EP2707346A1 - Procédé de préparation d'inhibiteurs de la protéase - Google Patents

Procédé de préparation d'inhibiteurs de la protéase

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Publication number
EP2707346A1
EP2707346A1 EP12723028.2A EP12723028A EP2707346A1 EP 2707346 A1 EP2707346 A1 EP 2707346A1 EP 12723028 A EP12723028 A EP 12723028A EP 2707346 A1 EP2707346 A1 EP 2707346A1
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EP
European Patent Office
Prior art keywords
formula
compound
ring
group
aliphatic
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP12723028.2A
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German (de)
English (en)
Inventor
Gerald J. Tanoury
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Vertex Pharmaceuticals Inc
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Vertex Pharmaceuticals Inc
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Filing date
Publication date
Application filed by Vertex Pharmaceuticals Inc filed Critical Vertex Pharmaceuticals Inc
Publication of EP2707346A1 publication Critical patent/EP2707346A1/fr
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered

Definitions

  • Thfe invention relates to processes and intermediates -for the preparation of protease inhibitors, i particular,, serine protease inhibitors.
  • HCV hepatitis C virus
  • Protease inhibitors and in particular serine protease inhibitors, are useful ' in the treatment of HCV infections, as disclosed in WO 02/18369, WO 02/18369 also discloses processes and intermediates; to the preparat on; of these compounds. These processes lead to raeemizatioii of certain steric carbon centers. See, e.g., pages 223-22, As -result,, a need remains for enanuose!ective processes for the preparation of these compounds.
  • the present invention is directed towards processes- and intermediates for the preparation of ' protease inhibitors, particularly serine protease inhibitors.
  • the invention provides processes and intermediates ' . for producing bicyelic deri atives of formula is or lb;
  • rin A is a eyeloatiphatic ring
  • ring B is a heterocycio-aliphatic ring containing an additional 0 to 2 hetero atoms, each independentl selected from O, N. and S, thai can be optional iy substituted with 1 to 4 groups, each independently selected from alkyf halo, aikox , aryl. and hydroxy!;
  • t is H or a protecting group
  • S3 ⁇ 4 is ⁇ ⁇ , a protecting group, or Ci.r>- aliphatic.
  • One aspect relates to a process for preparing enantioseleettveS compounds -of formula, la or lb over compounds of formul s lc - Ih;
  • n R ?3 ⁇ 4 is. a. protecting group, in the presence of a compound of formula 111;
  • R.$ and R, 3 ⁇ 4 are each independently a
  • P008J Another aspect is di a compound of formula 30:
  • xvhereur ? is defined above, and 7,2 is H or a protecting group
  • step a treating the 2-anion of step a with carbon dioxide to produce enantioseleciively a compound of fpmuvla la;
  • compounds of the ⁇ invention may be optionally substituted with one or more suhstiiuents, such as are illustrated general ly above, or as exemplified by particula classes, subclasses., and species of the inventi n.
  • pharmaceutical agent includes two or more pharmaceutical agents, and so forth.
  • the term ' com ound refers t the eonipoimdf s) that are defined b structural formulas- respectivel drawn herein.
  • the term “compound " ' can include a salt of the eompound(s).
  • aliphatic encompasses the terms alkyl, alkenyl, alkynyL an cyeloaiiphatic, each of which is optionally substituted as set ibrth. below.
  • an "alky! group refers to a saturated aliphatic hydrocarbon group containing 1 -8 (e.g., 1-6 o 1-4) carbon atoms.
  • An alkyi group ca be straight, cyclic, or branched.
  • Examples of alky ! groups include, but are not limited to. .methyl, ethyi, propyl, i.sopropyL butyl, i so but l. ,yee-bnty], e/T-butyl «-pcntyl, tt-heptyl, or 2-ethylhexyi..
  • An alkyi group can be substituted (he., optionally substituted) with one or more substitiients selected from the group which consists of halt), cyeloaiiphatic (e.g., eyeloalky! or eyc!oaikenyl).
  • beteraeycloaliphatie e.g., heterocyc!oalkyi or heterocyclpal.ke.nyl
  • aryl heterDar l e.g., aikoxy, aroyh heteroaroyi
  • acyl e.g,, (aiiphahe ⁇ earbouyl, (cycloaliphaiic)carbonyL or (heteroeyc!oa!iphatj ⁇ carhonyl
  • nitro, cyano, amido e.g., (cycioalky!alkyi)carboByiarnirto, aryleatbonylamino, aratkyfearbonylauhno, (heterocydoalky car onylamino,
  • heterocyc!oalkylarninoearbony arylaminocarhonyl or heteroaiylammoGarbcmyl amino (e.g., aiiphati amino, cycloaiiphaticammo, or heterocycloaliphaticammo).
  • sulfotayl e.g.., aliphatic- SO2-
  • su!fmyl sirliarryl sulfexy urea, thiourea, suiianioyL sitltkniide, 0x0 ⁇ , earhoxy, carbamoyl, cye!oahphaticoxy.
  • heterocyeloah iharleoxy ar loxy.
  • substituted alkyls include earboxyalkyl (such as HQOC-alkyi, alkoxycarbonylalkyL and alkylearbonyloxyalkyl), eyanoalkyt, hydroxyaiky alkoxyalkyi acylalkyi, araikyl, (alkoxyaryl)aikyl, (su!i1 ⁇ 2 i rai o)atk i (such as ⁇ aik i-SOi-atnino ⁇ aikyl) ? aniinoaikyi, amidoalky I. (cycloalipiiaitcjalky!, and haioalkvi.
  • earboxyalkyl such as HQOC-alkyi, alkoxycarbonylalkyL and alkylearbonyloxyalkyl
  • eyanoalkyt hydroxyaiky alkoxyalkyi acylalkyi
  • araikyl such as alkoxyary
  • an "alkenyi” group refers to an aliphatic carbon grou (hat. contains 2-8 (e.g., 2-6. or 2-4 ⁇ carbon atoms and at least one double bond- Like an aikyi group, an alkenyi group can be straight or branched. Examples of an afken.yi group include, but are not l mited, to. allyl, isoprenyl 2-butonyl, and 2 iexenyl.
  • An alkenyi group can be- optionally substituted with one or more subslituenrs such as halo, cyctoaliphatle (e.g., eycloalkyl or cyc-loalkenyl) . , heterocycloaliphatic (e,g,, teterocycroaik l or
  • heteroeycloalkenyl aryl, heteroaryL alkoxy, aroyk hcteroaroyL acyl (e.g.,
  • heteroarylcarbonylaiTiino hete.roaralkylcarbonyiavnino a!kyianunocarbonyl.
  • heteroarylammocarbonyl amino (e.g., aliphatieamino, eycloaiiphatieamino,
  • heterocycioaliphaticamino . or aliphaiicsulfon la.mirio
  • sulfonyl e.g., alkyl-S(3 ⁇ 4-,
  • substituted alkenyls include eyaaoalkenyl,
  • an "aikynyP group refers to an aliphatic carbon group that contains 2-8 (e»g token 2-6 or 2-4] carbon atoms nd has at least one triple bond.
  • An ajkynyi group can be .straight or branched.
  • an alkyn l group examples include, but are not limited to, pro ajrgyl and butyriyi.
  • An alkynyl group can be optionally substituted with one or more substituents such- as aroyl, heteroaroyl, a ' lk xy, c eloalkvioxy ? heterocycloalky!oiiy, ary-bxy-, heteroaryloxy, aralkyiox , nit.ro, carboxy, eyano.
  • sulfanyl ⁇ e.g., aiiphaticsulfanyl or cycloahphaticsiuifenyl
  • sulfmyl e.g., aliphatiesulfmylor cyeloaiiphaiicsulfmyl
  • sulfonyl e. aUphatic-SCV,- afjphaiicamjno-SO?-, or cycloaSipliatic- $ ( 3 ⁇ 4- ⁇ , amido (e.g,, aminocarbonyl, . alkyiaiiiinocarbonyL a!kylearbonyiamino,
  • heteroaralkylearbonylamino heteroarylcarbonyl mino or heteroarylaminoearbonyl
  • urea f thiourea suliamoyL sul&mide
  • aikoxycarhonyi alkylcarbonyloxy
  • cyclojaBphatic heieroeydoaiiphatie
  • -ary-L heteroaryl acyi (e.g., eydoaiiphatic)earbonyl or
  • carbony 1 amino; ' when used al ne or m connection with another group, refer to an amido group such as - ( X )-C(() ⁇ - or ⁇ C(0) ⁇ N(R x h, when used terminally, and they refer to an amide group such as -G(0 - (R; )- or -N(R x ⁇ -C 0 ⁇ - when used internally, wherein R x and R Y are . defined below.
  • amido groups include aiky!atnido ⁇ such as alk lcarbonyl amino or alkyiaminocarbonyl), (heterocyeloaliphaticjamido,
  • amino refers to -NR:" , wherein each ot R ' and is independently selected .from hydrogen, aliphatic, eyclo aliphatic,
  • arylcarboTvyk (aral iphatic)carbonyl, (beieroeycloaliphai ic ⁇ ca.rbony] ,
  • (heteroara!ipha.tic)carbonyl each of which, being defined herein and is. optionally substituted.
  • amin gr ups include alkyianiino, diai&yiamino, and aryiamino.
  • amino s not the terminal group ⁇ e,g., aikylearbcTfiyiam.m ⁇ ) f: it is represented by -NR A -.
  • R A has the same meaning as defined above.
  • an ry ⁇ y group used alone or as part of a larger moiety as in “aralfcyP, "araikoxy " , or ⁇ aryi xyalkyl” refers to monocyclic (e.g., phenyl):, bieyelie ⁇ e.g., IndenyL naphthalenyk teirahydronaphthyi, tetrahydroinden i), and tricyclic (e.g., finorenyl tetraliydro&norenyi or tetrahydroanthracenyl, anthracenyi) ring systems m which the monocyclic rin system is aromatic or at least one of the rings in a bicyclic or tricyclic ring system is aromatic.
  • the bicyclic and tricyclic groups include benzofused 2- to 3-membered carbocyclic rings.
  • a ben ofused group includes phenyl fused with two or mor Q-s carboeycHe moieties.
  • An aryi is optionally substituted with one or more substituents, such as aliphatic (e.g.. alkyl, alkenyl, or aikynyl), cycioaiiphatic, (eyeioaliphaticialipbaiic.. heierocyc!oaHphatie, (heteiOcycioaliphaticjaiiphatie, aryi heteroaryk aikoxy,
  • substituents such as aliphatic (e.g.. alkyl, alkenyl, or aikynyl), cycioaiiphatic, (eyeioaliphaticialipbaiic.. heierocyc!o
  • suHbnyi e.g.. aiiphaiie-SOj- or annno-SOs-i siilflnyl (eg.. aiiphatic ⁇ S( ⁇ )) ⁇ or cycloaliphatic-S(O)-
  • su!fanyt e.g., allphatic-S-k cyano, halo, hydroxy, mercapto,, sulfbxy, urea, thiourea, sulfamoyl.. snilarnide, .and carbamoyl
  • an aryi can. be unsubstituted..
  • Non-limiting examples of substituted ary!s include haloaryl (e.g., mono-, di- (such as /3 ⁇ 4/is!-dihaloa:ryl ⁇ , or (trihalo ⁇ aryi).
  • (carhQxy)aryl e.g., (a!koxycarbonyl ⁇ aryl,
  • an "araliphaUe” group such as “aralkyl” refers to an aliphatic group. (e.g., a M alkyl group) that is substituted with an ary! group. Aliphatic,. aikyL and aryl are defined herein. An example of araiiphatie such as an aralkyl group is benzyl.
  • a " 'aralkyT group refers to an alkyl group (e.g., a Cj.4 alkyl group) that is substituted, with an aryl group. Both alkyl and ary! have been ' defined above.
  • An example of an aralkyl group is benzyl.
  • An aralkyl is optionally substituted with one or more .subsiituents such as- .aliphatic (e.g., substituted or mrsubsiituted alk l.
  • alkcnyl, or alkyriyl including carboxya!ky!, hydroxyalkyl, or haloalkyl, such as tri ' flitoromethyl ⁇ , cye!oaliphatic (e.g., substituted or unsubsiituted eycloalkyl or eyeloaikeny!),
  • heteroarylcarbonyiamino, or heieroaralkylcarbpnylamino cyano. halo, hydroxy, acyi, mercapto, aikylsulfanyL suifoxy. urea, thiourea, suliamoy!, sulfkmide, ⁇ ,. and carbamo l
  • a "bicycHc ring system” includes S- to 12- (e.g.. 9, 10, or 1 1) membered structures that, form two rings, wherein the two rings have at least one atom in common (e.g., 2 -atoms in common).
  • Sieve lie ring systems include bieyeloa!iphatics (e.g., hicycloa!kyl or bicycioa! keny l ⁇ , bicycloheieroaliphaties, bieyelie ary is, and bie ehc heteroaryls.
  • a " cycloaliphauc” .group encompasses a “cyctoslkyl” group and a “cyctoalkenyl " group, each of which being optionally substituted as set forth below, [00025]
  • a ⁇ eycloalkyl” group refers to a saturated carboeyclic motto- or bieyclic (fused or bridged) ring of 3-1:0 (e.g., 5-10) carbon atoms.
  • eycloalkyl group examples include eyelopropyl, cyclobutyk cyc!openty!., eyciohexyl, eyeloheptyk adamantyk norboniy cubyl, oeta.hydro-indenyl, decahydro-naphthvi bicyefoj3.2.1 ]ociyl,
  • a "cyeloa!kenyP group refers to a non -aroma tic earboeyclic ring: of 3-10 (e.g., 4.-8) -carbon atoms having one or more double bonds.
  • cycloalkenyl groups include eyelopentenyl, 1.4- cyc!ohexa-di-enyf, eyclohep enyl. eyclooctenyl, hexahydro-indenyL oetalxydro-naphthyk eyelohexenyi eyelopentenyl, bicyclo 2.2.2 ⁇ octenyl, and bieyclo 3 «3.1 jnonenyl,
  • a eycloalkyl or cycloalkenyi group can be o tionally substituted with one -or more substituents such as aliphatic (e.g., aikyi, alkenyl, or lkynyl), eycloaiiphatie, (eycloaiiphatie) .aliphatic, heteiOcyeloaliphatie, (heterocycioa!
  • ac l e.g., (eyc!oaliphatic)carbonyl, (cycloaiipbatic) aiiphatic)oarboiiyi (aral iphati e)c arbonyi , eterocyc loal iphatic k arbony 1,
  • 'cyclic moiety includes cycloaiipbatic, heteroeycloalipha ic, aryi,. or heteroaryl, each of which has been defi ned previously,
  • heterocyeloalkyl group and a heteroeycloaikeny 1 group, each of which being optionally substituted as set forth: below,
  • a refers to a 3-3 G nrembered BT BO- or bky!k (fused or bridged.) (e.g., 5- to 1.0-membered mono- or bkycik) saturated ring structure, in which one or more of the ring atoms is: heteroatom (e.g., N, 0, S, or combinations thereof).
  • heteroatom e.g., N, 0, S, or combinations thereof.
  • heterocycloalkyl group include piperidyi, piperazyl.
  • a monocyclic heterocyeloaiky! group can- be fused with a phenyl moiety such as tetrahydroisoquinoiine.
  • heteroeycioalkenyf' group refers to a mono- or bkylic (e.g., 5- to 10- membered mono- or bk el ) non-aromatic ring structure having one or more double bonds, and wherein, one or more of the ring atoms is a heteroatom (e,g, 5 N, (), or S), Monocyclic and bicydobete oaliphaiics are numbered according to standard chemica! nomenclature. [00029] A eterocycl.oalk ! or heteroeyekaenseyl. group can. be optionally substituted with one or m re sabstituenis such as. aliphatic (e.g., alkyk alkenyl, or alkyiiyl),
  • eyeloalipkUic eyeloalipkUic. :(cycIoaliphaUc)aHphatie. heierocycloaiiphatic, (heterocycioalipl icjalipbatic, aryL heteroar l, a!koxy, (cycioalsphatic)osy, (beierocycloa]ipbatic)os.y, aryloxy,
  • a "heteroary group refers to a monocyclic, bicycl c. or tricyclic ring system ha ving 4 to 15 ring atoms, wherein: one or more of the ring atoms is a heteroatom (e.g., N, ().. S, or combinations thereof) and in which the monocyclic ring system is .aromatic or at least one of the rings in. the bicyclic or tricyclic ring systems is aromatic,
  • a heteroaryl group includes a benzol used ring system, having 2 to 3 rings.
  • a benzofused group includes benzo fused wi h one or two 4 to 8 merabered.
  • heteroeycloaiiphatic moieties e.g.. indolizy!, indolyl LsoindoiyL 3H-indoIyl, indoiinyl.
  • heteroaryl are azetidinyl. pyridyl, 1 H-indazolyl, furyl pyrroiyi, thienyl, ihiazoiyi, oxazolyt imidazo!yl, tetrazolyi, benzofuryl, isoquinoiinyb benzthiazoiyl, xantheue, thioxanthene.
  • monocyclic heteroaryls include .fur l, thiophenyl, 2,11- pyrroiyi, pyrroiyi, oxasiolyl. thazolyi, imidazoiyi, pyrazolyi isoxazolyl, isothiazolyl, 1 ,3,4- thiadiazo!yi, 2H ⁇ pyranyl, 4-B-pranyl, pyridyl, pyridazyl. pyrimidyL pyrazoiyl, pyrazyl, and 1.3,.5-triazyl. Monocyclic heteroaryls are .
  • bicyclie heteroaryls include tadelizyl, mdoiy isoindolyi, 3ii ⁇ md lyL mdolkyk benzcsfi i:u : r l beozo /j thiopheayl ⁇ qumofinyl, isoquinoiinyl, indoiizyk isomdelvl, indo!yi, ben3 ⁇ 4ojd]i3 ⁇ 4ryL bexo[/?]thiophenyk indazolyl, benzb dazyk benzthiaaaiyh purinyk 4H-quinol.feyl J quinolyl, isoquinolyk einnolyk phtbalazyk qivhwq!yl, qu oxalyi, 1.8-naphtbyridyk and pieridvl.
  • Bicyclie heteroaryls include tadelizyl, mdoiy iso
  • a beteroarv I Is optionally substituted with one or more substituents such as aliphatic (e.g., alky I, alkenyl or a!kynyl), cyeloaliphatk, icycioaliphatic)aIipb.atie T beterocycloaiipbatic, (heterocycloaUphatie ⁇ aHphatic. aryk heteroaryl alkoxy,
  • substituents such as aliphatic (e.g., alky I, alkenyl or a!kynyl), cyeloaliphatk, icycioaliphatic)aIipb.atie T beterocycloaiipbatic, (heterocycloaUphatie ⁇ aHphatic. aryk heteroaryl alkoxy,
  • heteroaryl can be unsubstituted.
  • Non-limiting examples of substi toted heteroaryk include (halo)heieroaryi (e.g., mono- and di-(halo)heteroaryt), (carboKy)hcieroary! (e.g., (alkoxycarbonyi)hcieroary!), eyanoheteroaryi, mimo ' heteroaiyl. (e.g.. ((alkyisuli3 ⁇ 4iwI ⁇ amin:o)beteroaryl
  • heteroaralkyr group refers to an alkyl group (e.g., a CM alky] .group), that is substituted with, a ..he ternary! group. Both "alkyl " and 3 ⁇ 4 3 ⁇ 4eteroaryP have been defined above.
  • a heteroaralkyl is optionally substituted with one or more substituenis, such as .alkyl (including carboxyaikyh hydroxyalkyi and hatoalkyl such as triiluoromethvl).
  • an 4i aey! ' grou refers to a forniyi grou or R A -C(Q (such as alkyl-C(O . K also referred to as * 'alkylcarbonyr>- wherein. R: and alkyl have been defined previously. Acetyl and pivaloyl are examples of acyl groups.
  • an "aroyP or 'lieteroaro ⁇ refers to an ary kC(O)- o a heteroaryl-C(O)-, The aryl and heteroaryl portion of the aroyl or heteroaroyl axe opiionaily substituted, as previously defined..
  • an ''alkox ' group refers to an alkyl-O- group, wherein, alkyl has bee defined previ usly,
  • a "carbamoyl '5 grou refers to a group having the structure -O-
  • carboxy ⁇ group refers to -CQOH, -COOR , -OC(C) ⁇ B, or -
  • haloalinhatie group refers to an aliphatic group substituted with 1 -3 halogens.
  • haloaikyl includes the gr u ⁇ C . 3 ⁇ 4 ,
  • a "mercapto" group refers to -Sl i .
  • a "suiter' gr up refers to -S(3 ⁇ 4H or -S(3 ⁇ 4R X when used terminally and ⁇ S ; ( ⁇ 3 ⁇ 4- when used internally.
  • a "sulikmi-de-' group refers to the structure ⁇ NR A ⁇ S(0)2- N V Z when used terminally and - X -$
  • a "sulfonamide” group refers to the structure -Si O ⁇ 2-NR A K' or -NR x -S(0) 2 ⁇ R when used terminally and -SiO 2- R x - or -NR X -S(C))r when used
  • a ' ⁇ ulfanyp group refers to -S-R x when used terminally and - S- when used internally, ⁇ wherein R A has been defined above.
  • sulfanyl include al ' ipiiatie-S-, cycfoaliphatic-S-, and aryl-S-, or the like.
  • a suifinyl grou refers to -S(0) ⁇ R A when used terminally and - S(0)- when used internally, wherein R x has heen defined above.
  • Exeniple of sulfmyl groups include aliphatic-SCO)-, aryi-S(O -, (cyeloaliphalic(aliphatic) ⁇ -S(OK cycloalky 1- :S(Q)-, heteroeycioaliphaiie-SiC))--. and heteroaryi-S(0) ⁇ , or the like.
  • a "sulfony ⁇ group refers to ⁇ S(Q ⁇ 2-R ' when used terminall and - S(0) - when used internally, wherein R A has been deilned above.
  • Exemplary sulfonyl groups include aliphatic-SCO ⁇ ;-, aryl-S( ⁇ 3 ⁇ 4r f - ⁇ eycloaiiphatie(aliphatic):) ⁇ S O3 ⁇ 4-, eyeloaliphatie- (0)2-, heteroeycloal.ipba ie-S(0)r. heterpai l-S(03 ⁇ 4>- f and
  • a "sulf xy "5 group refers to -Q-SO-R or ⁇ SO-0 ⁇ R X when used terminally and -O-S(O)- or -S ' (0 ⁇ -0- when used internally, wherein R: x has been defined above.
  • halogen or "h l ' " group refers to fluorine, chlorine, bromine, or iodine:.
  • an "afkoxyalkyf * group refers to an alkyl group such m. alkyl-O- alkyk wherein alkyl has been defined above.
  • a "carbonyr * group refer to -C(0 ⁇ -.
  • an 3 ⁇ 4 ⁇ ! ⁇ group refers to; :::: 0.
  • aminoalkyl refers to the structure ⁇ R x 2 -alk k
  • a "eyanoalkyl group refers to the structure ⁇ NC)-alkyl-.
  • are grou refers to the structure -N X -C()-MR3 ⁇ 4 and a "thiourea " group refers t the structure -NR X - €S ⁇ NR3 ⁇ 4 Z when used terminall and -KR S - CO-NR ' ⁇ or -NR X -CS-MR Y - when used internally, wherein R x , R Y , and R z have been defined above.
  • an "amid no" grou refers to the structure -C ::: fHR x )N ⁇ R x R ).
  • the term "vicinal” refers to the placement of substituents on a grou : that includes two or more carbon atoms, where n, the substituents are attached to adjacent carbon atoms.
  • geroinaP * refers to the placement of substituents on a group that includes two or more carbon atoms, wherein the substituents are attached to the same carbon atom
  • terminal and 'Internally refer t the location of a group within a substitueni.
  • a group is terminal when the group is present at the end of the substitueni and not further bonded to the rest of the chemical structure.
  • Caybox.yalk.yL i.e.. R x O(0)C ⁇ al.kyl is an example of a earboxy group used terminally,
  • a group is internal when it is not terminal Alkylcarboxy (e.g., a!kyl-C(O)-C)- or alkyl-O-C(O)-) and aikyiearboxyary!
  • cyclic group includes mono-, hi-, and tri-cyciic ring systems, such as cycloaliphaiic. heteroeyeloaHphatic, aryl. and. heteroaryl. each of which has been defined: above.
  • a "bridged hieyclie ring system” ' refers to a bicyclie
  • bridged bicyclie ring systems include, but. re not limited to, adamantanyL norbornanyl, bicyclo 3.2.1 fociyi bicycla[ .2 : ;2 ⁇ dctyl- bicyclo[3.3.1 jnonyl btcyeIo 3,2.3]nonyL 2 >xabieycio 2.2.2 ' joctyL l-azabieyc!o[2.2.2JoctyK 3- azabkycjop.2:J]oetyl, and 2,6-dioxa-iriCyclo[3,3.1.O ⁇ jnonyi
  • a bridged bicyclie ring system can be optionally substituted with one or more substituent such as alkyl (including carboxyaikyL bydroxyalky!, and hal
  • heteroaralkyloxy aroyf heteroaroyl, nit.ro, earboxy, aikoxycarbonyl, alkylearbony!oxy, ammoearbonyl aikylcarbonylaraino, eycloaikylearboBylamino, (cyc
  • an "aliphatic chain" refers to branched or straight aliphatic group (e,g., alkyl groups, alkenyl. groups, or alkynyl groups).
  • A. straight aliphatic chain has the structure -( €3 ⁇ 4)*-, where v is 1 -6,
  • a branched aliphatic chain is : a straight aliphatic chain that is substituted with one or more aliphatic groups.
  • a branched aliphatic chain has the structure -(CMQ y-, where y is 1.-6 and Q is hydrogen or an aliphatic group; however, Q shali be an aliphatic group in at least one instance.
  • the term aliphatic chain includes alkyl chains, alkenyl chains, and alkynyl chains, where alkyl. alkenyl and alkynyl are defined above,
  • the phrase "optionally substituted” is used interchangeabl wit the phrase “substituted or unsubstituted.”
  • compounds of the in vention can optionally be substituted with one or more substituents; such as; are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention.
  • the variables 3 ⁇ 4, 3 ⁇ 4, ? . and .3 ⁇ 4., as well as other variables encompass specific groups, such as alkyl and ary!. Unless otherwise noted, each of the specific groups for the variables R 5 , .
  • 3 ⁇ 4, 3 ⁇ 4, and 3 ⁇ 4, : and other variables contained therein can he optionally substituted with one or more substituents described herein.
  • Each substituent of a specific group is further optionally substituted with. one- to three of halo, cyano, oxo, alkoxy. hydroxy, amino, nitro, aryl cye!oaliphatic, heierocyeloaliphatic, heieroaryl, haloalkyl. and alkyl.
  • an alkyl group can be substituted with aikylsulianyl, and the alkylsultany] can be optionally substituted with one to three of halo, cyano, oxo. alkoxy. hydroxy, amino, nit . ro, . aryLhaloalk-yi, and -alkyl.
  • (eycloaikyl)ca bonyiamino can be optionally substituted with one to three of halo, cyano, alkoxy. hydroxy, nitro, haloalkyl, and alkyl.
  • the tw alkxoy groups can form a ring together with the atorn(s) to which they are bound.
  • substituted/ refers to the replacement of hydrogen radicals in a gi en structure with the radical of a specified substituent.
  • substituents are described above in the definitions and below in the description of compounds and examples thereof Unless otherwise indicated, an optionally substituted group can have a substituent at each substifiuable position of the group, and when more than one position in any gi ven structure can. be substituted with more than one su ituent selected from a specified group, the subsiitueni can be either the same or different at every position.
  • a ring snbstiluent such as a heterocycloa!kyl
  • Combinations of subsiituenis envisioned by this invention are those combinations thai result in the formation- of stable o chemicall feasible compounds.
  • a stable compound or chemically feasible compound refers to compounds that are not substantially altered when subjected, to conditions to allow for their production, detection, and preterahly their recovery, purification, and use for one or more of the purposes disclosed herein.
  • a stable compound or chemically feasible compound is one .that is not substantiall altered when kept at a temperature of 40 °C or less, in the absence of moisture or other chemically reactive conditions, for at least a week,
  • the phrase "preparing enaMi vSe!eeiive.iy' '> refers to asymmetric synthetic preparation of enantiomerica!ly-enriched compounds. This is further defined as the use of one or more techniques to prepare the desired compound in high enantiomeric excess (i.e., 60% or more).
  • the techniques encompassed may include the use o chirai starting materials (e.g., -chirai pool synthesis), the -use of.chiral auxiliaries and chirai catalysts, and the. application of asymmetric induction,
  • ⁇ enantiomeric excess' or ⁇ e.e,, ** refers to the optical purity of a compound.
  • encfa.'exo refers to the ratio of e3 ⁇ 4fo ⁇ iso.mers to exo-iso ers.
  • '"enantiomeric ratio is. the. ratio of the percentage of one enantiomer in a mixture to that of the other,
  • a "protecting group” is defined as a group that is introduced into a molecule to modify a functional group present in a molecule to prevent It from reacting in a subsequent chemical reaction and thus obtain chemoseleciivity. it is removed from the molecule at a later step, in the synthesis.
  • a carbobenzyloxy (Cbz) group can. replace the hydrogen on a amine to prevent it front reactin with an eieetrophile, then the. Cbz group can: be removed by hydrolysis in a later step.
  • Acid and amine protecting groups as used herein are: known: in the art (see, e.g., T.W. Greene & P.G.M Wutz, - 'Protective Groups in Organic Synthesis.” .3** Edition, John Wiley & Sons, inc. (1999)),
  • suitable protecting groups for acids include ttn- butoxy, benzyloxy, all ioxy, and inethoxyrnethoxy.
  • Suitable protecting groups for amines include 9-fi.tioreny.lmeth l carbamate, /er/ x «yf carbamate,, benzyl carbamate, irifiaoroaeeianiide, and p-teluenesuifonarnide; 007 ]
  • a "effective amount ' ' is defined a the amount required to. confer a tberapeiitic effect: on the treated patient and is typically determined based on age, surface area, weight and condition of the patient.
  • Body surface area may be approximatel determined from height and weight of the patient. See, e.g.. Scientific ' Tables, eigy
  • patient refers to a mammal, including a human.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diasiereomeric, and geometric (or conformational)) tottns of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (Ej conformational isomers.. Therefore, single isomeric (e.g., enantiomeric, diasiereomeric, and geometric (or conformational)) tottns of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (Ej conformational isomers.. Therefore, single isomeric (e.g., enantiomeric, diasiereomeric, and geometric (or conformational)) tottns of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond is
  • structures depicted herein are also meant to include compounds thai differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the. replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 'C- or 14 C-enriehed carbon are within the scope of this invention.
  • Such compounds are useful, for example * as analytical tools or probes in biological assays,
  • E ' DC is l H3 ⁇ hmethyiaminopropyl ⁇ 3-ethylearbodiimlde.
  • HBf is 1 -hydroxybenzotriaEole
  • Cbsf is beuzyloxyearbonyi is DCM
  • dichloromethane is dichloromethane
  • Boc "' is k?ri"-butoxycarhonyl
  • Hi N stands for proton nuclear magnetic resonance
  • TLC * stands for thin layer chromatography
  • the invention provides processes and. intermediates for producing bicyclic derivatives of formula la or lb:
  • ring A is a C 3 . 12 cycfoal phatie ring;
  • ring B is a G . s ?. beteroeycioaHphatic ring containing an additional 0 to 2 heiero atoms , each independently selected from O, M, d that can be optionally substituted with 1 to 4 groups, each independentl selected from alkyl, halo, alkoxy, aryL and hydroxy!;
  • Ri is H or a protecting group:
  • R? is H or C ⁇ - ⁇ 2 aliphatic
  • ring A is a C3-6 cycloaliplmtic ring.
  • ring A is eycIopfopyL
  • ring A is -dimeth leyclopropyL
  • ring B is aryL
  • ring B is phenyl. 100 901 More : particularly, ring B is:
  • .ring B is a S-raembered: heterocyclic ring.
  • nne B nne B
  • ring B is substituted with a aryi ring optionally substituted with I to 4 groups, each independently selected .firom lkyl, halo, alkoxy, and hydroxy L
  • j is H.
  • 5 is a protecting group.
  • R 2 is ii.
  • .3 ⁇ 4 is methyl ethyl, ff-propy!, im- ISO- b tyl, -w-peuty or i.w-penty;L
  • R 2 is fto-butyl
  • R 2 is /ert- uiyl. 1000104]
  • 3 ⁇ 4 is a c eloabphatic ring.
  • Another aspect relates to a process for preparing enaniioselectlvely compounds of formula. la or lb over com ounds of formi as ⁇ lb:
  • R ;!l is proteciing group, und of formula III:
  • R; and R4 are each independently a protecting group, C .n aliphatic, or a cyclic group selected from the group consisting of cyeloallphatic, hetcrocveioaiiphatie. aryh and heteroaryi
  • R is is i r/ ⁇ butyl carbamate (Boc .
  • the step of carboxyiating a . compound of formula II is in the presence of a compound of .formula Ilia:
  • the step of carboxyiating a compound of formula 0 is in the presence of a compound of .fo
  • the step of carboxyiating a compound of formula I ! is in the presence of a compound of formula. Hid;
  • 3 ⁇ 4 is C n aliphatic
  • 13 ⁇ 4 is C . unbranched aSkyl.
  • l t is CM branched alky!
  • is Cw branched a!kyL substituted with a cyclic group.
  • R 4 ls C M branched alkyl, substituted with a phenyl group.
  • iii s a cyclic group.
  • !3 ⁇ 4 is a bkyclie group.
  • the arboxylaiion step comprises treating compound of formula Ha or Ob with carbon dioxide and a lithi um base in the presence of an aproite solvent.
  • the aprotic solvent is selected from the group consisting of toluene, ethyl aeetate ? benzene, and methyl te'i-butyl ether (MTBE).
  • the aprotic solvent is MTBE.
  • the lithium base is .3 ⁇ 43 ⁇ 4' >iityl lithium.
  • the process of the present invention gives rise to a mixture of products including H a (exo% 1-3 (ex& 1-2: (endo), and 14 (emfo),
  • the combined . " weight percent in a mixture comprising eonvpotmds of formula la and .(the e:3 ⁇ 4:o-isomers) and compounds of ormula Ic and le (the endo4somtti) : is 100 weight percent, [000126] In one embodiment, the ratio of the eombined weight pereent of ia and id (exo- isomers): to: thai of le and le ( do-iso ets) is at least 60 to 40.
  • the ex&fendo ratio is at least 80 to 20.
  • the exafemh ratio is at least 90 to 10.
  • the exol ' endo ratio is at least 95 to 5.
  • the process further comprises the. step of removing a portion o the compounds of formula Ic and/or le f om Che produet mixture.
  • the compounds .of formula le and/or k are removed by crystallizing the compound of formula la or lb.
  • the compounds of formula Le and/or le are removed by recrysiailrang the -compound of formula ia or lb.
  • the ratio of the weight percent of la to Id is at leas 60 to 40. $00135] More particularly, the ratio of the weight percent of la to Id is at least 80 to 20, [0001 M] More particularly, the ratio of the weight percent o la to Id is at least 90 to 10, [000137) More particularly, the ratio of the weight percent of la to Id is at . least 95 to 5.. 000138] More particularly, he ratio of the weight percent of la to Id is at least 99 to 1 f 000139] More particularly, the ratio of the weight percent of la. to Id is at least 99.6 to 0,4. 1000140] More particularly 1, the ratio of the weight percent of la to id is at least 1 0 to 0, [000141 ] Another aspect is d a compound of formula 1 :
  • step a treating the 2-anion of step a with carbon dioxide to produce
  • the compound. of formula II ⁇ is a compound of formula Ola. ⁇ 43)
  • the com ound of formula HI is a compound of forraula Illb. ⁇ O0144
  • the compound of formula 26 is the compound of formula 26-a:
  • Another ispeci relates to a: compound of formula la-4 made by the processes
  • the compound of formula 10 is a compound of i rmul I0-a f wherein ⁇ s H f and 3 ⁇ 4is /erz-hutyl.
  • Another aspect relates to a compound of formula 10-b made y the processes disclosed herein:
  • the compound of formula 10 is a compound of formula 10-b, wherein Z? is H, and >is im-butYl. 000155] Another aspect relates to a compound of formula 10-d made by the processes
  • the invention provides: a process and intermediates for preparing a compound of formula. la as outlined in Scheme i, wherein Rj, R3 ⁇ 4 Ri, R4, and rin A are previously defined.
  • Carboxylation of the compound of formula Ilk is : achieved by first forming a 2- anion of ibrmula Ha in the presence of a compound of formula IIL
  • a compound of formula IIL For formation of similar anions, see, ,g Berry Daniel. J. Pippel, et, al, J. Org: O em., 199 , 63. 2; Donald J. Gallagher et at, J. Org. ahem., 1995, 60(22), 7092-7093: Shawn T. Kerrick. et al, ⁇ l Am. Chem, Sac. 199-1 , ⁇ 3.(25), 9708-9710; Donald .1. Gallagher et al., J Org. Chem.
  • the 2-anion of formula Ha (not. shown in Scheme 1 ⁇ is prepared by treatment of compound of formula. I la with a strong lithium base (e.g., ,vec-butyiliihiura or isopmpylliihium in a. suitable aprotic solvent (e.g., MTBE, diethyletlier, or toluene) in the presence of a compound of formula III.
  • a strong lithium base e.g., ,vec-butyiliihiura or isopmpylliihium in a. suitable aprotic solvent (e.g., MTBE, diethyletlier, or toluene) in the presence of a compound of formula III.
  • An optically acti ve compound of formul HI can induce enantioselective earboxylation to give a product having an enantiomeric excess (e.e.) of from abo t 10% t about 95% (see, e.g.. Beak c d., J. Org. Chem., 1 95, 60. 8148-S154 .
  • a compound of ibrmula Ila can be treated with carbon dioxide to give a mixture of exo ndo compounds, wherein the ex.o enda ratio is 60 to 40, 80 to 20, 90 to 1 (L 95 to 5, or greater than 98 to 2.
  • Scheme H I depicts the reaction of a compound of form ula -26- with a compound of formula la to form a compound of fo-rmuia ' 28, wherein R? is defined ' above.
  • eoinpoun.ds of formula 28 are intermediates in the synthesis of protease inhibitors according to Scheme IV .
  • Removing the protecting group Z in the tripeptide. of formula 30 provides a tree amino- tripeptide of formula 31.
  • Reaction of the aniino-tripeptide of formula 31 with the pyra ine- ' 2- carbosyHc acid of formula. 32 in the presence f a coupling reagent yields the amide- tripeptide ester of formula 33.
  • Hydrolysis of the ester of the amide- iri peptide ester of formula 33 provides the amido-tripeptkie acid of formula 34.
  • Reacting the amido-tripeptide acid of formula 34 with the amino-hydroxy amide of formula 18 to the presence of a coupling reagent gives the hydroxy-peptide of formula 35.
  • oxi dation of the hydroxy grou of the compound of formula 35 pro vides the compound of formula 4.
  • the process of Scheme HI can be scaled for large-scale production, e.g. in a manufacturing plant.
  • Large scale production can. for example, be sealed to greater than .1000 kilos.
  • aqueous NaHSCX (twice, 145 mL each) and water (1.45 mL). It was then concentrated to 300 mL unde vacuum. MTBE (300 mL) was added, a d the mixture was concentrated to reduce the water concentration to less tha 550 ppm. The concentrate was diluted with -MTBE (400 mL) to provide a solution of the title compound in MTBE.
  • the organic phase was heated to about 35 °C, diluted with DMF (300 mL), and concentrated at reduced pressure to the po nt at which distillation slowed significantly, leaving about 500 mL of concentrate.
  • the concentrate was iransfcrred without rinsing to a 1 L Schot batik.
  • the concentrate, a clear colorless solution weighed 1 1.6 g, Eksed on solution, assay analysis and the solution weight, the solution contained 187,2 g (0.706 ' mol) of
  • thermocouple, addition funnel and nitrogen inlet were charged H0BT « i3 ⁇ 4( (103.73 g. 0.678 mol 1 .20 molar eq.), EDC'HCI (129.48 g, 0.675 mol, 1 .20 molar eq.% and DMF (480 mL).
  • the slurry was cooled to 0 to 5 °C.
  • a 36.6 weight percent solution of the acid of Cbz-L-fer/- Leueine in DMF (4 1.3 , 0.745 mol., 1.32 molar eq.) was added over 47 minutes to the reaction mixture, while keeping the temperature at 0 to 5 °C.
  • the reaction mixture was stirred for 1 hour and .27 minutes.
  • the aqueous phase was; extracted with isopropyi acetate (716 m.L), and the organic phases were combined, 1 aqueous hydrochloric acid was prepared by adding 37 weight percent hydroehlorie acid ; C123 ⁇ 4.3 ml) to water ( 1435 mi). The organic phase was washed for about 20 minifies with the 1 N hydrochloric acid.
  • a 10 weight percent aqueous potassium, carbonate solution- was prepared by dissolvin potassium: carbonate (171 g, 1 .23 rool, 2.1 molar eq.) in water ( 154D nil,). The organic phase was washed with, the 10 weight percent aqueous-potassium carbonate solution for about 20 minutes.
  • the .final clear, pale yellow organic solution (1862.1 gL was sampled and submitted for solution assay. Based on. the solution, assay and the weight of the solution, the solution, contained 2.38.3 g (0.520 tnoi) of product of the title compound,
  • earboxyJate (as prepared by the method of Example 6, Method, t) in isopropy! acetate (3.9.39 g, 0.086 mol) was charged to the reactor, Isopropy! acetate (100 mL) was added to the reactor, A slurry of 50% water and wet 20% Pd( 013 ⁇ 4/earbon (3.97 g) in isopropyl acetate (168 m.L) was prepared and charged to the reactor, and agitation was started. ' The reactor was pressurized to 30 psig with nitrogen gas and vented, down to atmospheric pressure. This was repeated twice. ' Then, the reactor was pressurized to 30 psi with hydrogen and vented down to atmospheric pressure. This, was repeated twice.
  • the reactor was pressurized to 30 psig with hydrogen and stirred, at mbient temperature for 1 hour.
  • the mixture was filtered using a Buehner funnel with a Whatman #! filter paper to remove the catalyst.
  • the filter cake was. washed with isopropyi acetate (SO mL),
  • the ocedur was repeated twic more using 617 g and 290.6 g of the 12.8 weight percent solution of the starting compound.
  • the material from the thre hydrogenations were combined and distiiied at reduced pressure (28 torr).
  • the resultant solution (468.68 g) was assayed for the titl compound,

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  • Chemical & Material Sciences (AREA)
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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne un procédé de préparation énantiosélective d'un composé de la formule Ia ou Ib : par rapport à un composé des formules I-2...Ih.
EP12723028.2A 2011-05-13 2012-05-11 Procédé de préparation d'inhibiteurs de la protéase Withdrawn EP2707346A1 (fr)

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HN2002000136A (es) * 2001-06-11 2003-07-31 Basf Ag Inhibidores de la proteasa del virus hiv, compuestos que contienen a los mismos, sus usos farmaceuticos y los materiales para su sintesis
DE602005015834D1 (de) * 2004-02-27 2009-09-17 Schering Corp 3,4-(cyclopentyl)kondensierte prolinverbindungen als inhibitoren der ns3-serinprotease des hepatitis-c-virus
ES2449268T3 (es) * 2005-08-19 2014-03-19 Vertex Pharmaceuticals Inc. Procesos
AR064432A1 (es) * 2006-12-20 2009-04-01 Schering Corp Proceso para la preparacion de compuestos 6, 6-dimetil-3-aza-biciclo[3.1.0]-hexano utilizando intermediarios bisulfiticos derivados de pirrolidinas biciclicas, dichos intermediarios y un metodo para su obtencion.
EP2576508A2 (fr) * 2010-06-03 2013-04-10 Vertex Pharmaceuticals Incorporated Procédés et produits intermédiaires

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