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    • 专利摘要:
    32AbstractThe present âenveniien reåetee to e methed for preperatšen ef hetuššnše acšcš frembetušin. The methedi cempršeee exidizšng betuiin te betuišnic endfer hetuienšeaådehyde with e ruthenšurn basen eetaiyst eeteiyzed nxådeïšnn preeess in the presence of en exšáent, and further cenvening thebetuiinše endíer betuienieeidehyde te betuâšnšc acid.
    公开号:SE1150818A1
    申请号:SE1150818
    申请日:2011-09-12
    公开日:2013-03-13
    发明作者:Jukka Tulisalo；Niko Wickholm；Minni Pirttimaa；Sami Alakurtti；Jari Yli-Kauhauluoma；Salme Koskimies
    申请人:Stora Enso Oyj；
    IPC主号:
    专利说明:

    A method to derivatize wood chernicai component Fieid of the inventionThe invention reiates to cataiytic, environmentaiiy benign oxidation ot betuiin ieading to Synthesis of betuiinic acid.
    State ot the art Betuiin having the structure 'i shown beiow is naturaiiy occurring pentaoyciicterpene aicohoi ot iupine tamiiy, aiso known as betuiinoi and iup-20(29)-eeni~3ß,28-dioi. Betuiin is found in the bark oi some tree species, particuiariy in thebirch (Betala sp.) bark at best amounts up to 40% ot the birch outer bark dryweight. in addition to betuiin, aiso minor amounts ot betuiin derivatives are ob-tained trom tree bark. There are known methods mainiy based on extraction tor isoiation of betuiin trorn bark rnateriai. in some appiications, poor soiubiiity of betuiin causes probiems in respect touse and iormuiation, and accordingiy, betuiin is converted to its derivatives toimprove soiubiiity as weii as bioactivity. in the production of said derivatives,reactivities ot the tunctionai groups ot betuiin, that is, primary and secondarygroups and the doubie bond are typicaiiy utilized. Especiaiiy betuiinic acid and betuionic acid seem to posses high bioactivities in severai appiications.
    Suitabiiity of betuiin and the derivatives thereot tor medicai and cosmetic appii- cations and tor industriai chemical appiications is known to some extent. Use 2 of betuiinic acid in oosmetic appiications such as oromoters of growth and ascomponents in skin creams is known from WO 66103749. The oubiication ofWO 61174327 discioses the use of betuiinic acid in sun crearns for preventionof detrimentai effects of the tJV-iight. The pubiication of WG 2ÛÜ7ift4i389 dis-5 oioses the use of betuionic acid in severai cosmetic appiications. The pubiica-tion of WG 2OG7it4i383 discioses the use of betuiinic and betuionic acid as antifeedant agent for best management.
    Betuiinic acid having the structure of 3 shown in the scheme 'i beiow may be1G isoiated eg. from birch (Betala sp.) bark or cork of cork oak (Quercus sober L.)by extraction, and further may be produced by severai methods mainiy basedon direct oxidation of the betuiin or birch bark rnateriai. The reaction schemebeiow shows the direct oxidation of the betuiin *i according to US 5804575 as.Jones oxidation in the presence of chrorniumüli) oxide cataiyst to give betuiori-15 ic acid 2, toiiowed by the seiective reduction of betuionic acid 2 thus obtained to give betuiinic acid 3. w “'"¿>“***'*"., Jones oxidation _'“¿°**""&t.«-^'¿^~ fis ÜTÛ; __.«*“3“'~« NaBHti - j Perser: n ~ i i i Trix-ratar --»-----»gg sxä%f_,,-f;c sketcher THFi i .i . .j.tro i 2 Schema t. Oxidation of betuiin according to US 5504575, 2G The probiein with the above method is that chromium (Vi) oxide cataiyst is car- cinogenic and the reaction cumuiates aiso iarge arnounts of waste. 2.0 An aiternative process for the production of betuiinio acid is disciosed in US2GÛQ/0O76290 A1. The process shown heiow (scherne 2) inciudes contactinghetuiin with a oontposition that inciudes: a contpound of formuia ai dihydrogenpotassiuni phosphate (KHZPOQ and diiuted bieach with sodium chiorite (NaC-562) for a period of time effective to provide betuiinic aidehyde. Betuiinio aide-hyde is further oxidized to betuiinic acid with sodium ohiorite (NaCEGZ) in thepresence of dihydrogen potassium phosphate (KiigPOx). Üts .w ___. ., . .dt-f,,,,,,,, e* “xíumw üi k” 1 i ;> reco; transport K iftißPüi « i Schema 2. Cataiytio oxidation of betuiin according to US ZÜGQIGGÉZQG.
    The probiem with the above method is that the reaction time is long in the oxi-dation of hetuiin to ioetuiinio aidehyde and the vieid of betuiinic aidehyde is notvery high.
    An aiternative process for the production of hetuiinic acid is disciosed in US5,804,575, cornprising an oxidation step where S-heta-hydroxyi of hetuiin isprotected by acetyiation. isornerization and oxidation of secondary hydroxyi group of betuiin is thus prevented.
    The objects of the inventionQne object of the present invention is to deveiop environmentaiiy benign cata-iytio method for oxidation of betuiin to betuiinic andfor betuionic aidehyde, and further converting the hetulinic and/or betuionic aidehyde to hetuiinic acid. 1G 2G 3G 4 Another object of the present invention is to develop an oxidation process foroxidation of betuiin to betuiinic and/or loetuionic aldehyde, and further convert-ing the betulinic and/or betulonic aldehyde to betuiinic acid with a good yieid and effective Conversion.
    Another object of the present invention is to develop an oxidation process foroxidation of betuiin to betuiinic and/or betulonic aidehyde, with cataiyst andoxidant that are readily avaiiable and relatively cost effective, and further con- veiting the betulinic and/or betulonic aldehyde to betulinic acid.
    Another object of the present invention is to develop a synthesizing method for betuiinic acid which would require as few process stages as possible. ÛescriptionThe above mentioned objects can be achieved by the methods according to ciairns 'i and 16.
    When trying to solve problems related to prior art, the inventors have nowfound that in contrast to existing methods the present invention introduces amethod for oxidizing betuiin to betuilnic andlor betulonic aldehyde in an envi-ronmenteily benign catalytic method with a good yield and effective conver-sion, and further converting the hetuiinlc andior betulonic aidehyde to betuiinic acid.
    The invention is based on the idea that betulin is oxidized to betulinic and/orbetuionic aidehyde with a catalyst that is environmentally friendiy, compared tofor example chronfiiumCx/i) oxide, in the presence of an oxidant, and further converting betulinic andior betulonic aldehyde to betuiinic acid.
    The method according to the present invention relates more precisely to a rne-thod according to claim t. in said method betulinic acid is prepared from betulin by a process comprising oxidizing betuiin to betulinic aldehyde with a 2G 5 rutheniurn based cataiyst in the presence of an oxidant and further oxidizing the hetuiinic aidehyde to betuiinic acid.
    Furthermore, the method according to the present invention reiates more pre-ciseiy to a method according to ciairn 16. in said method betuiinic acid is pre-pared from petuiin hy a process comprisihg oxidizing hetuiin to hetuionic aide-hyde with a ruthehium based Catalyst in the presence of an oxidant. The betu-ionic aidehyde is oxidized to hetuiohic acid and the betuionic acid is reduced to hetuiinic acid The present invention provides an environntentaiiy benign cataiytic method foroxidation of betuiin to ioetuiinic andlor betuionic aidehyde and further convert-ing the betuiinic ahdlor betuionic aidehyde to hetuiinic acid. in the oxidation ofioetuiin to hetuiinic and/or betuionic aidehyde the cataiyst and the oxidant areenvironmentaiiy friendiy, compared to for exampie chrorniurnCi/i) oxide cataiystwhich is carcinogenic. Üue to a seiective conversion and the possibiiity to re-generate the rutheniurn based cataiyst the reaction is environmentaiiy benign.Furthermore, the cataiyst and the oxidant of the present invention are readiiy avaiiapie and relativeiy cost effective.
    The present invention aiso provides an oxidation process tor oxidation of betu-iin to hetuiinic andfor betuionic aidehyde and further converting the betuiinicand/'or betuionic aidehyde to betuiinic acid with a good yieid and effective con- version.
    The ciaimed methods reiates to preparation of hetuiinic acid from ioetuiin char-acterized in that the method comprises oxidizing hetuiin to hetuiinic andlor oe-tuionic aidehyde with ruthenium based catatyst cataiyzed oxidation process inthe presence of an oxidant and further converting the betuiinic and/or betuionic aidehyde to betuiinic acid.
    The cataiytic oxidation of hetuiin to hetuiinic aidehyde and further to betuiinic acid according to present invention proceeds according to schema 3. Oxida- 2G 6 tion of betuiin to betuiinio aidehyde (reaction i) is performed in the presence ofruthenium based oataiyst and an oxidant. Qptionaiiy a oocataiyst can be pre-sent in the oxidation of betuiin to betuiinio aidehyde. Oxidation of betuiinic al-dehyde to betuiinio aoid (reaction ti) oan ioe performed by any method known from the iiterature. - .., «__.~,titazsziwdw.
    Schema år Cataiytio oxidation of betuiin to betuiinic aidehyde and further to betuiinio acid according to present invention.
    Oxidation of ioetuiin to betuiinio aidehyde is performed in the presence of ru-thenium based cataiyst. The ruthenium based cataiyst can be any ruthenium based oataiyst that is oapabie of oataiyzing the oxidation reaction. in one embodiment of the present invention said ruthenium based oataiyst is represented by the formuia RumLmfig wherein Ru is ruthenium, i_ represents iigand, m is integer t, 2 or 3 and n is in-teger from O, 1, 2, 3, 4, 5 or 6. That is, one ruthenium moieouie oan have maximum of six iigands.
    The iigand(s) of the ruthenium based oataiyst are seieoted so that the ruthe-nium based oataiyst is oapaioie of oataiyzing the oxidation reaction of betuiin to betuiinic aidehyde. The iigand(s) can he monodentate andior poiydentate.
    St) 7 Exanipies ot mcncdentate iigands are, but not limited to, H20, RQi-i, NRs,RCN, OH", GQH, RS", RO", RCOO", OCN", SCN", Ng", CN] F", Ci", Br, i', 02",N63", N92] Sßf, S932", POÉ", organic phcsphates, organic phosphonates,organic suifates, organic suifonates, and arornatic N donors such as pyridines,pyrazines, pyrazoies, imidazoies, benziniidazoies, pyrirnidines, triazoies andthiazoies, With R being H, optionaiiy substituted aikyi or optionaiiy substitutedaryi. Specific exarnpies of rnonodentate iigands are phenoiate, acetate and theiike.
    Exampies of poiydentate iigands are, but not iirnited to, Sohiff base iigands andrnacrcpctycyciic rigid iigands. Specific exarnpies ot Schift base iigands are dis-ciosed for exanipie in publication Viswanathamurthi P, Karvernbu R, V Thera-neeswaran V, Natarajan K, J. Chem. Soi., 117, 235~238. Specific exampies otrnacropoiycyciic rigid iigands are discicsed tor exampie in pubiicationUS 2003/Gt7941 Ai. Another specific exarnpie of poiydentate iigands areN,NïEthyienebis(saiicyiirnine) (saien iigand, having CAS number 94-93-9) and its derivatives.
    Another exampies of the ruthenium based cataiyst are rutheniumfli) corn-pcunds or rutheniumNii) compounds. The Roman nunnerai in the parenthesisrefers to oxidation number of ruthenium. A specific exampie ot rutheniumfii)compound is dichiorotrisüriphenyiphosphine)rutheniunt(ii) (RUCEgPPhQS). Arutheniurritvii) propyianirnoniurnperruthenate (TPAP). specific exarnpie of compound is tetra-n- Oxidation of betuiin to betuiinic aidehyde is carried out in the presence of anoxidant. The oxidant shcuid be capabie of oxidizing the primary aicohoi ct be-tuiin in the presence of the rutheniurn based cataiyst. Exarnpies of suitabieoxidants are, but not iirnited to, dioxygen, N-rriethyimorphoiine-N-oxide (NMO)and sodiurnhypochiorite (NaQCi), sodium chiorite (NaCiOZ), potassiurn chiorite(KßiOgi potassiuni hypochicrite (KCCE), peroxides such as hydrogen peroxide(Hgüg), hypervaient iodine reagents (eg. â-iodoxybenzoic acid (EBX), 2-iodoxybenzenesuifonic (iBS)), Oxone (ZKHSO5, KHSOLi, KgâÛt) and phthaii- 3G 8 rnides such as N-hydroxyphthaiimide, and mixtures thereot. Dioxygen meanshere G2, which is present in atrnosphere, or 02, which has about the same ac-tivity as G2 present in atrnosphere. Preterabiy the oxidant is dioxygen originat-ing from atmospheric oxygen. Qxygen dissoiving to soivent system during the oxidation process can be taciiitated by stirring.
    The oxidation of betuiin to betuiinic aidehyde can be carried out in a soivent ormixture ot soivents. Many common organic soivents and soivent combinationscan be chosen and appiied. The soivent is seiected so that betuiin is soiubietherein. in a preferred ernbodirnent the soivent is an inert soivent, that is, itdoes not react essentiaiiy with betuiin or its derivatives or reactants. Exampiesof such inert soivents are aromatic hydrocarbons, saturated or unsaturated aii-phatic hydrocarbons, branched or unbranched aiiphatio hydrocarbons, ethers,haiogenated aiiphatic hydrocarbons, fiuorous soivents, esters, ketones, H20and rnixtures thereot. ivtost preterabiy the soivent is dichioromethane (CHZCEZ),(Dir/iF), (THF), (DMSÜ), pertiuoroaikane, toiuene, xyiene or mixtures thereot. dimethyitormamide tetrahydroturane dimethyi suitoxide By controiiing the temperature of oxidation ot betuiin to betuiinic aidehyde re-action time, Conversion and side reactions can be aftected. At very iow tem-peratures conversion is poor and reaction times are Hong. At very high tem-peratures the oxidation process is ditficuit to controi and more side reactionstake piace. The temperature during the oxidation ot betuiin to betuiinic aide-hyde with is from about O to about 150 °C, preferabiy trom about Û to about130 °C.
    Pressure can be optionaiiy appiied to the oxidation ot betuiin to betuiinic alde-hyde. By appiying pressure the oxidation occurs faster and with better conver-sion. The oxidation of betuiin to betuiinic aidehyde can be carried out underpressure at from about i to about 5G bar, preterabiy at about from i to about15 bar. 9 in the method of the present invention oxidation ot betuiin to betuiinio aldehydecan be affeoted by varying arnounts of the ruthenium based oataiyst. By in-creasing the amount of the ruthenium based oataiyst the yieid and Conversioninoreases. The amount of the rutheniurn based oataiyst in the oxidation reac- tion can be about i to about 30 moie percent, reiative to the betuiin.
    Optionaiiy a oooataiyst can be present in the oxidation of betuiin to betuiinio ai-dehyde. The optionai oooataiyst inoreases the yieid and oonversion. The op- tionai oooataiyst is represented by the formuia (5) :s Û .'\xfiå» f"'°v « _w “ri f"f” i w, \,2,! wherein each of R* and RE is independentiy hydrogen, aikyi, aikenyi, aikoxy,haio, haioaikyi, hydroxy, hydroxyaikyi, aryi, heteroaryi, heterooyoie, oyoioaikyi,aikanoyi, aikoxycarbonyi, arnino, irnino, aikyiantino, aoyiamino, nitro, trifiuoro-rnethyi, tritiuoromethoxy, carboxy, oarboxyaikyi, keto, thioxo, aikyithio, aikyisui-tinyi, aikyisuitonyi, oyano, oarboxyi, aoetamido, aoetoxy, aoetyi, benzarnido,benzenesuifinyi, benzenesuitonarnido, benzenesuifonyi, benzenesuifonyiami-no, benzoyi, benzoyiamino, benzoyioxy, benzyi, benzyioxy, benzyioxyoarbonyi,benzyithio, oarbarnoyi, oarbantate, isooyannato, suifantoyi, suitinamoyiy suiiino,suifo, suifoamino, thiosuiio, NRXRY or COORX, wherein each R* and Ry are in-dependentiy H, aikyi, aikenyi, aryi, heteroaryi, heterooyoie, oyoioaikyi or hy-droxyi; wherein any aikyi group is optionaiiy substituted on carbon with keto(=O); wherein any aikyi group is optionaiiy interrupted With one or more non-peroxide oxy (-Û-), thio (-8), imino (-N(i~i)-), methyiene dioxy t-GCHZO-L oar-bonyi (~C(=G)-), oarboxy (-C(=G)Q-), oarbonyidioxy (-QC(=G)O-), oarboxyiato 1G 1G (-ÛC(=G)-), imine (C=NH), suifinyi (SG), suifonyi (Süg) or [SiÛbc wherein x isabout 'i-iQOÜO; or R1 and Rz together are thioxo (=S) or keto (=O).
    Preferahiy R1 ia hydrogen and RQ is hydrogen, alkyi, aikoxy, haioaikyi, hydroxy,heterocycie, arnino, aikyiamino, cyano, carhoxyi; Wherein any aikyi group is op-tionaiiy substituted on carbon with keto (=O); wherein any aikyi group is ob-tionaiiy interruoted with one or more imino (-ii(H)-), carbonyi («C(=G)-) or[SiO]x, wherein x is about 'i-tüßüfi; or Rï and RE together are keto FO).
    The term "aikyi" refers to a branohed or unbranched saturated hydrocarhonchain preferabiy having frorn 1 to 'iG carbon atorne, preferabiy i to 6 carbonatorns, and rnore breferabiy trorn 1 to 4 carbon atorns. Exarnoiee are methyi(Nie, -Ci-ig), ethyi (Et, ~CH2CH3), 'i-propyi (n-Pn n-propyi, -Ci-igíïi-izCi-ig), 2-prooyi (i-Pr, i-oropyi, -CH(CH3)2), 'i-butyi (n-Bu, n-butyi, -CHZCE-igßiigßi-ß), 2-(i-Bu, i-butyi, -CHgtšihßi-iggg), Z-butyi (s-Bu, s-butyi, -CHKIHQCHQCHQ, Z-methyi-Z-propyi (t-Bu, t-butyi, -C(Ci-i3)3), 'i-pentyi (n-pentyi, -CHZCHZCHQCHZCE-ig), 2~pentyi (-Ci-i(CH3)CH2CH2CH3), S-pentyi (-CH(CH2Ci-i3)2), 2-rnethyi-2-butyi (-C(CH3)2CHZCH3), ß-methyi-Z-butyi (-CH(CH3)CH(CH3)2), B-rnethyi-'i-butyi (ßHgCHgtšt-KCHQZ), ßmethyi-i-butyi (-Ci-igßi-HSHQCHQCHQ, (-CH2CH2Ci-i2CH-2CH2Ci-i3), â-hexyi (-ciiroiißiciigcnzci-izcns), a-iiaxyi (ci-irciizci-ißitoiigci-igci-ißi), a-meiiiyi-z-pentyi (-C(CH3)2CHQCH2CHB), 3-methyi-2-pentyi («CH(Ci-=i3)Ci~t(Ci-i3)CH2CH3),Åi-rnethyi-Z-pentyi (-CH(Ci-t3)Ci~i2Ci~i(Ci~i3>2), S-methyi-ß-pentyi (-C(CH3)(CHQCH3)Q), É-methyi-B-pentyi (-CH(CH2CH3)Ci-i(Ci-i3)2), Zâi-dimethyi-2-butyi (-C(Ci-i3)2Ci-i(Ci-i3)2), Išß-dimethyi-Z-butyi (-CH(CH3)C(Ci-i3)3. The aikyican be unsubstituted or subetituted. niethyi-i -oropyi i-hexyi The terrn "aikenyi" refers to a hranched or unbranched partialiy unaaturatedhydrocarbon chain (i.e. a carbon-carbon, spå doubie bond) oreterabiy havingfrom 2 to 10 carbon atonis, preferahiy 2 to 6 carbon atorns, and more prefere-biy frorn 2 to 4 carbon atorns. Examoiea inciude, but are not iimited to, ethy-iene or vinyi (ßi-i-CHQ), aiiyi (áïi-igtli-i-Ci-ig), cyoiooentenyi (ßsi-iy), and 5»- 'iÛ 29 3G 11 hexenyi (TBH-tg Ci-tgCHzCid-gCi-i-Ci-ig). The aikenyi can be unsubstituted or subs-tituted, The term "aikoxy" refers to the groups aikyi-G-r, where aikyi is defined herein.Preferred aikoxy groups inciude, eg., methoxy, ethoxy, n-propoxy, iso-prcpoxy, 1,2-dimethyibutoxy, and the iike. The aikoxy can be unsubstituted or substituted. n-butoxy tert-butoxy, seo-butoxy, n-pentoxy, n-hexoxy, The term "aryi" refers to an unsaturated arornatic carbooyciic group of from 3to 12 carbon atoms having a singie ring (eg, phenyi) or muitipie condensed(fused) rings, wherein at ieast one ring is aromatic (eg, naphthyi, dihydrophe- nanthrenyi, fiuorenyi, or anthryi). The aryi can be unsubstituted or substituted.
    The term "cycioaikyi" refers to cyciic aikyi groups of from 3 to 'iQ carbon atomshaving a singie cyciic ring or muitipie condensed rings. Such cyoioaikyi groupsinciude, by way of exarnpie, single ring structures such as cyciopropyi, cycio»butyi, oyciopentyi, cyoiooctyi, and the iike, or muitipie ring structures such as adarnantanyi, and the iike. The cyoioaikyi can be unsubstituted or substituted.
    The term "haio“ refers to fiuorc, ohioro, bromo, and iodo. Simiiariy, the term "haiogen" refers to fiuorine, chiorine, bromine, and iodine, "Haioaikyi" refers to aikyi as defined herein substituted by 1-4 haio groups asdefined herein, which may he the same or different. Representative haioaikyigroups include, by way of exampie, trifiuoromethyi, B-fiuorcdodecyi, 121212-trifiuorododecyi, â-bromooctyi, B-bromo-ë-chioroheptyi, and the iike, The term “heteroaryi" is defined herein as a monocyciic, bicyoiic, or tricyciicring system containing one, two, or three arornatic rings and containing at ieastone nitrogen, oxygen, or suifur atom in an arcmatic ring, and which can be un-substituted or substituted, for exampie, with one or more, and in particular oneto three, substituents, seiected from aikyi, aikenyi, aikynyi, aikoxy, haio, haioai-kyi, hydroxy, hydroxyaikyi, aryi, heterocycie, cycioaikyi, aikanoyi, aikoxycar- 2G 12 bonyi, amino, aikyiamino, diaikyiamino, trifiuorornethyithio, difiuorornethyi, acy-iarnino, nitro, trifiuoromethyi, trifiuoromethoxy, oarboxy, oarboxyaikyi, keto,thioxo, alkyithio, aikylsuifinyi, aikyisuifonyi and cyano. Examoies of heteroaryigroups inoiude, but are not iimited to, Zi-i-pyrroiyi, ßi-i-indoiyi, 4H-quinoiizinyi,ßrni-i-carbazoiyi, aoridinyi, benzofbithienyi, benzothiazoiyi, [betaj-carboiinyi,oarbazoiyi, ohromenyi, oinnoiinyi, dibenzoiboifuranyi, furazanyi, furyi, irnida-zoiyi, irnidizoiyi, indazoiyi, indoiisinyi, indoiyi, isobenzofuranyi, isoindoiyi, iso-quinoiyi, isothiazoiyi, isoxazoiyi, naphthyridinyi, naptho[2,3-bi, oxazoiyi, perimi-dinyi, phenanthridinyi, ohenanthroiinyi, phenarsazinyi, phenazinyi, phenothia-zihyi, phenoxathiinyi, phenoxazinyi, phthaiazinyi, pteridinyi, purinyi, pyranyi,oyrazinyi, oyrazoiyi, pyridazinyi, pyridyi, oyrimidinyi, pyrimidinyi, pyrroiyi, qui-nazoiinyi, quinoiyi, duinoxaiinyi, thiadiazoiyi, thianthrenyi, thiazoiyi, thienyi, tri-azoiyi, and xanthenyi. in one embodirnent the term "heteroaryi" denotes a mo-nooyoiic aromatio ring containing five or six ring atonfis containing carbon andi, 2, 3, or 4 heteroatoms independentiy seieoted from the group non-peroxideoxygen, suifur, and N(Z) wherein Z is absent or is H, O, aikyi, phenyi or benzyi.in another entrbodiment heteroaryi denotes an ortho-fused bicyciio heterocyoieof about eight to ten ring atonis derived therefrom, partiouiariy a benz-derivative or one derived by fusing a propyiene, or tetramethyiene diradioai thereto. "i-ieterooyoie" as used herein inciudes by way of exampie and not iirnitationthose heterocyoies described in Paquette, Leo A; Princioies of Modern Hate-rocyoiio Chemistry (WA. Benjamin, New York, 19%), particuiariy Chaoters i,3, 4, 6, Tf, and 9; The Chemistry of Heterocyciio Cornpounds, A Series of Mo-nographs" (John Wiley år Sons, New York, 1956 to present), in particular Vo-iurnes 13, 14, 16, 19, and 28; and J. Ani. Chem. Soc. (19%) 823566. in onespecific ernbodirnent of the invention "heterooyoie" includes a "carbocycie" asdefined herein, wherein one or more (eg. i, 2, 3, or 4) carbon atorns have been repiaoed with a heteroatom (eg, O, N, or S).
    Exarnpies of heterooycies inoiude by way of exampie and not Iirnitation pyridyi, dihydroypyridyi, tetrahydropyridyi (piperidyi), thiazoiyi, tetrahydrothiophenyi, 1G 3G 13 suifur oxidizod tetrahydrothiophenyi, pyrimidinyi, furanyi, thianyi, pyrroiyi, pyra-zoiyi, imidazoiyi, tetrazoiyi, banzofuranyi, thianaphthaienyi, indoiyi, indoienyi,quinolinyi, isoquinoiinyi, bonzimidazoiyi, piperidinyi, 4-piperidonyi, pyrroiioinyl,Ill-pyrroiidonyi, pyrroiinyi, tetrahydrofuranyi, tetrahydroquinoiinyl, tetrahyoroiso-quinoiinyi, decahydroouinoiinyi, ootahyoroisoouinoiinyi, azooinyi, triazinyi, 65-t-1,2,5-tiiiadiazinyi, Zi-ißi-i-LSQ-oithiazinyi, thianyi, thiantnranyi, pyranyi, iso-benzofuranyi, ohromenyi, xanthenyi, phenoxatninyi, 2i-i-pyrroiyi, isotiriazoiyi,isoxazoiyi, pyrazinyi, pyridazinyi, indoiiziriyi, isoindoiyi, SH-inooiyi, *ii-i-inoazoiy,purinyi, 4H-ouinoiizinyi, pnthaiazinyi, naprithyridinyi, quinoxaiinyi, ouinazoiinyi,oinnoiinyi, ptarioinyl, 4ai-i-carbazoiyi, carbazoiyi, [betai-carboiinyi, pnenanthri-dinyi, aorioiinyi, pyrimidinyi, pnananthroiinyi, phanazinyi, phanothiazinyi, fura-zanyi, phenoxazinyi, isoohrornanyi, onromanyi, imiciazoiidinyi, imioazoiinyi, py-razoiidinyi, pyrazoiinyi, piperazinyi, indoiinyi, isoindoiinyi, quinuoiidinyi, morpho-iinyi, oxazoiidinyi, benzotriazoiyi, bonzisoxazoiyi, oxincioiyi, benzoxazoiinyi, isa- tinoyi, and bis-tetrahydrofuranyi.
    By way of example and not iimitation, carbon bonded hetarooyoies ara bonoadat position 2, 3, 4, 5, or 6 of a pyrioino, position 3, 4, 5, or 6 of a pyridazine,position 2, 4, 5, or 6 of a pyrimidina, position 2, 3, 5, or 3 of a pyrazina, position2, 3, 4, or 5 of a furan, totraitydrofuran, tniofuran, thiophone, pyrroio or tetra-hydropyrroia, position 2, 4, or 5 of an oxazoie, imidazoie or thiazoia, position 3,4, or 5 of an isoxazoie, pyrazoio, or isotniazoio, position 2 or 3 of an aziridine,position 2, 3, or 4 of an azatidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoiine orposition t, 3, 4, 5, o, 7, or 8 of an isoquinoiine. Stiil more typioaiiy, carbonbondad fiaterocyoios inoiude 2-pyriciyi, S-pyridyi, 4-pyridyi, S-pyridyi, ß-pyridyi,3-pyridazinyi, 4-pyrioazinyi, B-pyridazinyi, ê-pyridazinyi, Z-pyrimidinyi, 4-pyrirnidinyi, ä-pyrimidinyi, o-pyriniidiny/i, Z-pyrazinyi, S-pyrazinyi, ä-pyrazinyi, 6- pyrazinyi, 2-thiazoiyi, 4-thiazoiyi, or ä-thiazoiyi.
    By way of exanipia ano not iirriitation, nitrogen bondeci neterocyoies arabondad at position 'i of an aziridine, azetidina, pyrroia, pyrroiiciina, Z-pyrroiina,S-pyrroiino imidazoie, imidazoiioina, Z-imidazoiina, B-irnidazoiine, pyrazoie, pyrazoiina, Z-pyrazoiine, 3-pyrazoiino, piperidine, piperazine, indoie, incioiine, 1G 14 'iH-indazoie, position 2 of a isoindoie, or isoindoiine, position 4 of a morpho-line, and position 9 of a carhazoie, or [heta]-oarhoiine. Stiii more typicaiiy, ni-trogen honded heterooyoies inoiude f-aziridt/l, t-azetedyL 'i-pyrroiyi, 1-imidazoiyi, 'i-pyrazoiyL and 'i-piperidinyi.
    "Carhooyoie" refers to a saturated, unsaturated or aromatio ring having 3 to 'ïcarbon atorns as a monocvoie, 7 to 12 carbon atoms as a bicycle, and up toabout 30 carbon atoms as a pofycycie. Monooyciio oarhooyctes have 3 to 6ring atorns, stiii more typioaiiy 5 or 6 ring atoms. Bioyciio carbooyoles have 7 to12 ring atorns, eg., arranged as a hicyoio [4,5], [5,5], [dä] or [65] system, or 9or 10 ring atorns arranged as a hioyofo [äß] or [då] systern. Exarnpies of car-hooyoies inoiude oyciopropyf, oyoiohutyi, cycfopentyi, t-cyoiopent-t-enyi, 1-cyoEopent-Z-enyf, 'i-oyciopentßenyf, oyoiohexyi, t-oyciohexfi-enyi, i- oyoEohex-Q-enyi, *i-oyoiohex-ß-enyi, phenyi, spiryi and naphthvi.
    The term "atkanoyi" refers to C(-())R, wherein R is an aikyi group as previously defined.
    The term "aikoxyoarbonyi" refers to C(-O)OR, vvherein R is an aikyi group as oreviousiy defined.
    The term "amino" refers to -NH2, and the term "aikyiamino" refers to -NRÉJwherein at ieast one R is aikyi and the second R is aikyi or hydrogen. The term"aoyiamino" refers to RC(-O)N, wherein R is aikyi or aryf.
    The term "nitro" refers to N62.
    The term "trifiuoromethyi" refers to -CF3.
    The term "trifiuoromethoxy" refers to -OCF3.
    The term "cyano" refers to -CN 2G The term "hydroxy" refers to »Oi-i, As to any of the above groups, which contain one or more substituents, it isunderstood, of course, that such groups do not contain any substitution orsubstitution patterns which are sterioaiiy impractioai andior synthetioaiiy non-feasibie. in addition, the oompounds of this invention include aii stereochemi-oai isomers arising from the substitution of these oompounds.As used herein, "aidehyde" refere to the fuhotionai group -C(-G)H, or any com- pound that inoiudes such a group.
    As used herein, "nitroxyi radioai" refers to funotionai group (N-O.) and to oom- pounds that inciuoe such a group.
    The optionai oooataiyst of forrnuia 5 is most preferabiy2,2,6ß-tetramethyipiperidine-i-oxyi (TEMPO), having the CAS Registry No. of2564-83-2;4-(2-ohioroacetamicio)-2,2ßß-tetramethyi-*i-piperidihyioxy free radioai;4-(2-brornoaoetamido)-2Qßß-tetramethyi-t-piperidinyioxyg free radioai. TheCAS Registry Number is 24567-97-3;4-(2-iodoaoetamido)-2,2,6ß-tetramethyipiperidine “i-oxyi or 4-(2-iodoaoetamidm-ZQßß-tetramethyi-t-piperidinyioxy free radioai. The CASRegistry Number is 25Ti 324-0; 4-oyano-22,6ß-tetramethyipiperioine “i-oxy. The CAS Registry Number is38678-71-6; 4-maieimido-2ÅSS-tetramethyi-”i-piperidinyioxtn free raoioai. The CAS Regi-stry Number is 15178-63-9; 4-methoxy-2Qßß-tetramethyi-'i-piperidinyioxtig free radioat The CAS RegistryNumber is Qäéi-ÜT-SQ-S; 4-0xo-2ÅSß-tetramethyi-'i-piperidinyioxtn tree raciioai. The CAS Registry Number is 2896-70-9; 16 âißß-Tetramethyi-fi-piperinyioxy free radioai on siiica gei;4-Amine-Z,2,6ß-tetrarnethyipiperidinyioxy, tree radioai. The CAS RegistryNumber is 'i46Qt-88-4: Å-oarboxy-Q,2,6ß-tetramethyipiperidine t-oxyi;é--carboxy-Z,2,6ß-tetrarnethyipiperidinyioxy, tree radioai. The CAS RegistryNumber is 37149-18-1; Åi-Acetamido-Z2,6ß-tetramethyipiperidine “i-oxyi. The CAS Registry Number is1469t-8Q~5; 4-(2-ohioroacetamidcn-â,2ßß-tetramethyipiperidine 'i-oxyi". The CAS RegistryNumber is 367 5~23-2; 4-hydroxyi-Z,2,6ß-tetrarnethyipiperidine-'i-oxyi; poiymer-bound TEMPG. “Polymer bound TENEPO” refers to having a partioiesize 190-200 mesh, ioading: 1.9 mmoi/g, 1% oross-iinked with divinyibenzene; which is a oompound of the forrnuia wherein the wavy iines indioate bonds of the poiystyrene monomeric units to adjaoent monomeric unitst Oxidation of betuiinio aidehyde to betuiinio acid can be performed by any knowmethod in the iiterature. Oxidizing system in the oxidation of betuiinie aidehydeto betuiinio acid shouid seieotiveiy oxidize the aidehyde to the eorresponding oarboxyiio acid.
    There are many possibie aiternatives to be used as oxidizing systems in oxida-tion of betuiinic aidehyde to betuiinio acid. Such systems cornprise appropriateoxidizing agent(s), possible butier oompoundæ) and possibie auxiiiary agent-(s). 1G 2G 17 Exampies ot suitable oxidizing agents are, but not iirnited to, dioxygen (02),sodium hypochiorite (NaOCi), sodium chiorite (NaCiOZ), potassiurn chiorite(KCiOg), potassiurn hypochiorite (KÛCE), peroxides such as hydrogen peroxide(i-igOg), hypervaient iodine reagents (eg. â-iodoxyioenzoic acid (iBX), 2«iodoxybenzenesuifonic (iBSh, Gxone (2KHSG5, KHSO4, Kgêšüi) and phthaii-mides such as N-hydroxyphthaiimide and mixtures thereot. As to other possi- bie oxidizing agents we reter here to iiterature ot this tieid. in combination with above mentioned oxidizing agents it is otten usetui to usesuitabie hutfer in an oxidation system. Exampies of these hutfers are petas-stunt dihydrogen phosphate (Ki-igPürt) and sodium dihydrogen phosphate(NaHZPGQ. pti-ranges tor the above mentioned buffers are KttgPQr: pH 5.8 --8; Nai-i2PO4: pH 6 - 7.5. As to other possibie hutfers we reier here to iiteratureof this fieid.
    Auxiiiary agents can be oxidation preventative agents which wiii prevent unde-siraioie oxidation ot betuiin or its derivatives. Oxidation prevehtative agents areweii known in this tieid and they are usuaiiy compounds, which wiii itseit be-come reversihie oxidazed. Exampies of an oxidation preventative agent are 2-methyEQ-butene or tert-butanoi. The auxiiiany agents can aiso be (ruthenium)scavenging agents such as QuadraPure it/iercaptophenyiaminobut-Z-enoateester. As to other possihie auxiiiary agents we retar here to iiterature ot' thisfield.
    The oxidation of hetuiinic aidehyde to betulinio acid can be performed for ex-NaH2PO4 and 2.-rnethyibutene. Another example of suitabie oxidation system is disciosed in US290916073290 A1, where betuiinic aldehyde is oxidized to hetuiinic acid withoxidation system oomprising NaCiüz, Ki-TQPQ; and Z-methyi-Z-butene. ampie with oxidation system comprising NaOCEZ An aiternative route tor synthesis ot hetuiinio acid according to present inven-tion is presented in scherne 4 beiow. The aiternative synthesis route toiiows steps ia-iii-EV. Qxidation ot betuiin to betuionic aidehyde (reaction ia) is per- 18 formed according to present invention. in reaction ia the ruthenium basedoataiyst is TPAP and the oxidant is Nit/iQ. The hetuionic aidehyde is oxidized tobetuionio acid (reaction iii), tor exampie with an oxidation system corriprisingNaOC-ig, KHQPCh and 2-rnethyibutene. 'the betuionic acid is reduced to betuiinic acid (reaction EV), tor exampie with sodiumborohydride (NaBi-tii). Re- actions iii and iv can be performed by any known method in the literature.
    Schema 4. An aiternative route tor synthesis ot hetuiinic acid according to pre- sent invention.
    According to another emhodiment ot the present invention the betuiin is tirstoxidized with a ruthenium based cataiyst and air to betuiinic aidehyde and theobtained hetuiinic aidehyde is oxidized without puritication turther to betuiinicacid by using additionai oxidation agent. in practice the oataiytic oxidation otbetuiin and oxidation ot betuiinic aidehyde to oorresponding acid happen si~ muitaneousiy, in one pot (at the same vessei).
    Above mentioned so oaiied “one one pot oxidation method” comprises toiiow- ing process stages: 2G 3G 19 (a) oxidizing betuiin to betuiinic aidehyde in the presence of a ruthenium based cataiyst and an oxidant,(b) oxidizing said betuiinic aidehyde to betuiinic acid With an oxidizing system. in stage (a) cataiytic oxidation of betuiin is performed by a ruthenium basedcataiyst in the presence of dioxygen. The cataiytic oxidation reaction of betuiinto betuiinic aidehyde in stage (a) and oxidizing of betuiinic aidehyde tobetuiinic acid (stage b) are performed simuitaneousiy, in the same reaction vessei Because in this “one pot oxidation method" obtained betuiinic aidehyde is notisoiated but used as such, this method has an advantage of being effectiveand economic method for preparation betuiinic acid from betuiin. This embo-diment of the inventive method may be suitabie for a iarge scaie conversion of betuiin to betuiinic acid or betuionic acid.
    Neither above mentioned generai methods (reaction routes i and ii, and ia, iiiand HV) for synthesizing betuiinic acid nor above mentioned so caiied “one potmethod" needs functionai groups of betuiin to be protected with protectinggroups. Therefore neither cieavage of the protection groups is needed. Thus, reaction steps are reduced.
    Optionaiiy the ruthenium based cataiyst can be supported by any conventionai cataiyst support such as zeoiite, aiurnina, carbon, or the iike.
    Exampies in schema 5 is disciosed cataiytic oxidation of betuiin to betuiinic aidehyde andfurther to betuiinic acid according to the present invention. Reaction t is per-formed in the presence of ruthenium based cataiyst and an oxidant. Optionaiiya cocataiyst can be present in the oxidation of betuiin to betuiinic aidehyde.Oxidation of betuiinic aidehyde to betuiinic acid (reaction ii) can be performedby any known method in the iiterature. 26 HQ: Vífšaff :zšxšç Sshemeï 5. Catašytic øxiáatiøn of betuišn ts betuišnšc aidšehyde and fufiher tcbetuišnšc acid.
    En tabie 1 are presented ræsuåts sf cataâytšc Qxäëatäøn af betuišn te beiuäšnâc ai~dehyäe accsrding ts present inventšsn (reastšsn E), mm cosuwwm.. w.. ä 3A 3 8 M w ä., wa S ä 2 __, väva SN E n wa EN .Émw, øwèz _ .w ä.. ä. ä m äs M ä. ., »å E .__ E 2 :ös :HN E;%%%%%%% .. -Må ä åxå.äšflmøw. wa 3 ä ä.w i ä ä. ÅÅÅÅÅÅÅ .. ß .än .É H 2 .M .. åå. N. äga» 2% i _:Wchfàahaw ma: av .._ wšwnöoëwmfiuwfi N .å æ. ß .äm å.. M å - år a; Sw W. mcmšb :Mmm MMS mm ___ wa cm.w å . . ä.. ß sem å.. m E.. .. mf Qušfi mä acšæøw å. šæ wa å. .._ ä äE. w ä ä ß .än å.. m Q: chšmc. mmâmvmmufiæ .._ ufisåyw. äfl %%%% .. f.GWÉQÉGN .wufim 0% Mdu Mm _.. ME OmN m ä ä. .E .så ä.. m å. _... oflšmw ßwflmwwuwmusm _.. æëäwfi.. äw Emëfišvw s. wa S. E ä N ä ä i ...am .EN w E: oflšmh. _ ...ßfimmvwmunww Ewæzfiw mä Ésflyæhmqfi me å. ä ... E. å,N %%%%% .. N å ä.. ï .åw hä. w :Qz .._ cåâß ...AÉGWWNMQÅM ææeøw. .få 2CÉQ.Q.ÉQN NÉHN ME I» . .th N. N ä. .. Q 3 ka... .É .w å: ... æšâw. Ååwmvflmfim ëufiëë E. m Ü:så .må m: wšøm .. wa avN - E t -aan Na W S .W .... 1 Qmëwfi mmâßwmunwm . ææmwfi. QR Iewa mä äga32 åšæwæ ëšmgwmm æå ä rå wamwæäfiu aa.. æåWëfiü äæømsïm ëæmwswæm :awmäfifumw uEE. MmmEwG Énmmwbm . »Bov h “mnofiaü wmššwwv QEV wâàøm uflnäm »Enzšw .c zowëæëv :oncmšt Emwmñ 9 måuhouuw mnflšmumm umšmwwß B Emšmn B cømwmëxo uwamwmu .w mfifi.. vw 29 22 Reaction i Exampie i!!Betuiinic aidehyde: Betuiin (221 mg, 9,50 mrnoi), RuCi2(PPh3)3 (252 mg, 0,621 mrnoi) and TEii/EPG (9,8 mg, 505272 mmoi) in toiuene (40 mi) wasstirred under G2 at 'iO5°C for 24 hours. Reaction rnixture was iiitered through apad of aluminium oxide, which was washed with ioiuene (tät) mi) and di-chioromethane (ZXZÛO mi). Soivent was evaporated and residue was dried in avacuum oven to yieid hetuiinio aidehyde raw product 207 mg. GC purity anaiy-sis: betuiin 83%, betuiinic aidehyde 15%, others 2%.
    Exampie 1.5 Betuiinic aidehyde: Betuiin (5OÛ mg, 1,1 mmoi), RuCEQÜDPhQg, (80 mg, 0,98mmoi) and TEMPO (45 mg, 0,26 mmoi) in toiuene (50 mi) was stirred at 8 atmair pressure, with 2G rni/min air iiow, for 14 hours at 100 °C to yieid betuiinioaidehyde as main product. GC purity anaiysis: oetuiin 259%, betuiinic aidehyde55%, hetuionic aidehyde 3%, others 2%.
    Exampie 1.15 Betuiinic aidehyde: Betuiiri (221 mg, 0,59 mmoi), 4Å rrioiecuiar sieves (554mg) in dry diohioromethane (15 mi) was stirred under G2 atmosphere for 30min. TPAP (ißfi mg, 0,052 mmoi) was added and reaction mixture was stirredunder O; tor 166 min at room temperature. Reaction rnixture was fiiteredthrough pad ot siiioa gei, which was washed with EtOAc (185 mi). Soivent wasevaporated and residue was dried in vacuum oven to yieid betuiinic aidehyderaw product 235 mg. GC purity anaiysis: beiuiin 15%, betuiinic aidehyde 65%,betuionic aidehyde 25%, others 5°/s. *n nrvia (sno rviiiz, cocis) ers (s, si-i), oss (s, sia), sei (s, sii), os (s,sii), oss (s, sii), iss (s, sii), 2.85 (m, iii), si (sis, iii), ses (s, iii), sis(s, iii), ses (s, iii). 5 1G 23 in iabie 2 are presented results of oxidation of beiuiiriic aidehyde to betuiinic acid (reaction ii). 'rabie 2. Resuits of oxidation of beiuiinic aidehyde to oetuiinic acid (reaction ii).
    Exarnpie i Betuiinic ai- Oxidaiion systern Yieid of betuiinic acidi deiiyde (si)(mo)2.1 iooo NHPi (N-iiydi-Qxypiiiiiaiimide) Åsi 22 mg + Air2.3 iooo i Nalocizfsoc mg + NaiiQPoÅi-i i esâ-rneiiiyibutene2.4 icon Naocizfirocmg + Nar-snor, “rs+ a-meiiiyisuiene as sec i iiacioziisccmg + iizozi 2.0 i inmi (30%) + Nar-soon;2.6 oss Nacioz/zrocmg + Nar-sno; 22+ Z-meiiiyibuteneReaction iiExampie 2.1 Betuiinic acid: Betuiinic aideiiyde (1130 g, 2,3 mmoi) and NHPi (22 mg) in toiuerie was stirred, with 'iÛO mi/min air iiow, for 2,5 hours ai 3 “C to yieid betuiiriic acid as main product (48 %).
    Exampie 2.3 Betuiinic acid: Beiuiinic aidenyde (LOU g, 2,3 mmoi), NaÛCEZ (0,8 g) +Naiigiaüii (15 rni; 0,5 ivi) + Z-methyiiouiene (3 mi) + dimeinyi dioctadecyi arn- monium cnioride (QO mg) in toiuene (36 mi) was stirred for 20 hours ai 21 °C to yieid beiulinic acid as main product (68 %). 1G 24 Exampie 2.4 Betuiinic acid: Betuiinic aidehyde (fßü g, 2,3 mmoi), NaüCig (1,7 g) +Naii2PO4 (20 mi; 0,8 Ni) + Z-methyiioutene (3 mi) + tert-hutanoi (17 mi) in toiu-ene (St) mi) was stirred for 22 hours at 21 °C to yieid hetuiinic acid as mainproduct (76 %). in schema 6 is disciosed cataiytic oxidation of betuiin to betuionic aidehydeand further to betuionic acid. The betuicnic acid is reduced to betuiinic acid.Reaction ia is performed in the presence of rutheniurn based cataiyst TPAPand oxidant Nix/EG according to present invention. Qxidation of betuionic aide- hyde to hetuionic acid (reaction iii) and reduction of betuionic acid to hetuiinic acid (reaction EV) can be performed by any known method in the iiterature.
    Schema d. Cataiytic oxidation of beiuiin to betuionic aidehyde and further to betuionic acid, and finaiiy reduction to betuiinic acid. 16 26 36 Reaction ia Exampie 3.16 Batuionic aidehyde: Betuiin (221 mg, 6,56 mmoi), 4Å mcieouiar sieves (568mg), NMS (264 mg, 1,51 mmoi) in dry dichioromethane (15 mi) was stirredunder argon for 36 min. TPAP (17,4 mg, 6,656 mmoi) was added and reactionmixture was stirred for additionai 126 min. Reaction mixture was iiiteredthrough pad of siiica gei, which was wastied with EtOAc (186 mi). Soivent wasevaporated and residue was dried in a vacuum even to yieid betuionic aida-hyde as main product (218 mg). GC purity anaiysis: betuiin 4%, betuionic ai-dehyde 95%, others 1%. 111 NMR (366 MHz, CÜCh) 8,65; 4,74; 4,59; 2,851.136 NiViR (366 1111112, CDCE3) 218,64; 266,51; 149,61; 116,18; 66,48; 54,66; 48,77; 47,86; 47,43; 42,56; 46,72; 39,58; 38,76; 36,84; 34,68; 33,57; 33,12;26,68; 28,75; 26,78; 25,48; 21,23; 26,98; 18,58; 18,86; 15,93; 15,68; 14,14.
    Reaction iii Betuionic acid: Betuionic aidehyde (1,66 g, 2,3 mmoi), NaOCig (1,7 g) +Nai-i2PG4 (26 mi; 6,8 Ni) + Z-methyibutene (3 mi) + tert-butanoi (17 mi) in toiu-ene (36 mi) was stirred for 22 hours at 21 “C to yieid betuionic acid aa mainproduct (76 14).
    Reaction EV Betuiinic acid: To a soiution of betuionio acid (13 g, 2,3 mmoi), water (136mi), NaOi-i (26 mi, 5%) and 2-propanoi (126 mi) was added NaBi-ii; (1,2 g) andstirred for 3 hours. HCi soiution (136 mi, 16%) was added and precipitate wasfiitered, washed with water (4-*56 mi) and dried in a vacuum oven to yieidbetuiinio acid 12,24 g (94%). 26 The “one pot oxidation method” Exampie 1.5 Betuiinio aidehyde: 150 mi reactor was ioaded with hetuiin (15 g),RuCizPPhg (045 g), TEMPG (024 g) and toiuene (50 mi). Reaotor was pres~surized to 8 bar and airfiow was adjusted to 20 miímin. Heating (set temp 100OC) and stirring (300 rpm) were started and continued for 7 hours to yieidbetuiinic aidehyde as main product. CG purity anaiysis: 1 % betuiin, 50 %petuiinic aidehyde and others 19%. Ohtained fiitrate (inciuding betuiinic aids-hyde 80%) was suhseguentiy used in the next reaction step in one pot without further purification.
    Exarnpie 2.5 Betuiinio acid. 30 mi fiitrate (inciuding 0.65 g of betuiinic aidehyde, purity80%) from exampie 1.5 was fiitered into a 100 mi fiask. 0.1 g Nai-i2PC4 in 5 miH20 and 0.5 mi 30 % 14202 were added to the fiask. Reaction rnixture wasstirred (300 rpm) in an ice-water bath and 0.5 g NaügCi in 10 mi H20 wasadded dropwise during 30 min and reaction mixture was stirred for 5 hours.Additional 0.6 g NaH2PO4 in 10 mi H20, 1.5 mi 30 % H20; and 1.2 g NaügCi in20 mi H29 were added in two proportions to the fiask after 5 and 17 hours fromthe start of the reaction. Reaction mixture was tet to stir 6 more hours and CGsample was taken. GC showed that there were 32 % hetuiinic aidehyde, 10 %_ ioetuiinic acid, 34 % unknown component 1 and 11 % unknown component 2.
    Exampie 2.5 Betuiinic acid. 30 mi fiitrate (inoiuding 0.55 g of hetuiinio aidehyde, purity8096) from exampie 1.5 was fiitered into a 100 mi fiask. 8.5 mi t-BuOi-t and 5mi 2-methyi Z-butene and 1.3 g Nai-igPßt in 15 ml HZG were added to thefiask. 0.9 g NaCiCz in 10 mi HZO was added to the fiask dropwise during 30minutes and reaction mixture was stirred for 5 hours. Additionai 1.8 g NaCiCQin 20 mi H20, 2.6 g Nai-i2PO4 in 30 mi HgC and 4 mi Q-rnethyi Z-butene wereadded to in two proportions to the fiask after 5 and 17 hours from the start ofthe reaction. Reaction mixture was iet to stir 6 more hours and CG sarnpie was Qi taken. GC ehewee 'inet there were 54 % beiuiinic aieenyee, 22 % beiuiinieecie, 5 % unknown eenfipeneni 3 and 8 % unknewn eempenent 4.
    The inveniien iiee been eeeeribee with reference ie specifie ene preferree em-beeirnente and techniques. Hewever, ii eiieuid be uneereteed 'inet meny verie»iiene end rneeiiieeiiene fney be made wniie remaining within 'ine spirit andeeepe ei the inventien es ii ie set eui in the feiiewing eiairne.
    权利要求:
    Claims (17)
    [1] 1. A method for preoaration ot betuiinic acid from betuiin, characterized inthat said method comprises oxidizing betuiin to betuiinic aidehyde with a ru-theniurn based cataiyst cataiyzed oxidation process in the presence ot an oxi- dant, and the betuiinic aidehyde is oxidized to betuiinic acid.
    [2] 2. The method according to ciaim t, characterized in that the rutheniumbased cataiyst is represented by the formuia RumLm-nwherein Ru is rutheniurn, i. rebresents tigand, m is integer from 1, 2 or 3 and nis integer Q, 1,2, 3,4,5 orß.
    [3] 3. The method according to ciaim 2, characterized in that the iigand(s) isiare monodentate andior ooiydentate
    [4] 4. The method according to any one ot the previous ciaims, characterized inthat the rutheniurn based cataiyst is rutheniumtii) or rutheniumNii) compound,preferabiy dichiorotrisftriphenyiphosphinehfuthenium(ii) (RuCigPPhgg) or tetra-n-propyiamrnoniumberruthenate (TPAP).
    [5] 5. The method according to any one of the previous ciaims, characterized inthat amount of the rutheniurn based cataiyst is about t to about 3G moie per- cent, reiative to the hetuiin.
    [6] 6. The method according to any one oi the previous ciaims, characterized inthat the oxidant is dioxygen, n-rnethyimorohoiine-N-oxide (NiviÛ) or sodiumhy- pochiorite, preferabiy dioxygen originating from atmospherio oxygen. Y.
    [7] 7. The method according to any one of the previous ciaims, characterized inthat oxidation ot betuiin to betuiinic aidehyde is carried out in a soivent se-iected from the group consisting ot aromatic hydrocarbons, saturated or un- saturated aiiphatic hydrocarbons, branched or unbranched aiiphatic hydrocar- 2G 3G 29 bone, ethers, haiogenated aiiphatic hydrocarbons, tiuorous soivents, esters,ketones, H29 and mixtures thereot.
    [8] 8. The method according to ciairn 7, characterized in that soivent is Ci-igCig, SMF, THF, DMSQ, periiuoroaikane, toiuene, xyiene or mixtures thereot.
    [9] 9. The method according to any one ot the previous oiaims, characterized inthat temperature during the oxidation ot betuiin is from about 0 to about 1500G.
    [10] 10. The method according to any one of the previous ciaims, characterized inthat oxidizing betuiin to betuiinic aidehyde is carried out under pressure from about 'i to about 59 bar, preferabiy from about 1 to about 15 bar. ti.
    [11] 11. The method according to any one of the previous ciaims, characterized inthat oxygen dissoiving to soivent system during the oxidation process is faoiii- tated by stirring.
    [12] 12. The method according to any one of the previous ciaims, characterized inthat oxidizing betuiin to betuiinio aidehyde is carried out in the presence of a cocataiyst.
    [13] 13. The method according to ciaim 12, characterized in that the cocataiyst is represented by the formuia (5) u u*i.i i5 wherein each ot F31 and RE is independentiv hydrogen, aikyi, aikenyi, aikoxy, »ä ff haio, haioaikyi, hydroxy, hydroxyaikyi, aryi, heteroaryi, heterocycie, cycioaikyi, 3G aikanoyi, aikoxycarbonyi, amino, irnino, aikyiarnino, acyiantino, nitro, tritiuoro~rnethyi, trifiuoromethoxy, carboxy, oarboxyaikyi, keto, thioxo, aikyithio, aikyi-suifinyi, aikyisuifonyi, cyano, carboxyi, acetarnido, aoetoxy, acetyi, benzamido,benzenesuifinyi, benzenesuitonamicio, benzenesuifonyi, benzenesuifonyi-amino, benzoyi, benzoyiamino, benzoyioxy, benzyi, benzyioxy, benzyioxycar-bonyi, benzyithio, carbantoyi, carbantate, isocyannato, suifamoyi, suitinarnoyi,suifino, suito, suifoamino, thiosuito, NRXRY or COGRX, wherein each R* and Ryare independentiy i-i, aikyi, aikenyi, aryi, heteroaryi, heterocycie, cycioaikyi orhydroxyi; wherein any aikyi group is optionaiiy substituted on carbon with keto(=C)); wherein any aikyi group is optionaiiy interrupted with one or more non-peroxicie oxy 00-), thio (-S-), imino (-N(i-i)-), methyiene dioxy (GCHZO-L car-bonyi (-C(=O)-), carboxy (-C(=O)G-), carbonyidioxy (-ÛC(=O)O-), carboxyiato(-OC(=O)-), imine (C=NH), suifinyi (SO), suitonyi (SQZ) or iåiOix, wherein x is about t-'iüßütk or Ri and RZ together are thioxo (=S) or keto (=Q).
    [14] 14. The method according to ciairn 13, characterized in that, wherein Ri ishydrogen and Rz is hydrogen, aikyi, aikoxy, haioaikyi, hydroxy, heterocycie,arnino, aikyiantino, cyano, carboxyi; wherein any aiityi group is optionaiiy subs-tituted on carbon with keto (=0); wherein any aikyi group is optionaiiy inter-rupted with one or more irnino (~it(i-t)-), carbonyi (-C(=G)-) or [SiO]x, wherein xis about 1-'i0,0GO; or R1 and RQ together are keto (=G).
    [15] 15. The method according to oiairns 13-14, characterized in that the corn- pound of torrriuia (5) is 2,zoß-tetramethyipiperidine 'i-oxyi (TEMPO).
    [16] 16. A method for preparation of betuiinic acid trorn betuiin, characterized inthat said method cornprises(a) oxidizing betoiin to betuionic aidehyde with a ruthenium basedcataiyst cataiyzed oxidation process in the presence of an oxidant;(b) oxidizing the betuionic aidehyde ot step (a) to betuionic acid; and (o) reducing the betuionic acid oi step (b) to betuiinic acid 31 W. The methød according En cfiašm 1%, chzamateräzad En that the ruthenšumhasefi fiatašyst äs prøpyšammønšumperruthenate (TPAP) and the oxšdant is n»meïhyåmørphåæiinewflzaxšde (NR/EG).
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    同族专利:
    公开号 | 公开日
    WO2013038312A1|2013-03-21|
    PL2755990T3|2017-01-31|
    EP2755990A1|2014-07-23|
    SE537100C2|2015-01-07|
    EP2755990A4|2015-03-25|
    ES2599352T3|2017-02-01|
    EP2755990B8|2016-12-21|
    EP2755990B1|2016-07-20|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    CA2250481A1|1998-11-02|2000-05-02|Andre Pichette|Betulinol derivatives preparation process using silver birch bark|
    US20030073858A1|2001-01-11|2003-04-17|Krasutsky Pavel A.|Methods for manufacturing betulinic acid|
    CN101302244B|2008-06-06|2011-04-13|东北林业大学|Production process of betulinic acid|RU2565773C1|2014-10-20|2015-10-20|Федеральное государственное бюджетное учреждение науки Институт органической химии Уфимского научного центра Российской академии наук |Method for producing betulinic acid|
    EP3246984A4|2015-01-14|2018-06-06|Kabushiki Kaisha Toshiba|Nonaqueous electrolyte battery and battery pack|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    SE1150818A|SE537100C2|2011-09-12|2011-09-12|Procedure for derivatization of a chemical component in wood|SE1150818A| SE537100C2|2011-09-12|2011-09-12|Procedure for derivatization of a chemical component in wood|
    ES12832504.0T| ES2599352T3|2011-09-12|2012-09-07|Method for the preparation of betulinic acid|
    PL12832504T| PL2755990T3|2011-09-12|2012-09-07|Method for preparation of betulinic acid|
    EP12832504.0A| EP2755990B8|2011-09-12|2012-09-07|Method for preparation of betulinic acid|
    PCT/IB2012/054632| WO2013038312A1|2011-09-12|2012-09-07|Method for preparation of betulinic acid|
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