有机化学人才网 | 最新人才 | 最新职位 | 技术交易 | 药物合成 |
   
全站搜索: |
  您当前位置:网站首页 >> 药物合成路线图解
 

药物详细合成路线

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.

来源:药化网

作者:药化小编

摘要:本文合成路线介绍的是药物中文名硫酸茚地那韦;英文名Indinavir sulfate;MK-639;L-735524;Crixivan;CAS[157810-81-6]

 
推荐VIP企业
无锡景耀生物科技有限公司
杭州卢普生物科技有限公司
宁波赛伦化工有限公司
苏州昊赛生物科技有限公司
北京嘉盛扬医药科技有限公司
上海泽涵生物医药科技有限公司
河北固安三利化工公司
郑州凯普瑞生物技术有限公司
上海药谷药业有限公司
兰州康寓信生物科技有限公司
湖北朗昕生化药业有限公司
武汉福鑫化工有限公司
嘉兴市英南化工有限公司
苏州迪飞医药科技有限公司
北京富安凯科技有限公司
上海盛中医药化工有限公司
连云港天和化学有限公司
南京晨瑞医药科技有限公司
南京苏如化工有限公司
常州瑞盛化工有限公司
热门文章
华南地区BDO市场行情僵持整理
山东地区环己酮市场行情
山东地区木薯乙醇市场行情
华北地区丁二烯市场价格弱势
华北地区邻苯市场行情上涨
山东地区三氯甲烷价格
河北地区醋酸价格
江苏地区醋酸价格
华东地区醋酸价格
华北地区醋酸价格
陕西地区醋酸价格
华南地区苯酚市场高位稳定
山东地区苯酚市场稳定
华南地区BDO市场行情僵持整理
华东地区苯酚市场稳定
河南地区苯酚市场稳定
江苏地区二氯甲烷价格暂稳
华东地区BDO市场持续僵持
江西地区二氯甲烷价格暂稳
浙江地区二氯甲烷价格暂稳
 友情链接
有机化学人才网  
首页 | 广告服务 | 建站服务 | 关于我们 | 联系我们 | 版权声明