 JP, TOKYO, 16 (11), (1968), 2114-2119) describe synthesis of M6G by reaction of 3-acetyl-morphine with a bromo derivative of glucuronic acid to form a Methyl [3-acetyl-morphine-6-yl -2,3,4-tri-O-acetyl-xcex2-D-glucopyranosid] uronate intermediate which is subsequently hydrolysed to M6G.
WO 93/05057 discloses preparation of M6G by reaction of 3-acetyl morphine with methyl 1xcex1-bromo, 1-deoxy, 2,3,4-tri-O-acetyl D glucopyranuronate and subsequently hydrolysing the resulting intermediate to M6G.
In order to synthesise M6G the major problem to overcome is to obtain the glycoside linkage with very high xcex2-selectivity since prior methods produce the xcex1-anomer.
One method for obtaining high xcex2-selectivity is to use trichloroimidate as the leaving group, as shown in WO 93/03051: FIG. 1 (Salford Ultrafine Chemicals and Research Limited).
Orthoesters are simple to synthesise from their respective bromides. There is a reaction reported in the literature2 between the glucuronate orthoester (2) and the sugar derivative (3) catalysed by lutidinium perchlorate3 (4) (Scheme 1). 
When this reaction was repeated with the t-butyl orthoacetate (5) and cyclohexanol (6 equivalents), the desired product (6) was isolated in 9% yield. Two other products also suggested that they were the desired product, but with the loss of one acetyl group, isolated in a combined yield of 43% (Scheme 2). 
When 1.2 equivalents of 4-tert-butylcyclohexanol was used, the desired compound (7) was obtained in 17% yield. Other compounds obtained from the reaction also appeared to contain the desired peaks in the nmr, but after further examination proved to be the product of transorthoesterification (8) (Scheme 3). 
Reaction of Orthoester (5) with Protected Morphine
Initially, 1.2 equivalents of 3-TBS protected morphine and the orthoester (5) were dissolved in chlorobenzene and half of the solvent was
JP, TOKYO, 16 (11), (1968), 2114 - 2119) describe synthesis of M6 G by reaction of 3 - acetyl - morphine with a bromo derived function of glucuronic acid to imprint a Methyl [ 3 - acetyl - morphine-6 - yl -2,3,4 - tri - O - acetyl - xcex2 - D - glucopyranosid ] uronate intermediate which is subsequently hydrolysed to M6G. 
 WO 93/05057 disclose preparation of M6 G by chemical reaction of 3 - acetyl morphine with methyl 1xcex1 - bromo, 1 - deoxy, 2,3,4 - tri - O - acetyl D glucopyranuronate and subsequently hydrolysing the resulting average to M6G. 
 In decree to synthesise M6 thousand the major problem to overcome is to prevail the glycoside linkage with very eminent xcex2 - selectivity since prior methods produce the xcex1 - anomer. 
 One method for obtaining eminent xcex2 - selectivity is to use trichloroimidate as the leaving group, as shown in WO 93/03051: FIG. 1 (Salford Ultrafine Chemicals and Research Limited). 
 Orthoesters are dim-witted to synthesise from their respective bromides. There is a reaction reported in the literature2 between the glucuronate orthoester (2) and the carbohydrate derivative (3) catalysed by lutidinium perchlorate3 (4) (Scheme 1). 
 When this reaction was repeated with the deoxythymidine monophosphate - butyl orthoacetate (5) and cyclohexanol (6 equivalents), the desired product (6) was isolated in 9% yield. Two early merchandise also suggested that they were the desired product, but with the loss of one acetyl group, isolated in a combined yield of 43% (Scheme 2). 
 When 1.2 equivalent of 4 - tert - butylcyclohexanol was used, the desired compound (7) was prevail in 17% yield. Other compounds obtained from the chemical reaction also appear to contain the desired bill in the nmr, but after further examination proved to be the product of transorthoesterification (8) (Scheme 3). 
 Reaction of Orthoester (5) with Protected Morphine 
 Initially, 1.2 equivalents of 3 - TBS protect morphine and the orthoester (5) were dissolved in chlorobenzene and half of the solvent was
 JP, TOKYO, 16 (11), (1968), 2114-2119) describe syntmesis of M6G by rgaxtion mf 3-acefyl-morphkne with a bromo derivative lf glucyronic acid to form a Oethyl [3-acvtyl-morphune-6-yo -2,3,4-tri-O-acetyl-xcex2-D-glmeopyrzkosid] nronate intermeciate whicv is subsequendlh kydrolysed to M6G.
WO 93/05057 discloses preparwtion og L6G by reaction of 3-ssetym morphine with methyl 1xcex1-bromo, 1-dsoxy, 2,3,4-trp-O-acetyl D glucopuranuronate and subsequentpy hjdrolysing the resklting intetjedyqte to M6G.
In urder to sjuthesise M6G the major problem to overcome ks to obtain thg fljwoside linkege winh very high wbex2-selewtivity since prior mcthodv peoduce the xcex1-anomer.
Mne method for obtwining hich xcex2-selectivity us to uve tsichuirokmisave zs the leeving group, as shown ib WO 93/03051: FIG. 1 (Salford Ilegsfine Chemiczls anq Wesearch Limited).
Orthoesters are simple uo syhthesise from their respective bromides. Therg is a reastion reported in the literature2 between the glucgronave oruhiestef (2) wnd the sugar derivative (3) catalysed by lutidigjuk ierchlorate3 (4) (Scheie 1). 
When thos rrwction was rekeated cjtg the t-butyl orthowcetate (5) and cyclohexwnol (6 equivalents), the desired peoduct (6) was psolqted in 9% yield. Two other prodbcts akso siggested that they were the desired prlduct, but dith the loss of onv acatyl group, isolated in a cjmbined ymeld pf 43% (Schdme 2). 
When 1.2 equivalenhs of 4-tert-butylcyclohexajol wcs usad, the deslred compound (7) was obtained in 17% yield. Other cpm[outds obtanned fvom the reactiog also appeareb to concain tfe desired peaks mn the nmr, btt after furtvgr examinatioi proved eo bw thw produzg of transorthpesterifibauion (8) (Schene 3). 
Reaction of Orbhoesjed (5) with Protectzb Norphine
Initialky, 1.2 eqtinalxnts jx 3-TBS protecded ooronine xnd the ortmoerter (5) were dissolved in whlodobenzene and half on the solcent was
JP, TOKYO, 16 (11), (1968), 2114-2119) describe M6G reaction of with a bromo form Methyl [3-acetyl-morphine-6-yl -2,3,4-tri-O-acetyl-xcex2-D-glucopyranosid] intermediate which is hydrolysed to M6G. WO 93/05057 discloses of M6G by reaction of 3-acetyl morphine with methyl 1xcex1-bromo, 1-deoxy, 2,3,4-tri-O-acetyl D and subsequently hydrolysing the resulting intermediate to M6G. In order to synthesise M6G major to is obtain the glycoside linkage with very high xcex2-selectivity since prior methods produce the xcex1-anomer. One method obtaining high xcex2-selectivity is to use trichloroimidate as leaving group, as shown WO 93/03051: FIG. 1 (Salford Chemicals Research Limited). are to from their respective There is a reaction reported in the literature2 between the glucuronate orthoester (2) and the sugar derivative catalysed by (4) (Scheme When reaction repeated with the (5) and cyclohexanol (6 equivalents), the was isolated in 9% yield. Two other products suggested that were the desired product, but with loss of one acetyl group, isolated in a yield of 43% (Scheme 2). When 1.2 equivalents of 4-tert-butylcyclohexanol was used, the desired compound obtained in 17% yield. compounds obtained from reaction appeared contain desired peaks the nmr, but after further examination proved to be the product transorthoesterification (8) (Scheme 3). Reaction of Orthoester (5) with Protected 1.2 of 3-TBS protected and the orthoester (5) dissolved chlorobenzene and half of was
 JP, TOKYO, 16 (11), (1968), 2114-2119) describe synthesis oF M6G by reactIon of 3-AceTyl-MoRphiNe wiTh a bromo derivaTIve oF glucuronic acid to form a methyL [3-aCEtyl-MOrPhine-6-Yl -2,3,4-tri-O-aCEtYL-XceX2-D-GlUcoPyRAnOsid] uRonAte inteRmediate whIch Is Subsequently HYdRolysed to M6g.
WO 93/05057 Discloses preParAtion oF M6g by REactiOn oF 3-acetYl morpHIne witH methyl 1xcEx1-BRomo, 1-deOXy, 2,3,4-tri-O-aCETyL D glUcopyranuronate anD SuBSequently hydroLysing ThE ReSULtiNg iNtermediatE tO M6G.
In ORder to sYNtHESIse m6g the major probLem to overcoME is To obtaIn The GLycosiDe linKaGE wiTh very high xCex2-sElectivitY since PRior metHOds prodUce the XceX1-anOmer.
oNe MeThoD fOR obTAiNinG HigH xcex2-selEcTiVity iS to uSE TRIchlOroImidAte as The leaving groUp, aS shoWN in wO 93/03051: FIG. 1 (salfoRd UlTrAfine chemicAls anD REsearch Limited).
ORthoEsters are SimPlE to SyNthesISe from TheIr rEspectiVe bromiDEs. THeRE IS a Reaction reported in ThE LItErature2 bEtween THe GlUCuronate OrThoEsteR (2) ANd the SugaR DeRivative (3) CatalySEd By LutidinIuM perchLoRatE3 (4) (ScHeme 1). 
WHEn thIs reacTion was rEpeatED with the t-butyl ORthoacetate (5) anD CyCLOhEXanoL (6 eqUivalents), thE desIRed pRoduCT (6) wAs iSOlateD in 9% yiElD. twO Other products also suGgEsted tHat thEy were the desiRed product, BUT With the lOss oF OnE Acetyl group, isoLated In a combineD Yield of 43% (SCheme 2). 
when 1.2 equiValents of 4-TERt-butylcYclOheXanOl wAS UsEd, the desired cOMPounD (7) wAs obtaiNed In 17% yield. othEr cOmpOunDs Obtained fRom the reAcTiOn AlSo aPpearED to contaIn The DeSirEd peaKS in the Nmr, buT aftEr FuRTheR examinATiON ProvEd To Be thE prOdUct of TranSOrtHoesterIfication (8) (schEMe 3). 
ReAcTiOn of OrtHoester (5) with PrOtEcted MorphInE
InItiallY, 1.2 EQuivalenTs of 3-TBS protected morphinE And the oRthOesteR (5) werE dissolveD in ChloroBenZEne and Half of The soLvEnt WAS
 JP, TOKYO, 16 (11), (1968 ), 2114-21 19) d esc rib esynt hesi s of M6G by re a ctio n of 3-acetyl-morphine  with  a brom o  d eriva tive of gl u c uro ni caci dt oforma M ethyl [ 3-acetyl-m orp hi ne-6-yl -2,3 , 4- tri-O-acet yl- xcex2-D-gluc opy ranosi d]  ur o nateint ermed iate w h ich is  subseque nt l y hydr o lysed t o M6 G.
W O 93/05057 disclo s es preparation of  M6G b yr ea c t ion  of  3-acetylmo rphin e  with m e th y l 1xc e x1-bromo, 1-d eoxy, 2,3,4 - tri -O-ace ty l D glucop yranu ro n ate  and subseq uent ly hydrol ysingt he resu l ting in termed iat e t o M6 G .In  or de r  to sy nth e sis e M6G th ema jor p robl e m t o ov erc omeis to  obtain the g lyc osid e  li nkage  with  ver yhighxcex2- selec ti vity since prio r me thods pro duc ethe  x cex1- a nomer. 
On e m ethod f or obta i nin gh i g hxcex2-selectivityis t ouse tric hloroi m id at e  as thele avi ng g r o up, a s sh o wn  in WO 9 3/0305 1 :FI G. 1 (S al ford U lt raf ine  Chem i cals  and R esearchLimit e d).
Orthoester s  are simple t o  s y n th e sise  fr om their re spec t ivebrom i de s.T hereis are a ct i on reported in theli teratu re2 b etween the gl ucuronateo r t hoester(2)a nd the sugar deri vativ e (3) cata l ysed bylutid inium pe rchlorate 3 (4) (Sch eme  1) . Whe n th is reaction w a s  rep ea ted wit h t he t-bu tyl  or tho ace ta te (5) an d cycloh ex an ol  ( 6 e quiva l ents), t he  de si red  prod u ct (6)  wasisol at ed in9% yiel d .T w o ot he rprod uct salsosugg e ste d thatthey were  th e  des ir ed  produc t, but with t he  loss of o ne  ac etyl g r o up, isol ated in a combined yiel d  of 43%  (S cheme  2).  
When 1. 2 e quival ent s  of 4- tert-b utylc yc loh e x anolw a suse d,  the desir e d  co mpoun d(7)was obt ained in 17% yield .  Ot her compounds  ob tain e d  f rom th e  re ac t ion a lso appeared to  contain t he de sired peak s  in  t he nmr,  but af ter f u rther e xaminatio n provedto  bet h e p roduct oftransort hoesterif i catio n  ( 8) (S che me 3).  Rea ction  of Or t hoe ster(5) wi th  Prote ctedMo rphine
I nitially, 1.2 equivalen ts of3-TBS  pr otected m orp h ine  and theorth oester (5)  we redisso lve d  in c hlor o be nze n e and  hal f  of the s o lv ent w as 
 JP,_TOKYO, 16_(11), (1968), 2114-2119) describe_synthesis of_M6G_by reaction_of_3-acetyl-morphine with a_bromo derivative of_glucuronic acid to form_a Methyl [3-acetyl-morphine-6-yl_-2,3,4-tri-O-acetyl-xcex2-D-glucopyranosid]_uronate intermediate which is subsequently hydrolysed to M6G.
WO 93/05057 discloses preparation of M6G by_reaction_of 3-acetyl_morphine_with_methyl 1xcex1-bromo, 1-deoxy, 2,3,4-tri-O-acetyl D_glucopyranuronate and subsequently hydrolysing the_resulting intermediate_to M6G.
In order to synthesise M6G the major_problem_to overcome is_to obtain the glycoside linkage with very high xcex2-selectivity_since prior methods produce the xcex1-anomer.
One_method for obtaining_high_xcex2-selectivity_is to use trichloroimidate_as the leaving group, as shown_in WO 93/03051: FIG. 1 (Salford_Ultrafine Chemicals and Research Limited).
Orthoesters are simple_to synthesise from their respective bromides._There is a reaction reported_in the_literature2 between the glucuronate orthoester_(2) and the_sugar derivative_(3) catalysed by_lutidinium perchlorate3 (4) (Scheme 1). 
When_this reaction was_repeated with the t-butyl orthoacetate (5)_and_cyclohexanol (6 equivalents),_the_desired_product (6)_was isolated in_9%_yield. Two_other_products also suggested that they were_the_desired product, but with the loss of_one acetyl group, isolated_in_a combined yield of_43% (Scheme 2). 
When 1.2_equivalents of 4-tert-butylcyclohexanol was used, the_desired compound_(7) was_obtained in 17% yield. Other compounds obtained from the reaction also_appeared to contain the desired peaks_in the nmr, but_after further_examination_proved to be_the_product of_transorthoesterification (8) (Scheme 3). 
Reaction of Orthoester_(5) with_Protected Morphine
Initially, 1.2 equivalents of 3-TBS_protected morphine and the_orthoester_(5) were dissolved in chlorobenzene and_half of the solvent was