetates are the key intermediates of Pitavastatin Calcium, in currently used Pitavastatin Calcium synthetic route mostly
Need to synthesize this intermediate.
It is found by being retrieved to existing technology, the Pitavastatin Calcium synthetic route of mainstream mainly has several following at present:
Synthetic route one, in patent EP304063, E-3- [2- cyclopropyl -4- (4- fluorophenyl) -3- quinoline -2- methacrylaldehyde
It restored after being docked with ethyl acetoacetate, split into salt and obtain Pitavastatin Calcium, this method step is long, and technique is harsh, and first
It is split after docking, one of which is screened in four kinds of optical isomers, so that its yield is very low.
Synthetic route two, in patent WO2007/132482, by relatively short reaction step, under mild conditions
It is prepared for Pitavastatin and its salt.Reacted by Wittig, make 2- cyclopropyl -4- (4- fluorophenyl) -3- quinolylmethyl phosphonium salt and
(3R, 5S) -6- oxo -3.5- dihydroxy -3,5-0- isopropylidene tert-butyl acetate is reacted, obtained to have dioxane
After partial intermediate, then after being converted into the amine salt form of the intermediate with dihydroxy part, prepare Pitavastatin or
Its salt.The purity of the intermediate of this method preparation is not high, and has remained the triphenylphosphinc oxide that Wittig reaction generates, and in
The mode of mesosome post-processing takes into the form of ammonium salt, increases the complexity of processing, and the purity of final anti-configuration is not yet
It is high.
Synthetic route three, United States Patent (USP) US6875867B2 report a kind of new connection method, (4R, 6S) -6- are utilized
Methylol -2,2- dimethyl-1,3-dioxane -4- tert-butyl acetate and trifluoromethanesulfonic acid anhydride reactant, then with 1- phenyl -5- mercapto
Base tetrazole acts on forming thioether, is further oxidized to sulfone, and sulfone is had with statin parent nucleus aldehyde by Olefination react of Julia
There is the intermediate of good E formula stereoselectivity, and there is high yield and optical purity.But the shortcomings that route be using
The trifluoromethanesulfanhydride anhydride of price costly, and 1- phenyl -5- mercapto tetrazole is also used, Atom economy is high.
Synthetic route four, Chinese patent CN102174039A is with (4R, 6S) -6- methylol -2,2- dimethyl -1,3- dioxy
Six ring -4- tert-butyl acetates are starting material, and 1,1 '-(1.4- phenylene) bis- (1H-TETRAZOLE -5- mercaptan) and azoformic acid
Diisopropyl ester carries out Mitsunobu reaction in tetrahydrofuran, then obtains sulphones through oxidation reaction, finally with 2- cyclopropyl
Base -4- (4- fluorophenyl) quinoline-3-formaldehyde obtains Pitavastatin Calcium key intermediate under alkaline environment.The method step is long,
There is deep cooling to react so that condition is more harsh, and have passed through multiple column chromatography, yield is lower.
By above-mentioned summary it is found that at present about synthesis Pitavastatin Calcium main difficulty be and dock product solid select
The reaction effect of property.Above-mentioned route is bad because of the valuableness and Atom economy of raw material, or because the condition of reaction is more severe
Quarter needs column to chromatograph, or because post-processes complicated difficult to obtain the higher Pitavastatin Calcium of purity, so that the industry of above-mentioned route
There are bottlenecks for metaplasia production, therefore development raw material is cheap and easy to get, and reaction condition is mild, among the good Pitavastatin Calcium of Atom economy
The synthetic route of body has broad prospects.
Summary of the invention
Technical problems based on background technology, the invention proposes a kind of synthesis sides of Pitavastatin Calcium intermediate
Method, raw material of the present invention is cheap and easy to get, and route is novel, and Atom economy is good, and environmentally protective, reaction condition is mildly controllable, operation side
Just simple, purification process is simple, is suitble to industrialized production, stereoselectivity is good, high income, in the Pitavastatin Calcium being prepared
Mesosome purity is good.
A kind of synthetic method of Pitavastatin Calcium intermediate proposed by the present invention, includes the following steps: 2- cyclopropyl -4-
(4- fluorophenyl) quinoline -3- bromomethyl reacts to obtain substance A under sodium hydroxide catalyzed with tri-thiol s-triazine;Then through aoxidizing
Agent oxidation obtains substance B;Again with (4R-Cis) -6- aldehyde radical -2,2- dimethyl -1,3- dioxane -4- tert-butyl acetate
Reaction obtains Pitavastatin Calcium intermediate under sodium hydride catalysis;Wherein, substance A, substance B, Pitavastatin Calcium intermediate knot
Structure formula is as follows:
Preferably, oxidant is one of the mixture of ammonium molybdate tetrahydrate and hydrogen peroxide, metachloroperbenzoic acid.
Preferably, the reaction dissolvent for preparing substance A is alcohols solvent.
Preferably, the reaction dissolvent for preparing substance A is at least one of methanol, ethyl alcohol, isopropanol, n-butanol.
Preferably, the reaction temperature for preparing substance A is 10-50 DEG C;It is preferred that 40 DEG C.
Preferably, the reaction time for preparing substance A is 12-18h.
Preferably, the specific steps of substance A are prepared are as follows: by sodium hydrate aqueous solution, 2- cyclopropyl -4- (4- fluorophenyl) quinoline
Quinoline -3- bromomethyl, reaction dissolvent, tri-thiol s-triazine mix, and are reacted, and purifying obtains substance A.
The specific steps of purifying are as follows: PH is adjusted to neutrality, concentration removes reaction dissolvent, organic phase is extracted, dry, concentration,
Recrystallize to obtain substance A.
Preferably, organic phase is extracted with ethyl acetate.
Preferably, recrystallization solvent is ethyl alcohol.
Preferably, the reaction temperature for preparing substance B is room temperature.
Preferably, the reaction time for preparing substance B is 24-30h.
Preferably, when oxidant is the mixture of ammonium molybdate tetrahydrate and hydrogen peroxide, it is different for preparing the reaction dissolvent of substance B
Propyl alcohol.
Preferably, when oxidant is metachloroperbenzoic acid, the reaction dissolvent for preparing substance B is methylene chloride.
Preferably, the specific steps of substance B are prepared are as follows: substance A, reaction dissolvent, oxidant are mixed, reacted, it is pure
Change obtains substance B.
Preferably, when oxidant is the mixture of ammonium molybdate tetrahydrate and hydrogen peroxide, purification step is that object is obtained by filtration
Matter B.
Preferably, when oxidant is metachloroperbenzoic acid, purification step are as follows: use sodium sulfite quenching reaction, water is added to extract
Organic phase is taken, it is dry, it is concentrated to get substance B.
Preferably, the reaction dissolvent for preparing Pitavastatin Calcium intermediate is tetrahydrofuran.
Preferably, the reaction temperature for preparing Pitavastatin Calcium intermediate is -60 to 0 DEG C.
Preferably, the reaction time for preparing Pitavastatin Calcium intermediate is 12-24h.
Preferably, the specific steps of Pitavastatin Calcium intermediate are prepared are as follows: by substance B, reaction dissolvent, (4R-Cis) -6-
Aldehyde radical -2,2- dimethyl-1,3-dioxane -4- tert-butyl acetate mixes, cooling, and sodium hydride is added, and insulation reaction is warming up to
Room temperature, is added saturated aqueous ammonium chloride quenching reaction, and purifying obtains Pitavastatin Calcium intermediate.
Preferably, the specific steps of purifying are as follows: extraction organic phase, dry, concentration is recrystallized to give among Pitavastatin Calcium
Body.
Preferably, organic phase is extracted with ethyl acetate.
Preferably, recrystallization solvent is isopropanol.
Preferably, mole of 2- cyclopropyl -4- (4- fluorophenyl) quinoline -3- bromomethyl, tri-thiol s-triazine, sodium hydroxide
Than for 3-3.5:1:3.3-4.5.
Preferably, when oxidant is the mixture of ammonium molybdate tetrahydrate and hydrogen peroxide, substance A, ammonium molybdate tetrahydrate, peroxide
Change the molar ratio 1:0.15:12-18 of hydrogen.
Preferably, when oxidant is metachloroperbenzoic acid, the molar ratio of substance A and metachloroperbenzoic acid is 1:
12-18。
Preferably, the molar ratio of substance B and sodium hydride is 1:3.6-6;It is preferred that 1:4.5.
Preferably, substance B and (4R-Cis) -6- aldehyde radical -2,2- dimethyl-1,3-dioxane -4- tert-butyl acetate
Molar ratio is 1:3.15-4.5.
In the preparation process of above-mentioned substance A, the dosage of reaction dissolvent is not provided, determines its dosage according to concrete operations.
In the preparation process of above-mentioned substance B, the dosage of reaction dissolvent is not provided, determines its dosage according to concrete operations.
In the preparation process of above-mentioned Pitavastatin Calcium intermediate, the dosage of reaction dissolvent is not provided, it is true according to concrete operations
Its fixed dosage.
Preferably synthetic route of the invention is as follows:
Using 2- cyclopropyl -4- (4- fluorophenyl), quinoline -3- bromomethyl is starting material to the present invention, under sodium hydroxide catalyzed
Substance A is prepared with tri-thiol s-triazine, then through oxidant is fully oxidized obtains substance B, with ammonium molybdate tetrahydrate and hydrogen peroxide
One of mixture, metachloroperbenzoic acid constitute oxidation system, have good oxidation susceptibility, can increase of the invention
Yield;The Olefination reaction of Julia occurs under sodium hydride catalysis and obtains Pitavastatin Calcium intermediate for last substance B, has good
Stereoselectivity, greatly improve yield of the invention;And raw material of the present invention is cheap and easy to get, route is novel, and Atom economy is good,
Environmentally protective, reaction condition is mildly controllable, and easy to operate simple, purification process is simple, is suitble to industrialized production, is prepared
Pitavastatin Calcium intermediate purity is good.
Specific embodiment
In the following, technical solution of the present invention is described in detail by specific embodiment.
Embodiment 1
A kind of synthetic method of Pitavastatin Calcium intermediate includes the following steps: 2- cyclopropyl -4- (4- fluorophenyl) quinoline
Quinoline -3- bromomethyl reacts to obtain substance A under sodium hydroxide catalyzed with tri-thiol s-triazine;Then it is obtained through oxidant oxidation
To substance B;It is catalyzed again with (4R-Cis) -6- aldehyde radical -2,2- dimethyl -1,3- dioxane -4- tert-butyl acetate in sodium hydride
Lower reaction obtains Pitavastatin Calcium intermediate.
Embodiment 2
A kind of synthetic method of Pitavastatin Calcium intermediate, includes the following steps:
By sodium hydrate aqueous solution, 2- cyclopropyl -4- (4- fluorophenyl) quinoline -3- bromomethyl, isopropanol, tri-thiol equal three
Piperazine mixes, and is warming up to 10 DEG C, insulation reaction 18h, adjusts PH to neutrality, concentration removes reaction dissolvent, has been extracted with ethyl acetate
Machine phase, dry, concentration obtains substance A with ethyl alcohol recrystallization, wherein 2- cyclopropyl -4- (4- fluorophenyl) quinoline -3- bromomethyl, three
Sulfydryl s-triazine, sodium hydroxide molar ratio be 3:1:4.5;
It is the mixing of 30wt% hydrogen peroxide by substance A, isopropanol, ammonium molybdate tetrahydrate and mass fraction, reacts at room temperature for 24 hours, mistake
Filter obtain substance B, wherein substance A, ammonium molybdate tetrahydrate, hydrogen peroxide molar ratio 1:0.15:12;
By substance B, tetrahydrofuran, (4R-Cis) -6- aldehyde radical -2,2- dimethyl -1,3- dioxane -4- tert-butyl acetate
It mixes, is cooled to -10 DEG C, sodium hydride is added, insulation reaction 18h is warming up to room temperature, and saturated aqueous ammonium chloride is added and is quenched instead
It answers, organic phase is extracted with ethyl acetate, dry, concentration obtains Pitavastatin Calcium intermediate with recrystallisation from isopropanol, wherein object
The molar ratio of matter B and sodium hydride is 1:3.6, substance B and (4R-Cis) -6- aldehyde radical -2,2- dimethyl-1,3-dioxane -4-
The molar ratio of tert-butyl acetate is 1:4.5.
Embodiment 3
A kind of synthetic method of Pitavastatin Calcium intermediate, includes the following steps:
By sodium hydrate aqueous solution, 2- cyclopropyl -4- (4- fluorophenyl) quinoline -3- bromomethyl, n-butanol, tri-thiol equal three
Piperazine mixes, and is warming up to 50 DEG C, insulation reaction 12h, adjusts PH to neutrality, concentration removes reaction dissolvent, has been extracted with ethyl acetate
Machine phase, dry, concentration obtains substance A with ethyl alcohol recrystallization, wherein 2- cyclopropyl -4- (4- fluorophenyl) quinoline -3- bromomethyl, three
Sulfydryl s-triazine, sodium hydroxide molar ratio be 3.5:1:4;
Substance A, methylene chloride, metachloroperbenzoic acid are mixed, room temperature reaction 30h is added with sodium sulfite quenching reaction
Water extracts organic phase, dry, is concentrated to get substance B, wherein substance A and the molar ratio of metachloroperbenzoic acid are 1:18;
By substance B, tetrahydrofuran, (4R-Cis) -6- aldehyde radical -2,2- dimethyl -1,3- dioxane -4- tert-butyl acetate
It mixes, is cooled to -60 DEG C, sodium hydride is added, insulation reaction for 24 hours, is warming up to room temperature, and saturated aqueous ammonium chloride is added and is quenched instead
It answers, organic phase is extracted with ethyl acetate, dry, concentration obtains Pitavastatin Calcium intermediate with recrystallisation from isopropanol, wherein object
The molar ratio of matter B and sodium hydride is 1:6, substance B and (4R-Cis) -6- aldehyde radical -2,2- dimethyl-1,3-dioxane -4- second
The molar ratio of tert-butyl acrylate is 1:3.15.
Embodiment 4
A kind of synthetic method of Pitavastatin Calcium intermediate, includes the following steps:
By mass fraction be 10wt% sodium hydrate aqueous solution, 2- cyclopropyl -4- (4- fluorophenyl) quinoline -3- bromomethyl,
Methanol, tri-thiol s-triazine mix, and are warming up to 40 DEG C, insulation reaction 15h, are that 5wt% aqueous hydrochloric acid solution is adjusted with mass fraction
PH removes methanol to neutrality, concentration, and organic phase is extracted with ethyl acetate, and anhydrous sodium sulfate is dry, and concentration is obtained with ethyl alcohol recrystallization
Substance A, wherein 2- cyclopropyl -4- (4- fluorophenyl) quinoline -3- bromomethyl, tri-thiol s-triazine, sodium hydroxide molar ratio be
The bulking value (g/ml) of 3.05:1:3.3,2- cyclopropyl -4- (4- fluorophenyl) quinoline -3- bromomethyl and methanol is than being 356:
3000;
It is the mixing of 30wt% hydrogen peroxide by substance A, isopropanol, ammonium molybdate tetrahydrate and mass fraction, reacts at room temperature 27h, mistake
Filter obtains substance B, wherein substance A, ammonium molybdate tetrahydrate, the molar ratio of hydrogen peroxide are 1:0.15:15, substance A and isopropanol
Bulking value (g/ml) is than being 1:10;
By substance B, tetrahydrofuran, (4R-Cis) -6- aldehyde radical -2,2- dimethyl -1,3- dioxane -4- tert-butyl acetate
It mixes, is cooled to -30 DEG C, point 4 batches of addition contents are 60wt% sodium hydride, and insulation reaction 12h is warming up to room temperature, and saturation is added
Organic phase is extracted with ethyl acetate in aqueous ammonium chloride solution quenching reaction, and anhydrous sodium sulfate is dry, and recrystallisation from isopropanol is used in concentration
Obtain Pitavastatin Calcium intermediate, wherein the molar ratio of substance B and sodium hydride is 1:4.7, substance B and (4R-Cis) -6- aldehyde
The molar ratio of base -2,2- dimethyl-1,3-dioxane -4- tert-butyl acetate is 1:3.6, the weight of substance B and tetrahydrofuran
Volume (g/ml) is than being 1:10.
Embodiment 5
A kind of synthetic method of Pitavastatin Calcium intermediate, includes the following steps:
By mass fraction be 10wt% sodium hydrate aqueous solution, 2- cyclopropyl -4- (4- fluorophenyl) quinoline -3- bromomethyl,
Ethyl alcohol, tri-thiol s-triazine mix, and are warming up to 40 DEG C, insulation reaction 15h, are that 5wt% aqueous hydrochloric acid solution is adjusted with mass fraction
PH removes ethyl alcohol to neutrality, concentration, and organic phase is extracted with ethyl acetate, and anhydrous sodium sulfate is dry, and concentration is obtained with ethyl alcohol recrystallization
Substance A, wherein 2- cyclopropyl -4- (4- fluorophenyl) quinoline -3- bromomethyl, tri-thiol s-triazine, sodium hydroxide molar ratio be
The bulking value (g/ml) of 3.05:1:3.3,2- cyclopropyl -4- (4- fluorophenyl) quinoline -3- bromomethyl and methanol is than being 356:
3000;
Substance A, methylene chloride, metachloroperbenzoic acid are mixed, room temperature reaction 27h is added with sodium sulfite quenching reaction
Water extracts organic phase, dry, is concentrated to get substance B, wherein substance A and the molar ratio of metachloroperbenzoic acid are 1:15, substance
The bulking value (g/ml) of A and methylene chloride is than being 1:10;
By substance B, tetrahydrofuran, (4R-Cis) -6- aldehyde radical -2,2- dimethyl -1,3- dioxane -4- tert-butyl acetate
It mixes, is cooled to 0 DEG C, point 4 batches of addition contents are 60wt% sodium hydride, and insulation reaction 12h is warming up to room temperature, and saturation chlorine is added
Change aqueous ammonium quenching reaction, organic phase is extracted with ethyl acetate, anhydrous sodium sulfate is dry, and concentration is obtained with recrystallisation from isopropanol
To Pitavastatin Calcium intermediate, wherein the molar ratio of substance B and sodium hydride is 1:4.7, substance B and (4R-Cis) -6- aldehyde radical -
The molar ratio of 2,2- dimethyl-1,3-dioxane -4- tert-butyl acetates is 1:3.6, the bulking value of substance B and tetrahydrofuran
(g/ml) than being 1:10.
The intermediate of Statistics Implementation example 4,5 and the yield of Pitavastatin Calcium intermediate, and purity is detected, the result is as follows:
As can be seen from the above table, high income of the present invention, the Pitavastatin Calcium intermediate purity being prepared are good.
The foregoing is only a preferred embodiment of the present invention, but scope of protection of the present invention is not limited thereto,
Anyone skilled in the art in the technical scope disclosed by the present invention, according to the technique and scheme of the present invention and its
Inventive concept is subject to equivalent substitution or change, should be covered by the protection scope of the present invention.
Claims (10)
1. a kind of synthetic method of Pitavastatin Calcium intermediate, which comprises the steps of: 2- cyclopropyl -4- (4- fluorine
Phenyl) quinoline -3- bromomethyl reacts to obtain substance A under sodium hydroxide catalyzed with tri-thiol s-triazine;Then make through oxidant
Substance B is obtained with oxidation;Again with (4R-Cis) -6- aldehyde radical -2,2- dimethyl -1,3- dioxane -4- tert-butyl acetate in hydrogen
Change the lower reaction of sodium catalysis and obtains Pitavastatin Calcium intermediate;Wherein, substance A, substance B, Pitavastatin Calcium intermediate structural formula
It is as follows:
2. the synthetic method of Pitavastatin Calcium intermediate according to claim 1, which is characterized in that oxidant is four water molybdic acids
One of the mixture of ammonium and hydrogen peroxide, metachloroperbenzoic acid.
3. the synthetic method of Pitavastatin Calcium intermediate according to claim 1 or claim 2, which is characterized in that prepare the anti-of substance A
Answering solvent is alcohols solvent.
4. the synthetic method of any one of -3 Pitavastatin Calcium intermediates according to claim 1, which is characterized in that prepare substance
The reaction dissolvent of A is at least one of methanol, ethyl alcohol, isopropanol, n-butanol.
5. the synthetic method of any one of -4 Pitavastatin Calcium intermediates according to claim 1, which is characterized in that prepare substance
The reaction temperature of A is 10-50 DEG C;Preferably, the reaction time for preparing substance A is 12-18h.
6. the synthetic method of any one of -5 Pitavastatin Calcium intermediates according to claim 1, which is characterized in that prepare substance
The reaction temperature of B is room temperature;Preferably, the reaction time for preparing substance B is 24-30h.
7. the synthetic method of any one of -6 Pitavastatin Calcium intermediates according to claim 1, which is characterized in that preparation is cut down
The reaction dissolvent of statin calcium intermediate is tetrahydrofuran;Preferably, prepare Pitavastatin Calcium intermediate reaction temperature be -60 to
0℃;Preferably, the reaction time for preparing Pitavastatin Calcium intermediate is 12-24h.
8. the synthetic method of any one of -7 Pitavastatin Calcium intermediates according to claim 1, which is characterized in that 2- cyclopropyl
Base -4- (4- fluorophenyl) quinoline -3- bromomethyl, tri-thiol s-triazine, sodium hydroxide molar ratio be 3-3.5:1:3.3-4.5.
9. the synthetic method of any one of -8 Pitavastatin Calcium intermediates according to claim 1, which is characterized in that work as oxidant
When for the mixture of ammonium molybdate tetrahydrate and hydrogen peroxide, substance A, ammonium molybdate tetrahydrate, hydrogen peroxide molar ratio 1:0.15:12-
18;Preferably, when oxidant is metachloroperbenzoic acid, the molar ratio of substance A and metachloroperbenzoic acid is 1:12-18.
10. the synthetic method of any one of -9 Pitavastatin Calcium intermediates according to claim 1, which is characterized in that substance B with
The molar ratio of sodium hydride is 1:3.6-6;Preferably, substance B and (4R-Cis) -6- aldehyde radical -2,2- dimethyl -1,3- dioxy six
The molar ratio of ring -4- tert-butyl acetate is 1:3.15-4.5.
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