IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIUS010391091B2

(12) United States PatentWeber et ab

(10) Patent NO.: US 1053915091 B2(4s) Date of Patent: Ang. 27, 2019

(54) Ml(TIIOD OV.YIANUVA&'TURIN&'UPRKNORPIRNK

A.'«D ANAI,O&IUKSTIIKRKOI) PRO%I ORIPA«/INK

(sf) Refcrcnces Cited

IJ 8 PAI'I!N1 iX)&'I JMENTS

(71) Applicant: SIKGFRIKD AG. Zofingen (CH)tt,«57,NOZ BZ" 1 2013 Huang

)f)09 f)156NJ At 620t)') 9'ang et al

t'0 048') 08546 44

(72) Invmitors: Beat Theodur Weber, Gus)ala, CA(US), Lionel Roux. Hegenheim (FR) FOREIGN PATENT DOCUMENTS

(73) Assignee Siegfried A&L Zofingen (CH)

("

) Nntice Subject to any disclaimer„ the term of tluspatent is extended or adjusted under 35U S C. 154(b) by 0 days.

f'/EP&JB

WOWOWOWOWO

279NZJ BfiI 439 179

1 t)64539200708150620081)411957 At2009122436201006710120 1012 1 sfi9

«,it993( 2004

4 1')677(20074,i)008

10 20096(2010

tt),i)010

(65) Prior Publication Data

US 2017/0319574 Al Nov. 9, 2017

(30) Iforeign Application Priority Data

Nov. 19, 2014 (EP) ...

(21) Appl. No . 15/527,540

(22) PCT Filed. Oct. 13, 2015

(86) P("I Nor PCT/KP2015/073646

«( 371 (c)(1),(2) Date; May 17, 2017

(S7) PCT Pub. No.. WO2016/078833

PCT Pub. Date: Mav 26, 2016

14193857

0'l1 0 JR Pl J) ll I('A'I IONS

C uoll. F et sl . *'Cmbnn-13 Nuclou M ignetic Resonance Spectraof Mniphuic Alkaloids*'. Jbc )nurnal of Oi genic f'bemistiy t 197/i),vol 41, No 6, pp 996-1001Wernei, L et sl, "Synthesis of Buprenoiphine from Onpavane visN-l)cmcthylatinn of Oritssvtnc Ouatcinaiy Salts**, tbe .Jnuinal ofOrganic Chemistry (2011), vnl. 6. No I I, pp. 4628-4634Intemanonal Search Repnit for PCT(EP2015(07 646 dated Noi 19,201(Bentley ik Hardy .t Amcncaa f'hcnucal Soocty (19)6 ) 89(l i)3273-3280Bentley et al J Ameucan Chemical Society (1967) 89(13) 3267-3273Andre et al (1992) Synthetic Communications 22(16) 2313-2327l)ctlraw ct al (1') 8) )nuraal nf Vlcibcmal f'hcmistry 21(5). 415-427Bunvell .Ji (19«ro Chemical Re»ews, 54 615-685Contubution of Observation by Tturd Pmty foi EP 157789603dated May 23, 2018

'" cited by cxanuner

(51) lnt. Cl.C07D 489/12 (2006.01)xi 61K 31/485 (2006.01)

(Si2) IJ.S. CL('PC ..461K 31/485 (2013.01): Ci)7D 489/12

(2013 01)

(58) Field of Classification SearchCPC ....................... C07D 489/12; C07D 489/02USPC 546/39. 44See application file for complete search history.

i'ri mar) /:'xomi acr ('haranjit Aulakh(74) .4trnrne); lgent, or Firm Hunton Andrew s KutthI.I.P

(57) ABSTRACTThe invention relates to an improved method ol prepanngbuprenorplunc. a salt thcrcof. mialogs ol'buprmiorplune andtheir salts. In particular. the invention relates to a method ofpreparing buprenorplfine and related products and salts ineconomic and ecologic ways having increased yields

12 Claims, No Drawings

US 10,3911

METHOD OF lyhkNIIFACTURINGBUPRENORPHINE AND ANAI.OGUES

THEREOF FROM ORIPAVINE

CROSS-REFERENCE TO RELATEDAppl.l('A1'IONS

'lliis patent application is a national stage application ofInteuiational Patent Application No. PCT/EP2015/073646I,

111liled Oct. 13, 2015, which clauns pnunty to Europmin PatentApplication No. 14193857.1. filed Not. 19. 2014, the dis-closures of each of which arc herein mcorporatcd by rcfcr-ence.

FIELD OF THE INVENTION

STATE OF THE ART

lhiprenorphine (cyclopropylmethyl-7-((S)-3,3-dinlethyl-2-hydroxybutan-2-yli 6-methoxy-4.5-epoxy-6,14-ethano-morphinan-z-ol), genemslly administered in the tiirnl of itshydrochlonde salt. is a potent semi-synthetic opiate analge- itl

sic, for the relief ofmoderate. chronic and acute pain, as wellas in Ihc therapy ofopiold addicuon. Since ils approval il hasbema marketed us inlcclablc solution, various lypes of tabletsor patches. l3uprenorphine can be administered as sole

lsactive ingredient or in combination with other substancessuch as naloxone, for example

18,19-dihydroetorphine. an analogue of buprenorplune,can be used as strong analgesic. Its clinical propertiesindicate admuustrdtion as subhngual tablet or trmlsdemialpatches. Main application fields are Ihe Irmitmenl of very 40

intense pains and to treat addicts I ivan though the potencyof I 8.19-dihydroetorphine is sevensl thousand times lfigherthan that of nlorphine, the observed side effects are mild

Buprenorpbine and 18.19-dihydroetorphine can be shownby the following formula (H) wherein R's methylcyclopro-pyl, R" is tert-butyl and R'" Is H In case of buprcnorphule,and wherein R's methyl, R" is n propyl and R'" is H in caseof 18,19-dihydmetorphine

R'(F or tutti 3 I I)

OH

so

II is desirable to develop economic dnd ccologm methodsto nuuiufbcture such substances and their phamiaccuticallydcccpldbli: silhs. Ss

Several methods fiir synthesizing buprenorphine frontcompounds isolated from the opium poppy or compounds

1'he present invention relates to an impmved method ofpreparing buprenorplune, analogues of buprenorphine orsalts thereof: as well as a product produced by the method

20of the invention and the use of the product in B phamtaceu-ucal formulation as well as Ihc plmnuaceullcal formulation.111 partiCBIBr. IIIC 111VCllllon rCRIICS 10 d IIIIVCI I:Ihi:li:nl 111CIhoil

having economic and ecologic advantages

,091 B2

(I 3 is i st.t I I

OR OCHI

Wcrncr et al. (Warner, L., Macharu, A., Adiuns, D. R.,Cox. D. Pd Hudlicky, Tq f. Org. Chem. 2011. 76, 4628-4634) describe a synthesis starting from oripavine. How-ever, only a loiv yield can be obtained or a need for furtherreaction steps anscs for oblduung high ymlds of buprenor-plune Also particular slaps have hemi disclosed. WO 2010039210 (I ip 2 342 206) for example describes the hydroge-nation of the 18,19 etheno group

A problem of the actual known methods of preparingbuprenorphine is that the preparation still requires manysteps, a long process time and includes mther complicate andalso cnlical steps. Further. each step reduces ymld, andthCrCfolc'las Bn llupdCI till Ci:oniinuC Bull Ci:ologlc IdC1013.'I'here is a need for new routes for the synthesis of buprenor-phine mid analogues thereof.

In addition, there is further a need to optinlize the processfor synthesizing buprenorplune and analogues thereof froman economic and ecologic point of view

Thus, an oblix:t ol'hc present invention I ~ lo provule animproved, morc cllicimlt, method of obtaining buprenor-phine or a salt thereof, an analogue ofbuprenorphine or saltsthereof.

SUMMARY OF THE INVENTION

I'he current invention ofl'ers a novel method for manu-facturing buprenorphine. 18,19-dihydroetorphine and other

dcnvcd Ihcrelbom are known. Thc most conventional onesuse thcbaine as slarfing material. winch is shown in FonuulaI belolv wherein R is a methyl group and R'3 is methyl. WO2003/024972 and WO 2004/020220 (EP I 439 179) disclosea classical route of synthesis from thebaine to buprenorphineand to mialogues thereof 'I he synthetic route is a series ofchemical reacuon steps, including (I) adding methyl vinylkclouc to thcbiune, (ii) hydrogcnauou ol'hc 18,19 cthcnogroup, (iii) addition of the tertiary butyl group by a Ciri nardreaction, (iv) 17-N-demethyfation and introducin of acyano group (2 steps), (v) 3-0-demethylation, (vi) hydroly-sis of 17-N-cyano group, and (vii) addition of a cyclopropylmethyl group.

Thc number of steps, thc low yield in some cutical stepsand the restriction to thebaine as starting matenal are seriousdmv bacl s of this method.

WO 2007/081506 (I ip I 981 891) describes a process fiirpreparing buprenorphine fmm oripavine. which Is shown infilrmula I below whcrcui R is a methyl group and R'" Is H,and which also shows thc mmibenng of'arbon atoms ui thcstnicture of oripavine and analogues as well as productsderived therefrom. The process comprises a series of 8cheniical reactions. fiillotving along the conventional routeas described when usin thebaine as starting substanceDrawback of tlus route is thc need to protect the hydroxylgroiip 111 ptistlton 3 Wht:Il usulg orlpavuli: IIS Stal1ulg BIBII:-

rial Reported yield over all steps is calculated to less than11.5%

US 10,391,091 B2

R'iF r &s&: 111

C1H

analogues thcrcol; as well as acid add&non w&lls. An eco-nomic and ecologic v ay is presented to manufacnire thedes&real substances usuig a novel sequence of rcaclion stepsdelivering a satisfying yield and without the knov n andexplained drawbacks of actual procedures.

1'he inventors fiiund that such substances nr salts thereofcan easily be produced by choosing a novel series ofI'c;let&on& anti Ihus avoichng sonlc of thc conventional &cue-

&ion steps. niainly the pmtection of a side clmin. In addition,1&1

an elegant way of substituting thc N-methyl group by anyalkyl group has been found Further. an increased yield canbc oblmncd with &hc novel method.

Additinnaily. &t was fiiund out that it is eifective to carryoul &hc s&c)&s with low yield carlicr ui a rcacuon scqucncc inorder lo reduce production cost and ecological impact, as theantount of e . solvents and energy can be reduced. Theinventors found out that it is possible to carry out theproduction of buprenorphine and analogn&es thereof with anincreasing yield &n the steps by carryuig ou& lira«he con-version of the acetyl group m position 7 into a tertiary alkylalcohol and then redu cuig the ethcno group ui position I 8, I 9

of the buprenorphine structure. contrary to the niute cont-nioniy applied in the state of the art. I'unhermore, theamount of an expensive catalyst used can be reduced v hencarrying out the reducing step (iv-a) after the step ofconverting the acetyl group in position 7 (iii-a), i.e. in a Laterstep, compared lo carrying oui thc reducing slop (i&i-b)bcforc ihe conversion slap of thc acetyl group ui position 7

(iv-b). tlnis also reducing &nevitable losses of such catalyst &o

as well as avoiding further waste materialIn one aspect, the present im ention relates to a methnd of

preparing a compound of Fnrmula IL or a salt thereof. fmma compound of formula I, v herein in Formula II R'epre-sents s linear, branched and/or cychc alkyl group having I 1&

to 10 carbon a&orna. R" represcnls a luicar, branched and/orcvchc alkyl group havuig I &o 10 carbon atoms. and R'"

represents I I or a linear, branched and/or cyclic alkyl gmuphaving one to 6 carbon atoms, comprising

40

(n) &uldition of methyl vinyl kctonc &o obtmn 1[(So,7a)-17-all y1-4.5-epoxy-g-hydroxy-6-&nethoxy-6,14-ethenomor-plunan-7-yl]cdianonc or I[(fic&,7&x)-I7-alkyl-4.5-cpoxy-S-alkoxy-fi-methoxy-6,14-ethcnontorphinan-7-yl)ctll&ulonc:(&i&-a) conve&ting the acetyl mup in position 7 into a

tertiary alkyl alcohol having a general structure C(Ol1) ((.'ll,) 8". wherein 8" represents a linear,branched and/or cyclic alkyl ~Coup with I to 10 carbonatoms, and

(iv-s) reducing the etheno group in position 18.19 to fomithc compound of Fomiula II; and

(v) optionally converting the product front step (iv-a) or step(&v-b) into an add&non sall, preferably n phannacculicallyacceptable saltIn another aspect the present invention relates to a com-

pound of I'or&nula 11.

I Fwa&uls Ill

011

v herein in Fomiula I I R'epresents a linear, branched and/orcychc all yl group having I to 10 carbon atoms, R" repre-smils a linear, branchcxl and/or cychc alkyl group havuig I

to 10 carbon atoms, and R"'epresents H or a linear,branched and,'or cyclic alkyl group huving onc to 6 carbonatonig obtained by the method according to the invention

Also dcsvnbed is a phannsccutical formulation compris-ing the compound of Forniula ii obtained by the methodaccording the invention.

Also described is the pharmaceutical forniulation com-prisuig the compound of Fornn&ia II obtained by the methodaccording the imennon Ibr usc in a me&heine.

In addition, described is the use of the compound ofFornnda II obtained by &hc me&bod uccording thc uivcnlionin a pharmaceutical formulation

l&urther embodiments are disclnsed in the dependentclaims and can be taken fmm the followmg description andexamples, without being limited thereto.

OR OCI I

iF «»1. 11Dl 11'AII

Ill

) I )I ig('RI PTION 0l& 'll ll I Pgi igi

&N'I'N&pi&N11ON

sc

OR" Oi'll&

(1) optionally rcplacuig thc group R ui thc compound ofFomiula I, whcrcui R is H or methyl, by a group R'eing s&

a linear branched and/or cyclic alkyl on&up having I to 10carbon atoms:

All ranges disclosed herein are to be considered to besupplcmcntcd by thc &crm "abouf L unless clearly dclined totile coiins&y oi olllcl w&sc cli ai frolll lhc I:oiitcxl.

All numbers or pcrcen&agcs relaung to Iunounts ol'substance within this application are given in wt ')I&, unlessclearly defined to the contrary or otheovise clear fmm theccultcxt,

In regard to this invention. a reference to a linear,branched and/or cychc all yl group rcfi:rs to linear alkylgroups, branched alkyl groups, cyclic alkyl groups, cychcalkyl groups with luiear or branched alkyl groups auachcd,i e cycloalkylalkyl gmups, and hnear or branched alkylgmups with a cyclic alkyl group attached. i e. alkylcy-

US 10,391,091 B2i

cloalkyl groups, whcrcin thc cyclic alkyl group in thcalkylcycioalkyl groups can also have linear or branchedalkyl groups alurchixl.

'I]le present invention relates in a first aspect to a met]Ridof preparing a compound of Fomnda II. or a salt thereof,from a compound oi'ounula I, whcrcin ur Fonuula II R'epresentsa linear. branched and/or cyclic alkyl groupluiving I to 10 carbon atoms, R" represents a luu:ar,branched and/or cyclic alkyl gmup having ] to 10 carbonatoms. and R"'cprcscnts H or a linear, branched and/orcyclic alkyl gmup having ] to 6 carlxm atom~, comprising

OH

(F»wui. I)

iF 3 rur: 01

OH

lo

OR OCH3

/rrN

iF 3 r»i. Il

OR"'culIe:2q(i) optionally replacing the group R in the compound ofFormula I. whercur R rs H or methyl, by a group R', beingditferent from R, selected from II or a linear, branchedand/or cyclic alkyl group having I lo 10 carbon atoms:

(ii) addition of nlethyl vinyl ketone to obtain 1[(5ox7a)-17-alky]-4.5-epoxy-3-hydroxy-6-methoxy-6,14-ethenomorplr-inan-7-yl)clholonc or I [(511,7cr)-]7-alky]-4.5-epoxy-3-alkoxy-6-nrethoxy-6.14-ethenomorphinan-7-yl)ethanone,

(ill-a) collvcrllllg lllc eccl)'I group lll posltloll 7 allotertiary alkyl alcohol having a general stmcture / C(OH) (CH3)-R", wherein R" represents n hnear,branched and/or cyclic alkyl gmup with I to 10 carbonatoms, and

(n -a) rrxiucrng thc cthcno group ur posrtron 18.19 lo filmlthe compound of I'ormula Ik and

(v) optionally converting the product from step (iv-2) or step(rv-b) urlo an addrnon sall, prcfi:rably a phamraceutrcallyacceptable salt.

Further dcscribcd is a method of prepanng a compound ofllonmila II. or a salt thereof. from a compound of llornndaI, wherein in Fornulla H R'epresents a linear, branchedandior cychc alkyl gmup having ] to ]0 carbon atoms, R"

represents a linear. bmnched and/or cyclic alkyl grouphaving I lo 10 carbon aroma. and R"'cprcscnts H or a lurcar,branched and/or cyclic alkyl group having ] to 6 carbonstools.conlprbslllg''

il crural.r IV!

sc

0 IT

OH Oi:Hr

(i) optionally replacing thc 17-N nu:thy] group ur oripavuress by a group R beulg a lrncar. branchrxl and/or cychc alkyl

group having 2 to 10 carbon atoms to obtain a compoundof llomlula III, ]7-N-alk331 noronpavine:

(i) optionally replacing the group R in the conrpound of-" Formula L wherein R is H or methyl. by a mup R', bein

dr]pi:real from R, selected Ibom H or a lurcar, burnclrcxiand/or cyclic alkyl group having I to 10 carbon atoms;(ii) addition of methyl 1inyl ketone to obtaur 1-[(SO.7m)-17-alky]-4.5-epoxy-3-hydmxy-6-methoxy-6,14-ethenomor-

" phinan-7-yl[ethanone or I-[(5O,7O)-]7-alky]-4.5-epoxy-3-alkoxy-6-methoxy-6.14-ethenomorplunan-7-yl[ethanone;

(rir-b) reducing thc clheno group rn positron 18,19: and(rv-b) convcrung thc acetyl group rn positron 7 uric a

tertiary alkyl alcohol havina a general structure (ls

(OI I) (('113)-R". rvherein R" represents a linear,branched and/or cyclic alkyl group with I to 10 carbonatoms. to form the compound of Formula Ii: and

(v) optionaily converting the product from step (iv-a) or step(rv-b) into an addrnon will, prefi:rably a phannaccutically

40 acceptable sall.In Ilormulas I and II. R, Rk R" and R"'an be the same

or differenAccording to certain aspects. the present im entlon relates

to a method of preparing a compound of Formula IV. or n

salt thereof. from oripavine, wherein ln Formula IV R'epresr:ntsa hnear. branched and/or cyclm alkyl gmuphaving I to 10 carbon atoms and R" rcprcsenls a linear,branched and/or cyclic alk31 group having I to 10 carbonuterus conlpnsrllg'

US 10,391,091 B2

/N

group havuxg 2 Io 10 carbon atoms to obtain a compoundol'oumlla III, 170¹lkyl noronpavlnc,

/N

01( 00(H

OH 0001(u) ailditlon of methyl vinyl kc(one xo obtain I-[(SCC7ix)-

17-alkyl-4.5-epoxy-3-hydroxy-b-methoxy-6.14-ethe-

nomorphlnan-7-yliethanone:

(iii-x) convertin the acetyl group in position 7 into aio

teixiaxy alkyl alcohol havmg a general structure / C

(OH) (CH,) R", whcrcux R" rc7xrcscnxs a luxcar,

branched and/or cychc alkyl group with I to 10 carbonatoms; and

(0 -a) rixluclng thc cthcno group ux position 18.19 Io fixmx

the compound of Founula IV: or

(iii-b) reducing the etheuo gnxup in position 18,19, and

(iv-b) converting the acetyl group in position 7 into a so

tculary alkyl alcohol hdvlllg a gcllcl'Bl slrucullc M(OH) (CHB) R", whcrcux R" rc7xrcscnxs a luxcar,

branched and/or cychc alkyl group with I to 10 carbonatoms. to form the compound of I'ormula IV: and xs

(il) addition of methyl vinyl ketone to obtain I [(5(x,70)-17-alkyl-4,6-epoxy-3-hydroxy-d-xxxe(hoxy-6,14-cxhcnouxor-phinan-7-yliethanone:(m-d) convertuxg the acetyl group ln position 7 into s

tertiary alkyl alcohol having a eneml structure(OH) (CH1) R". wherein R" represents a hnear,branched and/'or cyclic alkyl group with I to 10 carbondlouis, Bllil

(lv-a) reducing the etheno group in position I 8.19 to formthe compound of Formula IV; and

(v) optionally converting the product front step (iv-a) or step(lv-b) into an addition salt. preferably a pharmaceuticallyacceptable saltIn addition. described is a method of preparing a com-

pound of Founula IV. or a salt thereof. from oripavine,whcrcin ln Fornulla IV R'epresents a hncar, braxxchcs)and/or cychc alkyl group Irdx lng I xo 10 carbon atoms andR" represents a linear, branched and/or cychc alkyl gmupllavhlg I to 10 carbol'I 'ltoiuscoulpl'Isulg'v)

optionally converting the product from step (iv-x) or step

(iv-b) into an addition salt. prefenxbly a pharmaceutically

acceptable salt40

According to certain aspects. the present invention relatesto a metlmd of preparin a compound of Fomiukx IV. or a

salt thereof, from oripavine, wherein in Formula IV R'epresentsa linear. branched and/or cyclic alkyl grouphaving I Io 10 carbon atoms and R" rcprcscnts a luxcar,

branched and/or cychc alkyl group lxaving I to 10 carbonatoms comprising. OH

R'

OOHx

00

(I mmalx IV!

R'

N

(I dxmvls IVI

c (i) optionally replacing thc 17-N nu:thyl group ux oripavuxeby a group R beuxg a hncar. branchixl and/or cychc alkylgroup lmving 2 to 10 carbon atoms to obtain a compoundof liomlula III, 17-N-alk3xl noroupavine:

(I Ouxxxxls. HI I

00sc

N

OH 0(.'Hx

ss(i) optionally replacing the 17-N methyl group in oripavine

by a group R being a hnear, branched and,'or cyclic alkyl

OH 0('H;

US [0,391,091 B210

(u) addition of methyl vinyl kctonc to obtain I [(5xu7o)-17-alkyl-4,5-epoxy-3-hydroxy-6-methoxy-6„14-ethenontor-phinan-7-yl[ethanone;(iii-b) reducing the etheno gnlup in position I g,19, and(iv-b) converting the acetyl group in position 7 into a

tertiary alkyl alcohol having a genemll structure C(OH) (CH3) R", whcrcul R" rcqtrcsents a lulcar,branched mid/or cyclic alkyl group with I to 10 carbonatom~. to form the compound of Formula IV: and

(v) optionally converting the product from step (iv-a) or step Io

(iv-b) into an addition salt. prefenlbly a pharmaceuticallyacceptable saltIn FormuLas IH and IV. R. R', and R" can be the same or

ihllcl'cnl.II is understood that all these reaction slaps (i) lo (v) work

under dill'creat conditions In general. there are no limita-tions in the choice of the solvents, temperature, reactiontinle. or aas pressure

The optional step (I) is a nucleophilic subsritution. notparticuLlrly limited, and can be suitably carried out as loknown Ibom gmlcral synthesis methods. Stop (i) consists oftwo sub-slaps to replace a 17-N R group by a dtffcrcnt17-N-alkyl mup I'irst the alkyl group R's introduced andR is released I'or example, the compound of lionnula I, e g.oripavine or thebaine, can react lvith an alkyl R''vhereinR'epresents a linear. branched and/or cyclic allylgroup having I to 10 carbon atoms and X'epresents asuitable leaving group like halogciude, india lo an addi-uon oi'alkyl and subscqucntly thc 17-N methyl group or thcH in position 17 can be removed to obtain 17-N-alkyl lonororipavine in case R"'s II. Depending on starting andtar et molecule, step (i) needs to be carried out or not.Preferably R is a methyl group and R'an be a hnear,branched and/or cyclic all yl Lrroup having I to 10 carbonatoms. ls

In certain mnboduncnts, thc reaction oi'tep (i) can becorned out al a tcmpcmturc bet w imn 0 and 100" C., c.g. 50to 90" (', preferably 70 to g5" (' filr a total tiine of less than24 bourn lvberein e g the addition step ofan alkyl amup canbe carried out in less than 20 hours and the elimination of the somethyl group or H in less than 4 hours. A solvent can besuitably seleclixl for thc reaction mid is not parlicularlylinn(ed ul step (3). It can be c.g. DMF (dimedlyllhmuunide)in Iheaddilion of an alkyl group and DMSO (dnnedtylsul-filxide) in the elimination step from the quaternary amine.

Oripavine or thebaine, serving as possible and preferredstarting materials. can thereby be obtained from knov nsources. Preferably oripavine and thebaine are extractedfrom lhe latex of certain types of papaveraccac. II is alsopossible lo usc synthetic or semi-synlheuc onpavulc or o

thcbtllnc ul Illc pri:sclll inc(boil.In certain embodiments a different starting material than

oripavine can be used and thus the substitution of theoriginal allyl Lrroup to the tertiary amine in step (i) by adifferent one is not limited to the substitution of methyl by ssmethyl cyclopropyl. In contrary. all kinds of linear. orbranchcxl alkyl groups havulg a total of3 to 10 carbon atomsas well as alkyl groups having a ring structure can bc usixkin case the alkyl group contams a ring the ring, mav have 3to 7 carbon atoms Preferably oripavine or thebaine is used roas educt and convetted to buprenorphine or I g,19-dihydme-torphine. Further preferably oripavine or thebaine is con-s ertcd lo buprcnorphine, and according to certam aspectsonpavine is convcrtcd to buprcnorplune.

In preferred cmboduncnls, thc group R's a lulcar, ssbranched and/or cyclic alkyl group having ] to 10 carbonatoms. e.g a methyl gmup ln embodiments lvherein

R'ontains

a cyclic group. c.g. an alkyl cycloalkyl group.R'as

preferably 3 to 10 carbon atoms. further prefemlbly 3 to7 carbon atoms, morc prefi:rably 3 to 5 carbon atoms. Asuitable and preferred example is e g a nlethylcyclopropylgrollp.

I'he addition of nlethylvinylketone in step (ii) can besuitably carried out using e.g. a Diels-Alder-reaction. Theaddition in step (ii) can be an addition of methyl vinyl ketone(MVK) by a Diels-Alder reaction to introduce an ethenogroup bclwcen Ihc atoms in position 6 and 14. While addulgthe etheno group between the atoms in position 6 and 14, anacetyl group is attached in position 7 ul such a reaclion.

In certain embodiments, the reaction can be cerned out ata tcmperaturc bclwxmn 0 and 100'., c.g. 50 to 90'.. fora total time of less than 24 hours, e.g. less than 15 hours A

solvent for the reaction can be suitably selected and is notparticuLlrly limited in step (ii).

The educt in step (ii) can be either the compound ofFormula L c.g. onpax inc or lhcbainc, ll'he optional slc73 (i)is not carried out, or can be e.g, the 17-N-alkylated productof Ihc compound oi formula (I) il slap (3) 3 ~ camcd out.

Step (iii-a), respectively step (iv-b) represent the conver-sion of the acetyl grmip in position 7 of the ring stnicture bya suitable reaction, e g by a (iri nard reaction with R"MgX,wherein R" represents a linear. branched and/or cyclic alkylgroup with I to 10 carbon atoms. and X represents a halogento iorm Ihc alcohol. Slap (ul-a), rcspccnvcly slap (lv-b) canalso bc scen as a corn craton of thc acetyl group in position7 into a 18,19-dehydrobuprenorphine denvative/analoguehaving different groups R'nrgor R" and/or R'". w:herein RLR" and R'" can be the same or ditferent. e g by reaction lvithR"MgX. wherein R" represents a linear. branched and/orcychc allyl group with I to 10 carbon atoms. and Xrepresi:nts a halogen.

In ccrlmn cmboxhmenls. Ihc Gmgnard reaction in slc73

(iu-a), rcspcctlvcly slap (iv-b) can be conducted with anysuitable substance to convert the acetyl group in position 7

to an alcohol For example tertiary butyl magnesium chlo-ride can be used to fonu a desired di-methyl butanol group(e-g a 3-(2,2-dimethylbutan-3-ol group). or n-propyl mag-ncsnlm chloride ls used to form thc dcsircd 2-penttmolgroup. It is understood tluil all kinds of linear. branchcxiand/or alkyl groups havulg a total of I to 10 carbon atoms.preferably 3 to 10 carbon atoms. further preferably 3 to 7

carbon atoins as well as alkyl groups having a ring structurecml be used. In case the alkyl group contains a rin the rinmay have e.g. 3 to 7 carbon atoms. For example, R" can bea tert-butyl group or ml n-propyl group, whcrcin R"'an bee g. H or CHs, c.g. H.

In certain mnbodnncnls, lhc reacuon can bc corned oul ala temperature between 0 and 100" (', e.g 50 to 90" (preferably 55 to g0" (', fora total time of less than 24 hours,e . less than 15 hours. A solvent for the reaction in step(iii-a). respectively step (iv-b)„can be suitably selected andis not particularly limited. According to prcfcrrcd cmbodi-mcnls. thc solvent in siep (ui-a) or (iv-b) comprises ml etheror is an ether.

liurther preferably the solvent in step (iii-a) or (iv-b)comprises an ether like tert-butylmethylether. 2-methyl-tetrahydrofilran. diethylether, dimethoxyethane, dime-thoxymethane or mixtures thereof. particularly tert-butylm-ethylcthcr, 2-methyl-tctrahyxlrofuran, dimcthoxymcthane ornuxturcs Ihcreol. 11&c solvent used ul (iu-a) or (iv-b) canliirlhcr compnsc solvmlls like dioxanc, tetrahydrofuran orcylcopentyl-methyl-ether, which are less preferable as solesolvents, though

US 10,391,091 B212

In cirtain aspects, Ihc solvmlt ul slcp (m-a) or (iv-b)comprises an ether like tert-butylmethylether. 2-methyl-tetrahydrofiiran. diethylether. dimethoxyethane, dime-thoxymethane or mixtures thereof lvith a least 30 wtpreferably at least 40 wt. %, with regard to all solvents usedin step (iii-a) or (iv-b), particularly tetr-butylmethylether,2-methyl-telrahydrofuran. dlmcthoxymclhane or nuxturcsthereof. In this I'cgard, other solvents hkc ihoxanco Iclrdh)'-dmfuran or cylcopentyl-methyl-ether can be cinntained in theSOIVCITT ITIIXIOI'1 I il

Preferably. step (iii-a) or (iv-b) is carried out usingessentially tert-butylmethylether, 2-methyl-tetmhydmfuran,diethylether, dimethoxyethane. dimethoxymethane or mix-tures thercol; parucularly tait-butylmcthylcthcr, 2-mcthyl-tctl'iihy'dliifuran. dnnclhoxvnlcthdnc ilr nnxtulcs lhincof. Iis I

solvent. In this regard. other solvents like dioxane. tetrahy-dm hiran or cylcopentyl-methyl-ether can be contained in thesolvent mixture with less than 10 wt. %. based on the totalweight of all solvents used in step (iii-a) or (iv-b).

According to certain embodiments, n linear, branched Ioand/or a ring contauung reagent RolvigX is used ul step(ni-d) or (iv-b) for thc convermon of die acetyl group into thehydroxyalkyl group. wherein Ro represents a hnear,branched and/or cyclic alkyl gmup with ] to 10 carbonatoms. and X represents a haklgen.

Step (iv-a). respectively step (iii-b) represents a reductionof the 18,19 etheno mup bond to form the desired sub-stance as free base, c.g. a rcduclion ol'he clhcno group inposition 18,19 to gct buprenorplunc or thc desired mlalo ucthereof. In certain enlbodiments the hydrogenation of the lccarbon-carbon double hound as disclosed to be step (iv) canbe executed with any known technology In certain embodi-ments conventional hydrogenation is indicated. in certainother embodiments the use of a hydrogen transfer agent isindicated. In the second case both ml cx(ennui and an intcnrdl lshydrogen source can bc used Prcfcrably tlus step Is carriedoui with hydrogen gas and any dppmpnale catalysl Apreferred reaction system is hydmgen gas and a palladiunlon carlxm as catalyst

The reaction can be cerned out using e.g. a hydrogenation do

reaction with a suitable catalyst like palladium on carbon,c.g. Pd/C with 6'!o Pd, or any otlmr suitable cauilyst. Thcprcssure for thc hydrogen In thc hydro cnalion rcacuon canbc suitably selected and cdn bc c.. bc(ween 4 mid 20 bar.Also different pressures can be used in step (iv-a) and step(iii-b). Ioor exanlple, a suitable pressure in step (iii-b) can bebetween 4-10 bar„whereas a suitable pressure in step (iv-1)can be between ll and 20 bar. Further, n solvent in step(iv-d). respixuvcly step (ui-b), cim bc suiidbly selected andcml bc e.g. an alcohol hkc methanol. ethanol. propimol hke o

n-prop;mol or i-propmlol, or butanol. ctc. In addition. thereaction time in step (iv-a) or step (iii-b) is not particularlylimited. and also not the reaction time Au suitable reactiontemperature can be e . between 10 and 100'.. preferablybetween 40 and 80" C. o.

In tins regard it has bccn found thai a(cps (iii-b) mid (iv-b)can beswappcd while maultaining all advantages of thcmethod. It luis further been found that step (iv-b) can bcconducted prior step (iii-b) without losing perfornlance,yield or other advantages of the actual invention. resultmg in ica reaction lvith steps (iii-a) and (iv-a). When carrying outsteps (iii-a) and (iv-a)„ the reaction with the generally lowerIciic11on 1'lckl ls cdrrlixl oifl fit sob c.g. In case of 11 OI1gnarilreaction being bc(ween 60 mid 65%. with a conversionbctwciil 75 and 86'!o. In con(rash thc hydmtion step (iv-a) ssenemlly has 1(X)%o conversion with yields between 75 to

90%, as can be seen e.g in the I ixamples. 'I'his way solvent

R'(I oo»oiio ii!

OTT

OR" Ot THI

whcrcin ul Furmula II R'cprcscnts a lulcar, branched and/orcyclic alkyl group having I to 10 carbon atoms, R" repre-sents a linear, bmnched and/or cyclic alkyl group having I

to 10 carbon atoms. and Ro'epresents II or a linear,

amount and energy consumption in the overall process canbe reduced. as lvill be shown for the Examples below.

Thc substance obtdulcd after step (iv-a) or step (Iv-b) thatv ay cml be transferred into an addition salt, preferably intoa pharmaccutically dcccptablc acid adihtion salts, usulgstandard procedures as dissolving the substance in an appnl-priate soll ent. adding the acid and ctystallizing.

In certain embodiment~. the optional step (v) can besuitably carried out with e.g. the compound of Formula (II)and a suitable, prcfcrably phannaccuticdl acccpuiblc, Inor-ganic acid lii e HCI, HBr, H3PO4, HZSO4, HNO3, or n

suitable, prcfi:rably pl»irnniccutmdl acceptable, organic acidlike maleic acid, malic acid. malonic acid, methanesulfimicacid. or 4-tolucncsulfonyl acid. 111c solvent and reactionconditions like temperature and pressure are not particularlylimited and can be suitably determined based on the com-pound of liormula (II) to be reacted and the acid. In certainembodiments. buprenorplgne can be reacted with an acid toproduce a buprcnorphmc snit, for cxamplc buprcnorphulchydrochloride. The production of a buprenorphine salt. e..buprmlorplunc HCI. cdn bc accomphshcd, and is not limit«»Ito. by any knovnl reaction routes after buprenorphine hasehm been fomled.

According to certain embodiments, Ro'epresents a linear,branched and/or cyclm alkyl group having I to 6 carbonatonls in the compound of lionnula I, e g thebaine In suchembodiments R'o can be converted to H at any suitable timedunng the present method, i e befilre step (i). after step (i),after step (ii). after step (iii-1) or (iii-b) or step (iv-a) or (iv-b)or after step (v). In certain embodiments. Ro's convened toH bcfilrc step (I) or after step (i) or after step (ii), prclbrablybcffirc stc71 (i). Thc conversion of thc alkoxy group inposrtlilf1 3 ill to a hydi'oxY gnnlp ill posltl oil 3 Is kiloumi ill thcart and can be suitably carried out using known nlethods (seee g. Andre, .I-iy et al, "0-Dcmeihy la/ non «f Dpi il id Dcri va-n vcs iriih Marha«e S«if«mr 4 rid!Mcihi amne dppli I a/iari toihc S) nrhcsis af /v'ala»one a»d .had/agnes", SyntheticConun., 22(16). 2313-2327 (1992).

According to certain mnbodimcnts Ro's H In tlus casenormally R'o is not convened anymore

According to certain enllxldinlents. 10 represents methyl-cyclopmpyl and R" represents tert-butyl or 10 representsmethyl and R" represents n-propyl in founula II, with R'o

being H in both cases.Furtlmr disclosed Is a product obtaulcd by thc present

melhod.According to another aspect. the present invention relates

to a conlpound of I'omtuia 11,

13US 10,391,091 B2

14branched and/or cyclic alkyl group havulg I to 6 carbonatoms. obtained by the method of the present invention

According to certain cmbodimenm Ihc present inventionrelates to a compound of I'ormula IM

disclosed starting Ibom onpavinc to buprcnorplune. Tlussequence of reactions is shorter and more efficient as con-vcntlonBI s)'Ilthcsis:

k' 0 drmvls IVI

OttHO

OH

wherein in I'ornlula IV R'epresents a linear, branchedand/or cyclic alkyl group havulg I to 10 carbon atonw andR" represents a linear, branched aod/or cyclic alkyl grouphaving I to 10 carbon atoms, which is obtained by thenlethod of the present invention

In addition. a pharnlaceutical formulation comprising thecompound of the present mvention is described Apart frontthat, the pharmaceutical formulation is not limited. Thepharmaceutical formulation can be e.g. in the form of Bninlcmtion solution, a tramdcnnal patch or lbr sublingualdppllCtaloll.

'Ihe pharmaceutical formulations can further conlprise lcone or more phannaceutically acceptable excipients, e g.water, stabilizers or antifungal.

These exciplents are well-known to the skilled person,e.g. from Remington„The Science and Practice of Phar-macv, 22" Edition, 2012, which is ulcorpomtcd hcrcul by 31

relcrcncc in regard to pharmaccuucal cxcipimlls. particu-larly volume I: "Thc Science ol'lmnnacy". pages 1049-1070 or front Rolve, R. (', Sheskey, 9 .I. Quinn. M. II,('ook, W. (i.. Iienton. M I i., *'I landbook of PharmaceuticalExcipients*k 7m Edition. 2012, which is incorporated herein do

by reference in regard to pharmaceutical excipients.lhc phannaccutical formulation can be used ul mcihcinc.

Also dcscnbnl is thc usc ol'hc compound dcscmbcd aboveul d phdnnaccunctll folultdation.

With regard to this mvention, an analogue of buprenor-pl'llilc iB B coolpoulld with thc satuc ling stiucnll'c'ls Bhov Il

in fonnukl II. Such analogues ofbuprenorphine or ofanothercompound can be obtained by choosing the Bppmpriatesubsutumlts R'ud/or R" and/or Rmk

In;m cxmuplary reacuou. the Rlllowing steps can be c

includlxt: 0) optionally thc addition of alkyl to thc ter(airyamine of the compound of liormula I, e.a oripavine orthebaine, to form a tertiary or quaternary amine, and remov-ing the 17-N-methyl group or hydrogen at the 17-N to get17-N-alkyl nomripavine or an analogue thereof with dlfier- ssmlt R'". EI) addiuou ol'methyl vinyl ketone by a Dials-Alderreaction to ullroduce the stheno group bc(ween the positions6 and 14. Eh) conversion of thc acciyl group by a Gltgnardreaction to foun an alcohol, and (iv) reduction of the I H.19etheno group to get bupienorphine or analogues thereof It ichas also been found that step (iv) can be conducted prior step/Iii). The product can then easily be tmnsfonned into Bndddllloli sBIH

A gcncral reaction scheme Rlr the production ol'buprcnor-phule ls shown below, wluch shows how excmpliiicd sibuprenorphine is formed from oripavine. A whole exenl-plary route of synthesis according to the present invention is

110

13—

H. BI

I IO

I IO

The following reaction scheme shows exemplified bothpossible routes of synthesis for 18,19 dihydroctorplunc I'rom

oilp'Ivlnc.

US 10,391,091 B216

HO

is(VX

/.1

0—

HO 0— HO

HO 0— HO 0—

EXAMPLES

lhc present invention will now be described in detail withreference to seveml examples thereof.

However. these examples are illustrative and do not limitthe scope of the inventionBuprenorphine from Oripavine

An cxmnplary stcpwtsc reaction scheme lor producuigbuprenorphine fmm oripavlne in 4 steps is given in thefollow uig Examples I to 4

stirred al 88'. for 16 hrs. Thereafter, tlun layer chroma-tography indicated no starting matenal. Hhe mixture waspartially'hsullcil lo gii 1: 15.0 g oi ihslillatc. Thc solution

40 was cooled slowly to 0" (2 during 12 brs. and filtrated togive the desired product (8.45 g. 70%). The analyses u ere inagreement with literature data.

I:xample 3

18,19-dchydrobuprenorplune

Example I

N-cyclopropyl methyl noronpavine is as synthesizedusing procedures as known fmm literature I'or example theroute proposed by Werner et al. (Werner, I .; Machara. A,Adamg D Hs (:ox, D 9: I ludlicky, I';.I. Oig (:hem 2011,76, 4(i28-4Ci34) is convenient and has a yield between 27%(chlonde as halo etude) up to SS% (bromide as halogenide).

Example 2

1-((5rr,7cx)-17-(cyclopropyi methyl)-4,5-epoxy-3-hydroxy-(i-methoxy-(i,14-ethenomorphinan-7-yi]-

ethanone

N-cyclopropyl methyl noronpavinc from example I (10 0

g, 29.64 mmol) was dissolved in ethanol (60 mL). Hydro-quinone (65 m, 0.593 nimol) and inethyl vinyl ketone (5 19nil.. 63.72 mmol) were added. 'Ihe reaction mixture was

A solution of ternary butyl magnesium chlonde (2 molar)in diethyl ether (3 I nil ) was added to tertiary butyl methylclhcr (MTBE) (3.5 g). Thc solution was distilled to give I.S

8 ofdistillate I eit-butyl methyl ether (3 5 8) was added, andthe resulting mixture was distilled to give 1.5 g of distillate.'I'his step v;as repeated ivith 2 a of tert-butyl methyl ether to

1. give 2 g of distiilate. I](50, 70)-17-(cyclopropylmethyI)-4,5-1:poxy-3-hydroxy-6-methoxy-6.14-cthenomorplunan-7-yl]ctlmnonc (O.S g, 1.223 mmol) from example 2, dissolvedin dioxanc (2.5 g), was added slowly dunng 15 minutes at20" (: to 22" (: The resulting white mixture was stirred

re dunng 4 h at (10" ( and then cooled to 0" ('he reactionv as quenched with a saturated NHsCI solution (10 mI ).After separation, the aqueous layer ivas extmcted twice withethyl acclalc (AcOEt. 2 tunes 10.0 mL). Thc combtncxIorganic layers werc dried oscr MHSOs mid concentrated.

ss The crude product was punlicd by ilash chromatography(ethyl acetate/heptane: 312) to give 18.19-dehydrobuprenor-phine (conversion 72iw yield: 54%. 0 199 8).

17'I'A131.1 t I

US 10,391,091 B218

continued

Con(era onv and y elda ur Faun le I ua n ddl'erenr aolyenta

Example Solvent Convera on.",veld'h

td3y

Z

MTBEthy I I tr: I ydmlln- o

rh lhyl It

d rnerhoxyrnerhanedl oxarrev lopentyl merhyl ether

76s.

73.2i

o

434((2

'.I( ul.:I(

tert-Bu'.vial.'IMTI3F

Drosaltc

Example 4

13uprenorphine

IN,l'3-dehydmbuprenorphine fmrn example 3 (2 0 g, yo

4.296 nunol) was dissolved in methanol (100.0 g). Palla-dium catalyst on curbon (0.5% Pd, 0.4 g) was added. Theblack mixture v, as stirred at 65'. under 15 bar of hydro-gt n. Alter 60 hrs. CI hi dlnlg lhc Icacntln solullon wats cooledto 22" (1 The mixture was filtered, washed yvith methanol(100.0 g) and concentrated. Thc crude buprcnorpiunc waspurified by fiash chronlatography (ethyl acetateiheptaneI/I) to give 1.475 g buprenorphine (80%). IH-NMR and13(ENMR analyses yvere in agreement with literature data.

lo1 he reaction schenle for the reactions ot examples I to 4

cml be shown as follows

H . Pd.'C

M OH

/8

3(

HO 0—

HO

DMF X — I.'I

X — 13r

'I'he disclosed route of synthesis gives a total yield of162% for buprenorphine. Tius Iigure la an increase of about

4040% compared to sunilar routes ol'ynthcsls

IN.19-dihydroetorphine front Oripavine

Exemplary reacuon schcmcs for produculg 18,19-dlhy-dloctolphnlc fionl onpay nlc arc '(en nl lhc IollownlgExamples 5 to 9.

t dude anetlncl I:xampie 5

11(50.70)-17-lntethyl-4.5-epoxy-3-hydroxy-6-methoxy-6.14-ethenomorphinan-7-yl)ethanone

'vlvlLtlrarrol

Onpavine (200 g, 0.672 mol) was suspmldcd in ethtmoi(1260 ml,) with hydrol)uirnyne (1.5 8, 0.0134 mol) and

o. methyl vinyl ketone (117 3 mi„ I 439 mol) was added. 'I hereaction mixture yves stirred at 88" (1 for 22 h 'I'he resultingsolution was concentrated partially (350 g of solvent wasevaporated). The mixture (yas cooled to 0" C, overnight.After filtratron. thc product was dncd. Yield. 85%. The

6o analyses werc ln agrimmcnl with Ihc htcrnlure.

Example 6

Elorplnnc

HO 0— A solution of n-propyl magnesiunl chloride ln diethylether (2 molar, 6.5 ml ) yves added to tertiary butyl methyl

19US 10,391,091 B2

20ether (7.0 g). Thc soluuon was disuiled to gne 3.0 ofdistillate. I'ertiary butyl methyl ether (7.0 g) was added. theresulting mixture was distilled to give 3 0 g ofdistillate 1'lusstep xvas repeated with 5 8 of tert-butyl methyl ether to give5 g of distillate. 1-[(5(x, 70)-17-xuethy)-4.5-epoxy-3-hy-droxy-6-methoxy-6.14-ethenomorphinan-7-yl]ethanone(0.964 g. 2.61 nunol) dissolved in diuxanc (5.0 ) was addedslowly xiuring 15 min at 22'. Thc resulluxg wlulc mixturewas stirred during 4 hrs at (10" ('nd then cooled to 0" C.'I'he reaction was quenched with a saturated NI 14('I solution la(10 0 ml.). After separation, the aqueous layer was extracteduvice with ethyl acetate (2 times 10 mL). The combinedorganic layers were dried over MgSO4 and concentrated.Thc crude product was puuiied by I'lash cluomatography(cihyl acclalc/heptane. 9/I ) lo give elorplnnc (conversion 1

83'i, yield: 61%, 540 nxg) 111-NMR and 13C-NMR con-fimxed that the desired substance was fixrined.

Example 7

18.19-dihydroetorphine fmin I itorphinexo

Example 8 (('omparative)

I-[(512.7(x)-I7-xxxethy1-4,5-epoxy-3-hydroxy-6-methoxy-6,14-clhanomorpluxwn-7-yl]elhanone

xs

11(5cu7cxl-)7-1methy1-4.5-epoxy-3-hydroxy-6-methoxy-6.1)-ethenomorphinan-7-ylJethanone (5 0 g. 13 61 mmol)

Etorplune from example 6 (0.452 e. 1.0098 mmol) wasdissolved in methanol (100.0 ). Palladium catalyst oncarbon (5%e Pd, 0.1 g) was added. Thc black mixture wassurrcd al 65'. under IS bar of hydrogen. Aficr 24 lus ofhealuxg. tlxc reaction mixture was coolctl to 22' Thenxixture was hltered, washed with methanol (100 8) andconcentrated 'I'he cnxde product was purified by fiash cine-matography (ethyl acetate/heptane: 3/2) to give 18.19-dihy- xo

droetorphine (yield: 77%. 0.35 g). IH-NMR and 13C-NMRconiinned thc dcsircd substance was lomxcd.

was dissolved ux propanol (100 g). Palladium catalyst oncarbon 5% Pd. 0.5 ) was added The black mixture wasstirred al 65'. uxxler 6 bar of hydrogen. Aller 16 lus. ofheatmg, the reaction mixture v as cooled to 22" ( 'lhemixture was Iiltcred. washcxi with methanol (100 g) andcmxcentrated to give 3 82 g (yield 76%) 1[(5cu7rx)-17-methyl-4,5-epoxy-3-hydroxy-6-methoxy-6.14-ethanomor-phinan-7-ylJethanone.

Exnmplc 9 (Comparauve)

18,19-dihydroetorphine from I-[(5cx.7rx)-17-xxxethyl-4,S-epoxy-3-hydroxy-6-methoxy-6,14-ethmxomorph-

inmx-7-yljethanone

A soluuon of n-propyl magnesium chloudc ux diethylether (2 molar. 25.0 mL) was added to tertiary butyl methylclhcr (28.0 g). The soluuon was distilled lo give 12.0 g ofdistillate. Ieitiary butyl methyl ether (28 0 g) was added, theresulting mixture v as disulled lo give 12.0 g of disullatc.'I'his step was repeated with 17 a of tert-butyl methyl etherto give 18 g of distilkxte. 1-[(50,70)-17-(cyclopropylm-ethyl)-4,5-epoxy-3-hydroxy-6-methoxy-6. 14-ethanomorph-inan-7-yl]-ethanone (3.67 e, 9.834 nmxol) dissolved in diox-ane (15.0 ) were added slowly duung 15 min at 22" ('. Theresulting mixture v as surred duruxg 16 lus. at 60" C. andlilcil coolexi to 0 C. lite reaction wile qucxlche'0 wuixsaturated NII4('I solution (20.0 ml ) After separation, theaqueous layer xvas extracted twice xvitlx ethyl acetate (2times 20.0 mL). The combined orgxanic layers were driedover MgSO4 and concentrated The cnide product waspuufied by fiash chronxatography (ethyl acetate/heptane:I/I) lo give 18,19-dihvxiroclorphinc (yield. 61%, 2.50 g).IH-NMR and 13C-NMR conliuncd thai thc desired sub-stance was formed

'I'he reaction schenxes for the reactions of exanxples 5 to9 cmx be shoxvn as folloxvs:

jMVK

/

0—

/N

ii-Pxepil Me Cit 1THF0 exeee

HO 0— HO

!

H . Pd C

e-PxOH!

H,PICe P OH

21

US 10,391,091 B2

-continued

22

a P cn I MS ( I

Minnn

Hr) 0— HO 0—

From thc above Examples, it can be scca that the methodsusing steps (iii-4) and (iv-4) IG the method whcrcui the step

Iwith(bc lower ymld is carried out lira(. Tlus lmids to savingsin solvent amounts and can also lead to reduced cost, as Isshoivn in the folloiving wherein it is assuined that the costfor materials nnd each process step are more or less thesame. For example, assuming material and process cost of

20Euro 100. for each reaction step in producing Buprenor-plnnc hydrochlondc, ns given ui the cxamplcs, thc Ihllowingcan bc calmilatcd for cxmnplary conversions given ihr eachstep, wherein the conversions are identical for steps (iii-a)and (iv-b) as well as (Iv-a) and (iii-bjReaction Sequence I:

Step (ii) (e.g formation of Diels Alder adduct) Step(iii-a) (e.g, formation of Ciri nard adduct (70%)) Step(iv-4) (c.g. formation of hydr@taxi product (86%)) step (v)(e.g. Ibrmauon of Buprcnorphinc HCI (90%)). Ton(1 yield54%Reaction Sequence 2

Step (ii) (e.g, formation of Dials Alder adduct) step(iii-b) (e.g formation of hydmqted product (86%)j step(iv-b) (e.g, formation of C(ngnard adduct (70%)) step (v) 3((c.g. formation of Buprenorplunc HCI (90%a)). Total yield54%

'Hie hrst and last steps are identical, respectively 1'he costfiir the 2 intermediate steps are thus:

0.7f itx) +0 86 tt 7tt l(a) =I 0 20

086 ifo +070 ()m) ltt() =14G 0

'Hiis amounts to 12% additional costsIncluding the first and last step. the cost for 0.54 mol

Buprenorphine HCI are thus

I I( f +0 7(f l()tf +0 86 ff 7(f it)ff +fJ Pll ll 860 70 !00 — 30 Rea t cn sequence I

other aitalogucs thcrcof, as well as their acid addition salts.As starting material usually oripavine is used With thepresent method, increased yields of products nnd interme-diate products can be obtained. resultmg in less side pmd-ucts and therefore a more economic nnd ecologic process. Inaddition, also lugher isomer purity can be obtauicd, wluchcan also be e., derived from the increased yields

All rcfbrcnces cited in this spccilicahon are herewithincnrporated by reference in their entirety

Thc prcscnt method has been describcxt in dctml withreference to certain enibodiments and specified byexamples. However, a skilled person v ill acknowledge thatalso other modificationg changes. or similar alterations canbe made to the present invention without devmting from thespint of the uivennon.

Thc uivcntion claimed is:I A method of preparing a cnmpound of I'ormula II, or a

salt thcrcol; I'rom a compound ol'ormula I, whcrcui in1(orniula it, R'epresents a linear, branched and/or cyclicalkyl group having I to 10 carbon atoms. R" represents alinear or branched alkyl gmup having I to 10 cm bun atoms,and Ru'epresents H or I 'Iq n comprising:

i Feunuia II)

OH

I if ( +(3 86 ltf(J +0 70 t) 86 1(ft) +t) Jl) lJ 7() 0f)SG !00 — 246 Rea tan sequence 2

1'his amounts to about 6% additional costs11nis. reaction sequence I is about 6% to 12% cheaper,

dependin if all steps are considered or only the relevantsteps. a.

A method has bccn shown lmreui lor prcyaring buprcnor-plnnc. 18.19-dihydroctorpluue, (malogucs thereof mid theirsalts. With the presmit method, it is possible lo obImnsubstances of high purity by a short synthesis even offeringtwo ditferent alternatives routes 1 further. the need nf intro- (0ducing and later releasing protective groups is avoided, thuslimiting efibtts nnd costs of the present process. Alsodescnbcd is a method allowing pcrfi)nmng step (ni) a(xi step(tv) nl dnv st: ci Iit: n1 Id I airangenlcut, I.tv s taps (111-II) Iiixl (iv-a )

or s(07)s (iii-b) aud (iv-b). 6(1'he current invention otfers an impmved method fiir

nianufacturing buprenorphine, I Y,19-dihydroetnrphine and

I Faun)tie I)

OHJ

(Ij nptionally replacin the grnup R In the compound ofFormula I, whcrcm R is H or methyl, by a groupR'emg

a linear. branched and/or cyclic alkyl gmuphaving I to 10 carbon atoms:

(Ii) adding methyl vinyl ketone to obtain 1-1(5( 07(I)-17-alkyl-4,5-epoxy-g-hydmxy-d-methoxy-6.14-ethenom-

23US ]0,39],09] B2

24orphinan-7-yl]ethmlone or I-[(goh7o)-17-alkyl-4.5-ep-oxy-3-alkoxy-6-methoxy-6. 11-ethenomorphinan-7-yl]ethanone;(iii-1) converting the acetyl gnlup in position 7 into a

tertiary alkyl alcohol having a eneral structureC (OH) (CH3)-R", wherein R" represents a

linear or branched alkyl group with I lo 10 carbonalonls, and

(lv-a) I'educing thc cthcno gl'oup ln position 18,19 tofornl the conlpound of I ormula 111 and Io

(v) optionally converting the pmduct froln step (iv-a) mtoan addition salt. preferably a pharmaceutically accept-able salt.whereat thc protection oi' side chain ls avoided

2. The method of elena 1, wherein slap (lil-a) compnsesthe use of a lp'MgX. wherein R" represents a linear orbranched alkyl group with I to 10 carbon atoms, and Xrepresents a halogen

3. The nlethod of claun 1, wherein step (iii-a) comprisesconverting the acetyl group in position 7 into a tertiary alkyl loalcohol usulg a solvent, whcrcul lhc solvent conlpl1scs ancthcr.

4 the method of clainl I, wherein step (iii-a) conlprisesconvertina the acetyl group in position 7 into a tertiary alkylalcohol in a solvent comprising tert-butylmethylether,2-methyl-tetrahydrofuran. diethylether, dimethoxyethane,dinlethoxymethane or mixtures thereof. 2-methyl-tetrahy-drohu Jn, dlnlclhoxy'mclhiurc ol nllxnlrcs thcrcof.

5. The method of clmm 1. whcrcln step (lil-a) is carriedout using essentially tert-butylmethylether, 2-methyl-tetra- Io

hydrofuran, diethylether. dimethoxyethane, dime-thoxymethane or mixtures thereof, particularly teu-butylnl-ethylether, 2-methyl-tetrahydrofuran, dimethoxymethane ormixtures thereof„as solvent.

6. lllc method of claim 1, wherem m ibmlula II, R'lrepresents mclhylcyclopropyl and R" rcprcsmlls Icrl-butyl orR'c3trescnts methyl and R" represents n-propyl.

7 The method of claim I, wherein in step (i) the alkylmup introduced in the 17-N position has 3 to 10 carbon

atoms and has a linear. a branched and/or a rin smlcture so8. The method of claun 1, wherein R'epresents CH, in

the compound of Fonuula I.9. The method of clmm 8. whcreul R'" ls converted to H

bcforc step (i) or after step (1) or after step (li).10. 'I'he method of claim l. lvherein R's 11

11 I he method of clainl 4. wherein the solvent conlprisestert-butylmethylether.

12. 38 nletlmd of preparing a compound of Formula II, ora salt thcrcoi: from a compmuld of Furmula I, wherein ln

OH

/8

(F»mal. 0

OR Oc/I3

(1) optionally replacin the group R ln the compound ofFormula I, wherein R is H or methyl, by a youpR'eulga hncar. branched and/or cychc alkyl grouphaving I to 10 carbon atoms:

(li) addition oi'methyl ilnyl kctonc to obtain 1-[(So.7m)-17-alkyl-4,5-epoxy-3-hydroxy-G-methoxy-6.14-ethe-nomorplunan-7-yl]cllranonc or I-[(gct,7&1)-I7-alkyl-4.S-epoxy-3-alkoxy-6-methoxy-6.14-ethenomorphinan-7-yl]clltanonc:(ni-a) convertulg Ihc acetyl group ln position 7 ullo a

tertiary alkyl alcohol having a general structureC (OII)~(')13)-R". wherein R" represents a

linear or branched alkyl group with I to 10 carbonatoms: and

iv-a) reducing the etheno group ln position 18. 19 toform Ihc compound of Formula II, and

(v) opuonally convcrung Ihc product lrom slc73 (lv-a) mloml addition salL, prcfbrably a pharmaceuucally accept-able salt.

t t t

Formula H R'cprcscnls a lulcar, branched mldlor cychcalkyl group having I to 10 carbon atoms. R" represents alulcar or branched alkyl group having I to 10 carbon atoms,and R'" represents 11 or ('H„consisting of