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              Name Indinavir sulfate;MK-639;L-735524;Crixivan
              Chemical Name 2(R)-Benzyl-5-[2(S)-(N-tert-butylcarbamoyl)-4-(3-pyridylmethyl)piperazin-1-yl]-4(S)-hydroxy-N-[2(R)-hydroxyindan-1(S)-yl]pentanamide sulfate (1:1)
                    N-tert-Butyl-1-[2(S)-hydroxy-4(R)-[N-[2(R)-hydroxyindan-1(S)-yl]carbamoyl]-5-phenylpentyl]-4-(3-pyridylmethyl)piperazine-2(S)-carboxamide sulfate (1:1)
              CAS 157810-81-6
              Related CAS 150378-17-9 (free base), 180683-37-8 (hydrate)
              Formula C36H49N5O8S
              Structure
              Formula Weight 711.88463
              Stage 上市-1996
              Company Merck & Co. (Originator), Banyu (Not Determined)
              Activity/Mechanism AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY, HIV Protease Inhibitors
              Syn. Route 5
              Route 1
              1) the reaction of cis-(1s,2r)-indanediol (i) with acetonitrile and concentrated h2so4 gives cis-(1s,2r)-1-aminoindan-2-ol (ii), which is cyclocondensed with 3-phenylpropionyl chloride (iii), isopropenyl methyl ether and triethylamine to yield the acetonide amide (iv). the condensation of amide (iv) with (s)-(+)-glycidyl p-toluenesulfonate (v) in the presence of lithium hexamethyldisylazide (lhs) affords the chiral epoxide (vi), which is condensed with 4-(tert-butoxycarbonyl)-n-tert-butylpiperazine-2(s)-carboxamide (vii) in refluxing isopropyl acetate and deprotected with aqueous hcl to give the dihydroxy-diamide (viii). finally, this compound is condensed with 3-(chloromethyl)pyridine (ix) by means of triethylamine in dmf.2) the amide (iv) can also be alkylated with allyl bromide and butyllithium to the pentenyl amide (x), which is diastereoselectively converted to the chiral iodohydrine (xi) by means of n-iodosuccinimide (nis). finally, this compound is cyclized in basic medium, yielding the epoxide (vi), already obtained.
              List of intermediates No.
              tert-butyl (2r)-2-[[(methylsulfonyl)oxy]methyl]-1-pyrrolidinecarboxylate
              1-methyl-1h-pyrrole-2-carbonyl chloride (ix)
              methyl 2-(1,3-benzodioxol-5-ylmethyl)-7,8-dimethoxy-1,1-dioxo-4-[[(trifluoromethyl)sulfonyl]oxy]-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate (i)
              1,3-benzodioxole-5-thiol (ii)
              8-methoxy-2h-chromene-3-carboxylic acid (iii)
              8-methoxy-2h-chromene-3-carbonyl chloride (iv)
              (8-methoxy-2h-chromen-3-yl)(4-morpholinyl)methanone (v)
              (8-hydroxy-2h-chromen-3-yl)(4-morpholinyl)methanone (vi)
              3-(4-morpholinylmethyl)-2h-chromen-8-ol (vii)
              (2s)-1-(benzylamino)-3-(benzyloxy)-2-propanol (viii)
              benzyl [(2r)-4-benzylmorpholinyl]methyl ether (x)
              [(2r)-4-tritylmorpholinyl]methanol (xi)
              2-amino-2-imino-n-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]ethanimidamide
              Reference 1:
                  maligres, p.e.; upadhyay, v.; rossen, k.; cianciosi, s.j.; purick, r.m.; eng, k.k.; reamer, r.a.; askin, d.; volante, r.p.; reider, p.j.; diastereoselective syn-epoxidation of 2-alkyl-4-enamides to epoxyamides: synthesis of the merck hiv-1 protease inhibitor epoxide intermediate. tetrahedron lett 1995, 36, 13, 2195-8.
              Reference 2:
                  mealy, n.; castaner, j.; indinavir sulfate. drugs fut 1996, 21, 6, 600.
              Reference 3:
                  askin, d.; volante, r.p.; eng, k.k. (merck & co., inc.); process for making hiv protease inhibitors. wo 9502584 .
              Reference 4:
                  verhoeven, t.r.; roberts, e.f.; senanayake, c.h.; ryan, k.m. (merck & co., inc.); regiospecific processes to make cis-1-amino-2-alkanol from diol or halohydrin. us 5449830 .
              Reference 5:
                  askin, d.; eng, k.k.; rossen, k.; purick, r.m.; wells, k.m.; volante, r.p.; reider, p.j.; highly diastereoselective reaction of a chiral, non-racemic amide enolate with (s)-glycidyl tosylate. synthesis of the orally active hiv-1 protease inhibitor l-735,524. tetrahedron lett 1994, 35, 5, 673-6.
              Reference 6:
                  dorsey, b.d.; levin, r.b.; mcdaniel, s.l.; et al.; l-735,524: the design of a potent and orally bioavailable hiv protease inhibitor. j med chem 1994, 37, 21, 3443-51.

              Route 2
              3) the alkylation of 5(s)-(tert-butyldimethylsilyloxymethyl)tetrahydrofuran-2-one (xii) by means of benzyl bromide (xiii) and lithium diisopropylamide (lda) gives the corresponding 3(r)-benzyl derivative (xiv), which is deprotected with aqueous hf, yielding the hydroxymethyl compound (xv). the esterification of (xv) with trifluoromethanesulfonic anhydride affords the corresponding triflate (xvi), which is condensed with the chiral piperazine (vii) by means of diisopropylethylamine in isopropanol, giving the substituted furanone (xvii). ring opening of the furanone (xvii) with lioh, dme and imidazole yields the substituted hydroxypentanamide (xviii), which is protected with tert-butyldimethylsilyl chloride to afford the protected amide (xix). the trans-amidation of (xix) with 2-hydroxyindan-1-amine (ii) by means of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (edc) and 1-hydroxybenzotriazole (hobt) in dmf gives the protected dihydroxy diamide (xx), which is deprotected with trimethylsilyl triflate, affording the dihydroxy diamide (vii), already obtained. this compound is then alkylated with 3-(chloromethyl)pyridine (ix) as before.
              List of intermediates No.
              2,6-dichloro-3-cyano-1,4-quinoxalinediiumdiolate (xiii)
              1-methyl-1h-pyrrole-2-carbonyl chloride (ix)
              1,3-benzodioxole-5-thiol (ii)
              3-(4-morpholinylmethyl)-2h-chromen-8-ol (vii)
              (2s)-1-(benzylamino)-3-(benzyloxy)-2-propanol (viii)
              triphenylchloromethane; 1-[chloro(diphenyl)methyl]benzene; trityl chloride (xii)
              (2r)-2-([[3-(4-morpholinylmethyl)-2h-chromen-8-yl]oxy]methyl)-4-tritylmorpholine (xiv)
              1,2,3,4-tetrahydro-7-isoquinolinol (xv)
              tert-butyl 7-hydroxy-3,4-dihydro-2(1h)-isoquinolinecarboxylate (xvi)
              ethyl 2-[4-(benzyloxy)phenyl]-2-chloroacetate (xvii)
              ethyl 2-[4-(benzyloxy)phenyl]acetate; p-(benzyloxy)phenylacetate (xviii)
              tert-butyl 7-[1-[4-(benzyloxy)phenyl]-2-ethoxy-2-oxoethoxy]-3,4-dihydro-2(1h)-isoquinolinecarboxylate (xix)
              tert-butyl 7-[2-ethoxy-1-(4-hydroxyphenyl)-2-oxoethoxy]-3,4-dihydro-2(1h)-isoquinolinecarboxylate (xx)
              tert-butyl 7-[1-(4-[[1-(tert-butoxycarbonyl)-4-piperidinyl]oxy]phenyl)-2-ethoxy-2-oxoethoxy]-3,4-dihydro-2(1h)-isoquinolinecarboxylate (xxi)
              Reference 1:
                  mealy, n.; castaner, j.; indinavir sulfate. drugs fut 1996, 21, 6, 600.
              Reference 2:
                  vacca, j.p.; holloway, m.k.; dorsey, b.d.; hungate, r.w.; guare, j.p. (merck & co., inc.); hiv protease inhibitors useful for the treatment of aids. ep 0541168; jp 1993279337; wo 9309096 .
              Reference 3:
                  vacca, j.p.; guare, j.p.; dorsey, b.d.; holloway, m.k.; hungate, r.w. (merck & co., inc.); hiv protease inhibitors in pharmaceutical combinations for the treatment of aids. ep 0617968; jp 1996508496; wo 9422480 .
              Reference 4:
                  vacca, j.p.; dorsey, b.d.; guare, j.p.; holloway, m.k.; hungate, r.w.; levin, r.b. (merck & co., inc.); hiv protease inhibitors useful for the treatment of aids. ep 0696277; jp 1996509980; us 5413999; wo 9426717 .

              Route 3
              4) the condensation of the chiral piperazine (vii) with (s)-(+)-glycicyl 3-nitrobenzenesulfonate (xxii) by means of diisopropylethylamine in dmf [or with (s)-glycidol (xxiii), tosyl chloride and nah] gives the epoxide (xxiv), which is condensed with the propionamide (iv) by means of butyllithium in thf, yielding the protected hydroxyamide (xxv). the deprotection of (xxv) with aqueous hcl affords the dihydroxy-diamide (viii), already obtained, which is finally alkylated with 3-(chloromethyl)pyridine (ix) as before.
              List of intermediates No.
              1-methyl-1h-pyrrole-2-carbonyl chloride (ix)
              8-methoxy-2h-chromene-3-carbonyl chloride (iv)
              3-(4-morpholinylmethyl)-2h-chromen-8-ol (vii)
              (2s)-1-(benzylamino)-3-(benzyloxy)-2-propanol (viii)
              ethyl 2-[4-(4-piperidinyloxy)phenyl]-2-(1,2,3,4-tetrahydro-7-isoquinolinyloxy)acetate (xxii)
              ethyl 2-[4-([1-[amino(imino)methyl]-4-piperidinyl]oxy)phenyl]-2-([2-[amino(imino)methyl]-1,2,3,4-tetrahydro-7-isoquinolinyl]oxy)acetate (xxiii)
              benzyl (2r)-2-(benzylamino)-4-methylpentanoate (xxiv)
              methyl(phenyl)phosphinic chloride (xxv)
              Reference 1:
                  mealy, n.; castaner, j.; indinavir sulfate. drugs fut 1996, 21, 6, 600.
              Reference 2:
                  askin, d.; reider, p.; rossen, k.; varsolona, r.j.; wells, k.m. (merck & co., inc.); process for making hiv protease inhibitors. wo 9502583 .

              Route 4
              5) the double bond of the pentenylamide (x) (as obtained in scheme 1) is oxidized with oso4 and n-methylmorpholine n-oxide in tert-butanol/water to give the 4(r,s),5-dihydroxy-compound (xxvi), which is esterified selectively with methanesulfonyl chloride, yielding the terminal monomesylate (xxvii). the condensation of (xxvii) with the chiral piperazine (vii) by means of k2co3 in hot isopropanol yields the condensation product (xxviii) with the (r,s)-configuration at the 4-oh group. the optical resolution of this 4-oh group with (s)-(+)-camphosulfonic acid affords the protected hydroxy-amide (xxv), already obtained in scheme 19918303a.
              List of intermediates No.
              3-(4-morpholinylmethyl)-2h-chromen-8-ol (vii)
              benzyl [(2r)-4-benzylmorpholinyl]methyl ether (x)
              methyl(phenyl)phosphinic chloride (xxv)
              benzyl (2r)-2-[benzyl[methyl(phenyl)phosphoryl]amino]-4-methylpentanoate (xxvi)
              (2r)-2-[benzyl[methyl(phenyl)phosphoryl]amino]-4-methylpentanoic acid (xxvii)
              (2r)-2-[benzyl[methyl(phenyl)phosphoryl]amino]-n-(benzyloxy)-4-methylpentanamide (xxviii)
              Reference 1:
                  mealy, n.; castaner, j.; indinavir sulfate. drugs fut 1996, 21, 6, 600.
              Reference 2:
                  vacca, j.p.; guare, j.p.; dorsey, b.d.; holloway, m.k.; hungate, r.w. (merck & co., inc.); hiv protease inhibitors in pharmaceutical combinations for the treatment of aids. ep 0617968; jp 1996508496; wo 9422480 .
              Reference 3:
                  vacca, j.p.; dorsey, b.d.; guare, j.p.; holloway, m.k.; hungate, r.w.; levin, r.b. (merck & co., inc.); hiv protease inhibitors useful for the treatment of aids. ep 0696277; jp 1996509980; us 5413999; wo 9426717 .

              Route 5
              6) the chiral piperazine (vii) can be obtained by several different ways:6a) the sequential protection of piperazine-2(s)-carboxylic acid (xxix) gives 1-(benzyloxycarbonyl)-4-(tert-butoxycarbonyl)piperazine-2(s)-carboxylic acid (xxx), which is condensed with tert-butylamine by means of edc and hobt to afford the tert-butylamide (xxxi). finally, this compound is selectively deprotected by hydrogenation with h2 over pd/c in methanol, yielding the chiral piperazine (vii).6b) the partial hydrogenation of n-tert-butylpyrazine-2-carboxamide (xxxii) with h2 over pd/c gives the tetrahydro derivative (xxxiii), which is sequentially protected as usual to the 1-(benzyloxycarbonyl)-4-(tert-butoxycarbonyl)-1,4,5,6-tetrahydropyrazin e -2-carboxamide (xxxiv). finally, this compound is hydrogenated using the chiral catalyst [r-binap(cod)rh]otf to afford the chiral piperazine (xxxi), already obtained.6c) the n-tert-butylpyrazine-2-carboxamide (xxxii) is fully reduced with h2 over pd/c in propanol, giving the racemic n-tert-butylpiperazine-2-carboxamide (xxxv), which is submitted to optical resolution with (s)-(+)-camphosulfonic acid, yielding the (s)-isomer (xxxvi), which is then selectively protected with tert-butoxycarbonyl anhydride to give the desired chiral amide (vii).
              List of intermediates No.
              3-(4-morpholinylmethyl)-2h-chromen-8-ol (vii)
              benzyl (2r)-2-amino-4-methylpentanoate (xxix)
              (2r)-2-[benzyl[methyl(phenyl)phosphoryl]amino]-n-(benzyloxy)-4-methylpentanamide (xxx)
              ethyl 2-methylpropanoate (xxxi)
              4-hexyl-3,3-dimethyl-2-azetidinone (xxxii)
              4-[[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]benzonitrile (xxxiii)
              3-[(4-cyanobenzoyl)amino]-2,2-dimethylnonanoic acid (xxxiv)
              (2s)-3-ethoxy-1-phenyl-3-buten-2-amine (xxxv)
              enanthic aldehyde; 1-heptanal; heptaldehyde; oenanthol; oenanthaldehyde; enanthal; oenanthal; heptyl aldehyde; n-heptaldehyde; enanthaldehyde; enanthole; 1-heptaldehyde; heptanaldehyde; n-heptanal; oenanthic aldehyde; n-heptylaldehyde; heptanal (xxxvi)
              Reference 1:
                  mealy, n.; castaner, j.; indinavir sulfate. drugs fut 1996, 21, 6, 600.
              Reference 2:
                  rossen, k.; weissman, s.a.; sager, j.; reamer, r.a.; askin, d.; volante, r.p.; reider, p.j.; asymmetric hydrogenation of tetrahydropyrazines: synthesis of (s)-piperazine-2-tert-butylcarboxamide, an intermediate in the preparation of the hiv protease inhibitor indinavir. tetrahedron lett 1995, 36, 36, 6419-22.
              Reference 3:
                  vacca, j.p.; guare, j.p.; dorsey, b.d.; holloway, m.k.; hungate, r.w. (merck & co., inc.); hiv protease inhibitors in pharmaceutical combinations for the treatment of aids. ep 0617968; jp 1996508496; wo 9422480 .
              Reference 4:
                  vacca, j.p.; dorsey, b.d.; guare, j.p.; holloway, m.k.; hungate, r.w.; levin, r.b. (merck & co., inc.); hiv protease inhibitors useful for the treatment of aids. ep 0696277; jp 1996509980; us 5413999; wo 9426717 .
              Reference 5:
                  askin, d.; reider, p.; rossen, k.; varsolona, r.j.; wells, k.m. (merck & co., inc.); process for making hiv protease inhibitors. wo 9502583 .
              Reference 6:
                  verhoeven, t.r.; roberts, e.f.; senanayake, c.h.; ryan, k.m. (merck & co., inc.); regiospecific processes to make cis-1-amino-2-alkanol from diol or halohydrin. us 5449830 .
              Reference 7:
                  dorsey, b.d.; levin, r.b.; mcdaniel, s.l.; et al.; l-735,524: the design of a potent and orally bioavailable hiv protease inhibitor. j med chem 1994, 37, 21, 3443-51.
              Reference 8:
                  askin, d.; eng, k.k.; rossen, k.; purick, r.m.; wells, k.m.; volante, r.p.; reider, p.j.; highly diastereoselective reaction of a chiral, non-racemic amide enolate with (s)-glycidyl tosylate. synthesis of the orally active hiv-1 protease inhibitor l-735,524. tetrahedron lett 1994, 35, 5, 673-6.

              來源:藥化網

              作者:藥化小編

              摘要:本文合成路線介紹的是藥物中文名硫酸茚地那韋;英文名Indinavir sulfate;MK-639;L-735524;Crixivan;CAS[157810-81-6]

               
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