+

WO2003066614A1 - Epoxydation asymetrique d'olefines deficientes en electrons - Google Patents

Epoxydation asymetrique d'olefines deficientes en electrons Download PDF

Info

Publication number
WO2003066614A1
WO2003066614A1 PCT/US2003/003147 US0303147W WO03066614A1 WO 2003066614 A1 WO2003066614 A1 WO 2003066614A1 US 0303147 W US0303147 W US 0303147W WO 03066614 A1 WO03066614 A1 WO 03066614A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
olefin
protecting group
ketone
epoxide
Prior art date
Application number
PCT/US2003/003147
Other languages
English (en)
Inventor
Yian Shi
Original Assignee
Colorado State University Research Foundation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Colorado State University Research Foundation filed Critical Colorado State University Research Foundation
Priority to AU2003219702A priority Critical patent/AU2003219702A1/en
Publication of WO2003066614A1 publication Critical patent/WO2003066614A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D301/00—Preparation of oxiranes
    • C07D301/02—Synthesis of the oxirane ring
    • C07D301/03—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds
    • C07D301/14—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds with organic peracids, or salts, anhydrides or esters thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/10—Spiro-condensed systems

Definitions

  • the present invention is directed to a method for enantioselectively epoxidizing olefms having at least one electron withdrawing group attached to the olefmic moiety.
  • Chiral epoxides having at least an electron withdrawing group attached to the epoxide carbon are useful intermediates for the synthesis of a variety of enantiomerically enriched or enantiomerically pure complex molecules, including therapeutically useful compounds.
  • asymmetric epoxidation of electron deficient olefins presents an attractive strategy for the synthesis of optically active corresponding epoxides, for example, producing glycidic esters from , ⁇ -unsaturated esters.
  • One aspect of the present invention provides a method for producing an enantiomerically enriched epoxide from an electron deficient olefin, said method comprising admixing the olefin, an enantiomerically enriched chiral ketone, and an oxidizing agent under conditions sufficient to produce the enantiomeric enriched epoxide, wherein the yield and the enantiomeric excess of the epoxide is at least about 50% and at least about 80%, respectively.
  • the electron deficient olefin is selected from the group consisting of an ⁇ , ⁇ -unsaturated ester, an ⁇ , ⁇ -unsaturated ketone, a vinyl sulfone compound, a vinyl nitrile compound, and a vinyl nitro compound. More preferably, the electron deficient olefin is an ⁇ , ⁇ -unsaturated ester.
  • the chiral ketone is a cyclic chiral ketone of the formula:
  • bonds a, b and c are any combination of cis- or trans-configuration relative to one another;
  • X is hydrogen, halide, or alkoxide
  • Y is -OR 1 , hydrogen, or halide
  • R 1 is selected from the group consisting of a carboxyl group, carbamate, carbonate, alkyl, and other hydroxy protecting group
  • R 2 is selected from the group consisting of a carboxyl group, carbamate group and a carbonate group
  • each of R 3 and R 4 is independently a hydroxy protecting group or R 3 and R 4 together form a diol protecting group.
  • Another aspect of the present invention provides, a method for producing an enantiomerically enriched ⁇ , ⁇ -epoxy ester comprising admixing an ⁇ , ⁇ -unsaturated ester, an enantiomerically enriched cyclic chiral ketone, and an oxidizing agent under conditions sufficient to produce the ⁇ , ⁇ -epoxy ester at a yield of at least 50%.
  • the enantiomeric excess of the cyclic chiral ketone is at least about
  • bonds a, b and c are any combination of cis- or trans-configuration relative to one another;
  • X is hydrogen, halide, or alkoxide;
  • Y is -OR 1 , hydrogen, or halide;
  • R 1 is selected from the group consisting of a carboxyl group, carbamate, carbonate, alkyl, and other hydroxy protecting group;
  • R 2 is selected from the group consisting of a carboxyl group, carbamate group and a carbonate group; and each of R 3 and R 4 is independently a hydroxy protecting group or R 3 and R 4 together form a diol protecting group.
  • compound of Formula II is of the formula:
  • R 1 , R 2 , R 3 , R 4 , a, b, and c are those defined herein.
  • R 1 and R 2 are independently a carboxyl group.
  • R 3 and R 4 together form a diol protecting group.
  • chiral ketone of Formula II is of the formula:
  • electron withdrawing group refers to a moiety whose electronegativity increases the nucleophilic attack of the olefinic moiety to which it is attached to.
  • the electron withdrawing group comprises an unsaturation which is conjugated with the olefinic moiety.
  • Exemplary preferred electron withdrawing groups include esters, ketone, sulfone, nitrile, and nitro. More preferably, the electron withdrawing group is an ester.
  • esters and “ester group” are used interchangeably herein and refer to a moiety of the formula -CO 2 R, where R is optionally substituted alicyclic, cyclic, aliphatic, aromatic hydrocarbon moiety or a combination thereof comprising at least one carbon atom.
  • the present invention provides a method for producing an enantiomerically enriched epoxide from an electron deficient olefin.
  • Methods of the present invention can also be used for kinetic resolution of the electron deficient olefins.
  • the method generally involves converting one of the stereoisomer of the electron deficient olefin to an epoxide at a higher rate than the other isomer, which results in a relative enrichment of the other stereoisomer.
  • enrichment and “relative enrichment” are used herein interchangeably to describe an increase of one stereoisomer relative to the other. It should be appreciated that enrichment of an electron deficient olefin is a result of a decrease in the amount of one stereoisomer by conversion to an epoxide. Olefin
  • an "electron deficient olefin” refers to an olefin having at least one electron withdrawing group bonded directly to the olefinic moiety.
  • the olefin is an ⁇ , ⁇ -unsaturated ester, i.e., where at least one of R a , R b , R c and R d
  • the initial concentration of the olefin is from about 0.001 mole/liter
  • Methods of the present invention generally comprises admixing the olefin, an enantiomerically enriched chiral ketone, and an oxidizing agent under conditions sufficient to produce the enantiomeric enriched epoxide.
  • asymmetric epoxidation of the present invention can be performed in a variety of different sequences.
  • the addition sequences of the olefin, the chiral ketone, and the oxidizing agent can be interchanged.
  • the oxidizing agent is added to a reaction mixture comprising the chiral ketone and the olefin.
  • a reverse-addition technique can also be used depending upon the reactivity of each component.
  • contacting an oxidizing agent with a chiral ketone produces a chiral dioxirane, which is believed to be the active species in generating the epoxide from the olefin.
  • the chiral dioxirane is generated and used in situ by contacting (i.e., reacting) a chiral ketone with an oxidizing agent in the presence of the olefin.
  • the actual epoxidizing agent e.g., dioxirane
  • the chiral ketone and the olefin may be generated in a separate reaction prior to contacting with an olefin, it is more advantageous to combine the chiral ketone and the olefin in a single reaction mixture and generate the dioxirane in situ by adding an oxidizing agent to the reaction mixture.
  • the present invention is described in reference to dioxirane as being the actual epoxidizing agent, the scope of the present invention is not limited to such. Generally, any reactive species which stereoselectively generates the epoxide from the reaction mixture provided herein is within the scope of the present invention. However, for brevity and consistancy throughout this disclosure, the reactive species is described as being a dioxirane of the chiral ketone.
  • the ketones of the present invention have a turn-over number of at least about 3, more preferably at least about 50 and most preferably at least about 100. Moreover, since the ketones have such a high turn-over number, the amount of the ketones required to epoxidize a given amount of olefin can be less than the stoichiometric amount, i.e., one equivalent, of the olefin. Preferably no more than about 0.3 equivalents of ketone is used to epoxidize olefins, more preferably no more than about 0.05 equivalents, and most preferably no more than about 0.01 equivalents.
  • the chiral ketone is a cyclic chiral ketone.
  • the cyclic chiral ketone is of the formula:
  • bonds a, b and c are any combination of cis- or trans-configuration relative to one another;
  • X is hydrogen, halide, or alkoxide;
  • Y is -OR 1 , hydrogen, or halide;
  • R 1 is selected from the group consisting of a carboxyl group, carbamate, carbonate, alkyl, and other hydroxy protecting group;
  • R 2 is selected from the group consisting of a carboxyl group, carbamate group and a carbonate group; and each of R 3 and R 4 is independently a hydroxy protecting group or R 3 and R 4 together form a diol protecting group.
  • Suitable hydroxy protecting groups are well known to one skilled in the art.
  • R 3 and R 4 together form a dial protecting group.
  • diol protection groups are well l ⁇ iown to one skilled in the art. See, for example, Protective Groups in Organic Synthesis, 3rd edition, T.W. Greene and P.G.M. Wuts, John Wiley & Sons, New York, 1999, pp.
  • bonds a, b, and c can be any combination of cis- or trans-configuration relative to one another.
  • bonds a and b are of cis-configuration relative to each other.
  • bonds a, b and c are of cis-configuration relative to each other.
  • One of the advantages of the present invention is availability of relatively inexpensive starting materials for producing chiral ketones.
  • chiral ketones of Formula I can be synthesized in high overall yield from readily available carbohydrates, such as fructose and sorbose.
  • Formula I is derived from a carbohydrate.
  • the chiral ketone is derived from an oxidation of an unprotected hydroxy group of a carbohydrate compound having at least one protected hydroxy group.
  • the protecting groups for protected hydroxy groups are selected from the group consisting of silyl ethers, ethers, acetals, ketals, esters, ortho esters, sulfonates, phosphates and mixtures thereof.
  • the protecting groups for two or more hydroxy groups of the carbohydrate or its derivative can be interconnected. For example, an acetonide group protecting 4,5-hydroxy groups of fructose can be considered to be "two interconnected acetal protecting groups" since they protect two hydroxy groups on the fructose.
  • oxidation of a hydroxy group of a carbohydrate to form a carbonyl group is well known to one skilled in the art. See Mio et al. Tetrahedron 1991, 47, 2133-2144.
  • pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), Swern oxidation condition or other oxidizing conditions can be used to oxidize a hydroxy group of a carbohydrate or its derivative to a ketone compound of the present invention.
  • the carbohydrate is selected from the group consisting of fructose, sorbose, arabinose, mannose, and glucose.
  • the carbohydrate is selected from the group consisting of (D)-fructose, (L)- fructose, (L)-sorbose, (L)-arabinose, and (D)-arabinose.
  • the oxidizing agent is added as a solution or a solid to the reaction mixture comprising the chiral ketone and the olefin.
  • the chiral ketone can be used in an amount less than the stoichiometric amount relative to the amount of the olefin. It should be appreciated that in situ generation of dioxirane from a ketone generally requires the oxidizing agent to be more reactive towards the ketone than the olefin to avoid competing oxidation of olefin by the oxidizing agent.
  • the amount of ketone used is at least about 3 times more than the amount olefin, more preferably at least about 5 times, and most preferably at least about 10 times.
  • the initial concentration of the oxidizing agent is from about 0.1 M to about 1 M, more preferably from about 0.2 M to about 0.5 M.
  • the rate of addition of the oxidizing agent to the reaction mixture will vary depending on a various factors, such as the reaction temperature, the size of the reaction, and the olefin substrates.
  • any oxidizing agent capable of providing dioxiranes from a corresponding ketone can be used in the present invention.
  • a relatively inexpensive oxidizing agents such as peracids, hydrogen peroxide, sodium hypochlorite, peroxomonosulfate (e.g., potassium peroxomonosulfate), sodium perborate and hypofluoride (HOF) are preferred.
  • Non-organic oxidizing agents i.e., a compound that does not contain any carbon atom
  • the amount of oxidizing agent used in the present invention depends on a variety of factors including the reactivity of the ketone, olefin, and the decomposition rate of ⁇ the oxidizing agent. Typically, the amount of an oxidizing agent used is at least about 1 times the amount of the ketone, preferably at least about 9 times, and more preferably at least about 100 times. In another embodiment of the present invention, the amount of an oxidizing agent used is less than about 10 times the amount of the olefin, and more preferably less than about 3 times. However, it should be appreciated that the present invention is not limited to these particular amounts of the oxidizing agent.
  • the oxidizing agent is potassium peroxomonosulfate.
  • oxidizing agent any suitable oxidizing agents known to one skilled in the art can be used.
  • suitable oxidizing agents include, but are not limited to, peracids (e.g., mCPBA), hydrogen peroxide and a mixture of hydrogen peroxide and a nitrile compound.
  • a longer reaction period generally provides higher yield of the epoxide.
  • reaction time is from about 5 h to about 48 h, preferably from about 10 h to about 36 h, and more preferably from about 20 h to about 30 h.
  • the present invention is not limited to these particular reaction times.
  • methods of the present invention can also comprise adjusting the pH of the reaction mixture.
  • the useful pH range is broad. Typically, however, the pH is preferably at least about pH 5. Because the pH can fluctuate during the course of reaction, the reaction pH referred to herein refers to an apparent pH.
  • the pH of the reaction is from about pH 5 to about pH 14, more preferably from about pH 5 to about pH 10, and most preferably from about pH 7 to about pH 9.
  • the pH of the reaction solution can be conveniently achieved by adding sufficient amount of base to maintain the pH at the desired level. The base can be added separately, it can be added to the solution containing the ketone, or it can be added to the solution containing the oxidizing agent.
  • a solid mixture of the base and oxidizing agent can be added to the reaction mixture.
  • a base is used to control the reaction pH, preferably the base is selected from the group consisting of hydroxides, carbonates, bicarbonates, borates and phosphates.
  • the base is selected from the group consisting of potassium carbonate, potassium bicarbonate, lithium carbonate, lithium bicarbonate, sodium carbonate, sodium bicarbonate, calcium carbonate, sodium borate, sodium phosphate, potassium phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide and calcium hydroxide, most preferably the base is selected from the group consisting of potassium carbonate, potassium bicarbonate, sodium bicarbonate, sodium carbonate, sodium hydroxide, sodium borate, sodium phosphate, potassium phosphate and potassium hydroxide.
  • the desire pH of the reaction can be more easily maintained by using a buffer solution.
  • solvent system Another factor that can determine the yield of the epoxide and/or enantioselectivity of the reaction is the solvent system used.
  • any relatively inert organic solvent can be used for the present invention.
  • Exemplary solvents include, nitriles such as acetonitrile and propionitrile, dimethoxymethane (DMM), dimethoxyethane (DME), ethers such as tetrahydrofuran (THF), dichloromethane, chloroform, ethyl acetate, hexane, benzene, toluene, xylenes, dioxane, dimethyl formamide (DMF), pentane, alcohols including, but not limited to, methanol, ethanol and t-propyl alcohol, and mixtures thereof.
  • the solvent is selected from the group consisting of acetonitrile,
  • the temperature of the reaction can also affect the yield of the reaction and enantioselectivity of the epoxide. Generally, a lower reaction temperature requires a longer reaction time but results in higher enantioselectivity.
  • the reaction temperature is about 50 °C or less, more preferably about 30 °C or less, and most preferably from about 0 °C to about room temperature.
  • the scope of the present invention is not limited to these particular reaction temperatures.
  • methods of the present invention results in the yield of the epoxide being at least about 50%, more preferably at least about 60% and most preferably at least about 70%.
  • the enantiomeric excess of the resulting epoxide is at least about
  • the enantiomeric excess of the resulting epoxide is at least about 80%, more preferably at least about 85%, and most preferably at least about 90%.
  • combinations of the preferred embodiments of any particular characteristics or properties described herein form other preferred embodiments.
  • methods of the present invention provides an enantiomerically enriched epoxide at a yield of at least about 50%) and enantiomeric excess of at least about 80%.
  • epoxides were purified by flash chromatography and gave satisfactory spectroscopic characterization. c. 0.30 eq. Ketone used. d. 0.25 eq. ketone used. e. 0.20 eq. ketone used.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Epoxy Compounds (AREA)

Abstract

L'invention concerne un procédé d'époxydation énantiosélective d'oléfines déficientes en électrons, telles que des esters α,β-non saturés. Ce procédé consiste à mélanger l'oléfine déficiente en électrons, un cétone chiral énantiomériquement enrichi, et un agent oxydant dans des conditions suffisantes à produire un époxyde énantiomériquement enrichi.
PCT/US2003/003147 2002-02-04 2003-01-29 Epoxydation asymetrique d'olefines deficientes en electrons WO2003066614A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003219702A AU2003219702A1 (en) 2002-02-04 2003-01-29 Asymmetric epoxidation of electron deficient olefins

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US35440002P 2002-02-04 2002-02-04
US60/354,400 2002-02-04

Publications (1)

Publication Number Publication Date
WO2003066614A1 true WO2003066614A1 (fr) 2003-08-14

Family

ID=27734369

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2003/003147 WO2003066614A1 (fr) 2002-02-04 2003-01-29 Epoxydation asymetrique d'olefines deficientes en electrons

Country Status (2)

Country Link
AU (1) AU2003219702A1 (fr)
WO (1) WO2003066614A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1770095A1 (fr) * 2005-09-26 2007-04-04 Institut Catala D'Investigacio Quimica Catalyseurs efficaces pour l'epoxydation asymetrique d'olefines deficientes en electrons ainsi que d'olefines non deficientes en electrons
EP1770094A1 (fr) * 2005-09-26 2007-04-04 Institut Catala D'Investigacio Quimica Synthese efficace d'un cata lyseur d'epoxydation asymetrique
WO2012167406A1 (fr) * 2011-06-10 2012-12-13 中国科学院化学研究所 Procédé de préparation d'ambrisentan (+)- et de darusentan (+)- optiquement purs

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998015544A1 (fr) * 1996-10-08 1998-04-16 Colorado State University Research Foundation Epoxydation asymetrique catalytique

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998015544A1 (fr) * 1996-10-08 1998-04-16 Colorado State University Research Foundation Epoxydation asymetrique catalytique

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE HCAPLUS [online] (COLUMBUS, OH, USA); YANG ET AL.: "Novel cyclic ketones for catalytis oxidation reactions", XP002965416, accession no. STN Database accession no. 1998-748088 *
J. ORG. CHEM., vol. 63, no. 26, 1998, pages 9888 - 9894 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1770095A1 (fr) * 2005-09-26 2007-04-04 Institut Catala D'Investigacio Quimica Catalyseurs efficaces pour l'epoxydation asymetrique d'olefines deficientes en electrons ainsi que d'olefines non deficientes en electrons
EP1770094A1 (fr) * 2005-09-26 2007-04-04 Institut Catala D'Investigacio Quimica Synthese efficace d'un cata lyseur d'epoxydation asymetrique
WO2007039492A1 (fr) * 2005-09-26 2007-04-12 Institut Català D'investigació Química (Iciq) Synthese efficace d'un catalyseur i d'epoxydation asymetrique
WO2007039493A1 (fr) * 2005-09-26 2007-04-12 Intitut Català D'investigació Química (Iciq) Catalyseur efficace destine a l'epoxydation asymetrique d'alcenes deficients ou non deficients en electrons
WO2012167406A1 (fr) * 2011-06-10 2012-12-13 中国科学院化学研究所 Procédé de préparation d'ambrisentan (+)- et de darusentan (+)- optiquement purs
US9040698B2 (en) 2011-06-10 2015-05-26 Institute Of Chemistry Chinese Academy Of Sciences Method for preparing optically pure (+)-ambrisentan and (+)-darusentan

Also Published As

Publication number Publication date
AU2003219702A1 (en) 2003-09-02

Similar Documents

Publication Publication Date Title
US6348608B1 (en) Catalytic asymmetric epoxidation
WO2003066614A1 (fr) Epoxydation asymetrique d'olefines deficientes en electrons
Asami et al. A concise asymmetric synthesis of (−)-untenone A
US6369245B1 (en) Epoxidation of olefins
US6409769B1 (en) Kinetic resolution of olefins
US6686483B2 (en) Catalytic asymmetric epoxidation
US6600062B2 (en) Preparation of chiral 6,7-dihydroxy geranyloxy compounds
EP1647551B1 (fr) Derive d'halohydrine optiquement actif et procede de fabrication d'un derive d'epoxy-alcool optiquement actif a partir de celui-ci
WO2007039492A1 (fr) Synthese efficace d'un catalyseur i d'epoxydation asymetrique
US5157131A (en) Epoxides and a process for their preparation
Zhu et al. Template effect of Pd (II) in the synthesis of differently substituted enantiopure γ-butyrolactones and its synthetic applications
US20040039209A1 (en) Compounds containing oxazolidinone moiety and uses thereof
Sharma et al. p-Methoxybenzyl trityl ether (p-MBTE): a new and improved tritylating reagent
US5175373A (en) Process for preparing cyclocitral
WO2007000329A2 (fr) Epoxydation de cetones $g(a),$g(b)-insaturees
WO2007039493A1 (fr) Catalyseur efficace destine a l'epoxydation asymetrique d'alcenes deficients ou non deficients en electrons
Wu Synthetic Studies on Phorboxazole Tail Domain and Amphidinolide C
Farah Chiral iminium salts as catalysts for asymmetric epoxidation
OH 3.1 Chiral Ketone-Catalyzed Epoxidation 3.1. 1 Early ketones
Albury Total syntheses of (-)-cryptocaryolone and (-)-cryptocaryolone diacetate, progress towards the total syntheses of (±)-sinensigenin A and C and the development of a novel electrophilic allylsilane methodology
JP2007031353A (ja) ３−オキサ−７−オキサ（又はチア）トリシクロ［４．２．１．０４，８］ノナン−２−オン誘導体
KR20040070361A (ko) 황산 망간 (ⅱ) 촉매를 사용한 라세믹 인덴 옥시드의 제조 방법.

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SC SD SE SG SK SL TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载