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 Aliskiren fumarate;CGP-60536(free base);SPP-100B;SPP-100(free base);CGP-60536B;Rasilez
Chemical Name (2S,4S,5S,7S)-5-Amino-N-(2-carbamoyl-2-methylpropyl)-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropoxy)benzyl]-8-methylnonanamide hemifumarate
CAS 173334-58-2
Related CAS 173334-57-1 (free base), 173399-03-6 (monohydrochloride)
Formula C64H110N6O16
Structure
Formula Weight 1219.6209
Stage 上市-2007
Company Novartis (Originator), Speedel (Licensee)
Activity/Mechanism CARDIOVASCULAR DRUGS, Heart Failure Therapy, Hypertension, Treatment of, Renal Failure, Agents for, RENAL-UROLOGIC DRUGS, Treatment of Renal Diseases, Renin Inhibitors
Syn. Route 13
Route 1
alkylation of 3-hydroxy-4-methoxybenzyl alcohol (i) with 1-bromo-3-methoxypropane (ii) gives ether (iii). subsequent conversion of benzyl alcohol (iii) into bromide (iv) is carried out using bromotrimetylsilane. the chiral isovaleryloxazolidinone (v) is alkylated with bromide (iv) by means of lihmds to afford (vi), which is hydrolyzed to the (s)-2-aryl-2-isopropylpropionic acid (vii) by means of lithium peroxide. the reduction of acid (vii) to the corresponding alcohol with nabh4/i2 reagent, followed by treatment with pph3 and nbs, provides bromide (viii). alkylation of the chiral dimethoxydihydropyrazin (ix) with bromide (viii) produces (x). further hydrolysis of the pyrazine ring of (x) with hcl, followed by boc protection of the resulting (s,s)-amino ester, yields compound (xi). reduction of the ester group of (xi) with dibal gives aldehyde (xii). this compound is condensed with the grignard reagent (xiii) to afford the diastereomeric mixture of amino alcohols (xiv). treatment of mixture (xiv) with 2,2-dimethoxypropane (xv) and tsoh produces a mixture of oxazolidines, from which the required (s,s,s)-isomer (xvi) is isolated by flash chromatography. hydrogenolitic deprotection of the benzyl ether of (xvi) gives alcohol (xvii).
List of intermediates No.
[(1r)-2-[(z)-(6-amino-9h-purin-9-yl)methylidene]cyclopropyl]methyl acetate (ix)
(2r,3s,4r,5r)-2-(hydroxymethyl)-5-[6-[[2-(methylsulfanyl)ethyl]amino]-2-[(3,3,3-trifluoropropyl)sulfanyl]-9h-purin-9-yl]tetrahydro-3,4-furandiol (xv)
(3r,4s,5s,6r,8r,9r,10e,12e,15r)-5-[3,6-dideoxy-4-o-(2,6-dideoxy-3-c-methyl-3-o-propionyl-alpha-l-allopyranosyl)-3-(dimethylamino)-beta-d-glucopyranosyloxy]-6-(formylmethyl)-3,9-dihydroxy-4-methoxy-8-methylhexadeca-10,12-dieno-15-lctone (ii)
(2s)-2-[3-(5-[(1r)-2-(benzyloxy)-1-[(tert-butoxycarbonyl)amino]ethyl]-2-methoxyphenoxy)-5-methoxyphenyl]-2-[[(2r)-3-(4-fluoro-3-nitrophenyl)-2-(propionylamino)propanoyl]amino]ethanoic acid (i)
methyl (6r,9r)-9-(3-bromo-4-methylphenyl)-12-[(r)-[[tert-butyl(dimethyl)silyl]oxy](4-fluoro-3-nitrophenyl)methyl]-6-(3,5-dihydroxy-4-methylphenyl)-2,2-dimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecan-13-oate (iii)
methyl (8r,11r,14s,15r)-11-(3-bromo-4-methylphenyl)-8-[(tert-butoxycarbonyl)amino]-15-[[tert-butyl(dimethyl)silyl]oxy]-4,5-dihydroxy-18-nitro-9,12-dioxo-2-oxa-10,13-diazatricyclo[14.2.2.1(3,7)]henicosa-1(18),3(21),4,6,16,19-hexaene-14-carboxylate (iv)
methyl (8r,11r,14s,15r)-11-(3-bromo-4-methylphenyl)-8-[(tert-butoxycarbonyl)amino]-15-[[tert-butyl(dimethyl)silyl]oxy]-18-chloro-4,5-dihydroxy-9,12-dioxo-2-oxa-10,13-diazatricyclo[14.2.2.1(3,7)]henicosa-1(18),3(21),4,6,16,19-hexaene-14-carboxylate (vi)
2-[(1s)-1-[[(benzyloxy)carbonyl]amino]-2-[(2-methoxyethoxy)methoxy]ethyl]-4,6-dimethylphenylboronic acid (vii)
methyl (8r,11r,14s,15r)-11-(2-[(1s)-1-[[(benzyloxy)carbonyl]amino]-2-[(2-methoxyethoxy)methoxy]ethyl]-4,6,6-trimethoxy[1,1-biphenyl]-3-yl)-8-[(tert-butoxycarbonyl)amino]-15-[[tert-butyl(dimethyl)silyl]oxy]-18-chloro-5-hydroxy-4-methoxy-9,12-diox; methyl (8r,11r,14s,15r)-11-(2-[(1s)-1-[[(benzyloxy)carbonyl]amino]-2-[(2-methoxyethoxy)methoxy]ethyl]-4,6,6-trimethoxy[1,1-biphenyl]-3-yl)-8-[(tert-butoxycarbonyl)amino]-15-[[tert-butyl(dimethyl)silyl]oxy]-18-chloro-5-hydroxy-4-methoxy-9,12-diox (viii)
methyl (8r,11r,14s,15r)-11-(2-[(1s)-1-[[(benzyloxy)carbonyl]amino]-2-[(2-methoxyethoxy)methoxy]ethyl]-4,6,6-trimethoxy[1,1-biphenyl]-3-yl)-8-[(tert-butoxycarbonyl)amino]-18-chloro-5,15-dihydroxy-4-methoxy-9,12-dioxo-2-oxa-10,13-diazatricyclo[14.; methyl (8r,11r,14s,15r)-11-(2-[(1s)-1-[[(benzyloxy)carbonyl]amino]-2-[(2-methoxyethoxy)methoxy]ethyl]-4,6,6-trimethoxy[1,1-biphenyl]-3-yl)-8-[(tert-butoxycarbonyl)amino]-18-chloro-5,15-dihydroxy-4-methoxy-9,12-dioxo-2-oxa-10,13-diazatricyclo[14. (x)
(8r,11r,14s,15r)-11-(2-[(1s)-1-[[(benzyloxy)carbonyl]amino]-2-[(2-methoxyethoxy)methoxy]ethyl]-4,6,6-trimethoxy[1,1-biphenyl]-3-yl)-8-[(tert-butoxycarbonyl)amino]-18-chloro-5,15-dihydroxy-4-methoxy-9,12-dioxo-2-oxa-10,13-diazatricyclo[14.2.2.1(3; (8r,11r,14s,15r)-11-(2-[(1s)-1-[[(benzyloxy)carbonyl]amino]-2-[(2-methoxyethoxy)methoxy]ethyl]-4,6,6-trimethoxy[1,1-biphenyl]-3-yl)-8-[(tert-butoxycarbonyl)amino]-18-chloro-5,15-dihydroxy-4-methoxy-9,12-dioxo-2-oxa-10,13-diazatricyclo[14.2.2.1(3 (xi)
(8r,11r,14s,15r)-11-(2-[(1s)-1-amino-2-[(2-methoxyethoxy)methoxy]ethyl]-4,6,6-trimethoxy[1,1-biphenyl]-3-yl)-8-[(tert-butoxycarbonyl)amino]-18-chloro-5,15-dihydroxy-4-methoxy-9,12-dioxo-2-oxa-10,13-diazatricyclo[14.2.2.1(3,7)]henicosa-1(18),3(21; (8r,11r,14s,15r)-11-(2-[(1s)-1-amino-2-[(2-methoxyethoxy)methoxy]ethyl]-4,6,6-trimethoxy[1,1-biphenyl]-3-yl)-8-[(tert-butoxycarbonyl)amino]-18-chloro-5,15-dihydroxy-4-methoxy-9,12-dioxo-2-oxa-10,13-diazatricyclo[14.2.2.1(3,7)]henicosa-1(18),3(21 (xii)
tert-butyl (1r,13s,16s,17r,28r)-20-chloro-17,25-dihydroxy-5,8,10,24-tetramethoxy-13-[[(2-methoxyethoxy)methoxy]methyl]-15,29,31-trioxo-22-oxa-14,30,32-triazahexacyclo[14.14.2.2(18,21).1(2,6).1(23,27).0(7,12)]hexatriaconta-2(36),3,5,7,9,11,18,20,23(3; tert-butyl (1r,13s,16s,17r,28r)-20-chloro-17,25-dihydroxy-5,8,10,24-tetramethoxy-13-[[(2-methoxyethoxy)methoxy]methyl]-15,29,31-trioxo-22-oxa-14,30,32-triazahexacyclo[14.14.2.2(18,21).1(2,6).1(23,27).0(7,12)]hexatriaconta-2(36),3,5,7,9,11,18,20,23(3 (xiii)
(1r,13s,16s,17r,28r)-28-amino-20-chloro-17,25-dihydroxy-5,8,10,24-tetramethoxy-13-[[(2-methoxyethoxy)methoxy]methyl]-22-oxa-14,30,32-triazahexacyclo[14.14.2.2(18,21).1(2,6).1(23,27).0(7,12)]hexatriaconta-2(36),3,5,7,9,11,18,20,23(35),24,26,33-dodeca; (1r,13s,16s,17r,28r)-28-amino-20-chloro-17,25-dihydroxy-5,8,10,24-tetramethoxy-13-[[(2-methoxyethoxy)methoxy]methyl]-22-oxa-14,30,32-triazahexacyclo[14.14.2.2(18,21).1(2,6).1(23,27).0(7,12)]hexatriaconta-2(36),3,5,7,9,11,18,20,23(35),24,26,33-dodeca (xiv)
(xvi)
(xvii)
(v)
Reference 1:
    mealy, n.e.; casta?er, r.m.; silvestre, j.s.; casta?er, j.; aliskiren fumarate. drugs fut 2001, 26, 12, 1139.
Reference 2:
    rigollier, p.; stutz, s.; goeschke, r.; yamaguchi, y.; maibaum, j.; wood, j.; structural modification of the p2 position of 2,7-dialkyl substituted 5(s)-amino-4(s)-hydroxy-8-phenyl-octane-carboxamides: discovery of a potent non-peptide renin inhibitor active after once daily dosing in marmosets. 15th european federation for medicinal chemistry international symposium on medicinal chemistry (sept 6 1998, edinburgh) 1998, abst p.230.
Reference 3:
    g?schke, r.; maibaum, j.k.; schilling, w.; stutz, s.; rigollier, p.; yamaguchi, y.; cohen, n.c.; herold, p. (novartis ag); delta-amino-gamma-hydroxy-omega-aryl alkanoic acid amides with enzyme especially renin inhibiting activities. ep 0678500; ep 0678503; jp 1996053434; jp 1996081430; us 5559111; us 5627182; us 5646143 .

Route 2
this alcohol is oxidized to aldehyde with nmmo and tetrapropylammonium perruthenate (tpap), and further oxidized to carboxylic acid (xviii) with kmno4 and tetrabutylammonium bromide (tbab). coupling of (xviii) with aminoamide (xix) by means of diethyl cyanophosphonate and tea gives (xx). finally, acid hydrolysis of the oxazolidine ring and boc protecting groups of (xx) furnishes the corresponding amino alcohol, which is finally converted to the hemifumarate salt.
List of intermediates No.
(xviii)
n-[tert-butyl(dimethyl)silyl]-2,2,2-trifluoro-n-methylacetamide (xix)
(xx)
methyl (2s)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-methyl-3-phenylbutanoate
Reference 1:
    mealy, n.e.; casta?er, r.m.; silvestre, j.s.; casta?er, j.; aliskiren fumarate. drugs fut 2001, 26, 12, 1139.
Reference 2:
    rigollier, p.; stutz, s.; goeschke, r.; yamaguchi, y.; maibaum, j.; wood, j.; structural modification of the p2 position of 2,7-dialkyl substituted 5(s)-amino-4(s)-hydroxy-8-phenyl-octane-carboxamides: discovery of a potent non-peptide renin inhibitor active after once daily dosing in marmosets. 15th european federation for medicinal chemistry international symposium on medicinal chemistry (sept 6 1998, edinburgh) 1998, abst p.230.
Reference 3:
    g?schke, r.; maibaum, j.k.; schilling, w.; stutz, s.; rigollier, p.; yamaguchi, y.; cohen, n.c.; herold, p. (novartis ag); delta-amino-gamma-hydroxy-omega-aryl alkanoic acid amides with enzyme especially renin inhibiting activities. ep 0678500; ep 0678503; jp 1996053434; jp 1996081430; us 5559111; us 5627182; us 5646143 .

Route 3
the intermediate gamma-butyrolactone (xxviii) has been obtained as follows: allylation of the imidazolidinone intermediate (v) with allyl bromide (xxi) and lihmds in thf gives the chiral intermediate (xxii), which by dihydroxylation and cleavage of the chiral auxiliary with oso4 and nmmo in tert-butanol/acetone/water yields the lactone alcohol (xxiii). oxidation of (xxiii) with naio4 and rucl3 in ccl4/acetonitrile/water affords the carboxylic acid (xxiv), which by treatment with (cocl)2 in toluene provides the acyl chloride (xxv). esterification of (xxv) with benzyl alcohol gives the corresponding benzyl ester as a diastereomeric mixture, from which the desired isomer (xxvi) is separated by flash chromatography. hydrogenolysis of the benzyl ester (xxvi) with h2 over pd/c in ethyl acetate yields the carboxylic acid (xxvii), which is treated with oxalyl chloride in toluene to afford the desired gamma-butyrolactone intermediate (xxviii).
List of intermediates No.
tert-butyl (2r)-2-[[(methylsulfonyl)oxy]methyl]-1-pyrrolidinecarboxylate (xxi)
(v)
bis(phenylmethyl) 5-nitro-1,3-benzenedicarboxylate (xxii)
bis(phenylmethyl) 5-amino-1,3-benzenedicarboxylate (xxiii)
n-{[(1,1-dimethylethyl)oxy]carbonyl}-2-fluorophenylalanine (xxiv)
bis(phenylmethyl) 5-{[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-3-(2-fluorophenyl)propanoyl]amino}-1,3-benzenedicarboxylate (xxv)
bis(phenylmethyl) 5-{[2-amino-3-(2-fluorophenyl)propanoyl]amino}-1,3-benzenedicarboxylate (xxvi)
1h-benzimidazole-5,6-dicarboxylic acid (xxvii)
1h-furo[3,4-f]benzimidazole-5,7-dione (xxviii)
Reference 1:
    mealy, n.e.; casta?er, r.m.; silvestre, j.s.; casta?er, j.; aliskiren fumarate. drugs fut 2001, 26, 12, 1139.
Reference 2:
    rüeger, h.; maibaum, j.; stutz, s.; spindler, f.; g?schke, r.; a convergent synthesis approach towards cgp60536b, a non-peptide orally potent renin inhibitor, via an enantiomerically pure ketolactone intermediate. tetrahedron lett 2000, 41, 51, 10085.

Route 4
the reduction of the chiral propionic acid (vii) with nabh4 in thf gives the primary alcohol (xxix), which by reaction with socl2 and pyridine in chcl3 yields the chloride (xxx). condensation of (xxx) with the butyrolactone intermediate (xxvii) by means of mg and dibromoethane affords the ketonic adduct (xxxi). reduction of the exocyclic carbonyl group of (xxxi) with nabh4 in thf/ methanol provides a 3:1 diastereomeric mixture of the desired chiral alcohol (xxxii) and its oh-epimer (xxxiii) that are separated by flash chromatography. reaction of (xxxii) with mscl and tea, followed by treatment with nan3, affords the azido derivative (xxxiv), which is condensed with 4-amino-3,3-dimethylbutyramide (xix) by means of 2-hydroxypyridine and tea to provide the adduct (xxxv). finally, the azido group of (xxxv) is reduced with h2 over pd/ in meoh to yield the target amino alcohol.an extensive study on the stereoselective reduction of the ketonic adduct (xxxi) has been performed. no better diastereoselectivity than 3:1 has been obtained for the synthesis of the chiral alcohol (xxxii). however, excellent diastereoselectivity (97:3) has been obtained for the synthesis of its oh-epimer, alcohol (xxxiii), with k-selectride in thf, which could potentially provide access to the target amino alcohol via a double inversion protocol.
List of intermediates No.
2-[(1s)-1-[[(benzyloxy)carbonyl]amino]-2-[(2-methoxyethoxy)methoxy]ethyl]-4,6-dimethylphenylboronic acid (vii)
n-[tert-butyl(dimethyl)silyl]-2,2,2-trifluoro-n-methylacetamide (xix)
1h-furo[3,4-f]benzimidazole-5,7-dione (xxviii)
6-[({2-[(3,5-bis{[(phenylmethyl)oxy]carbonyl}phenyl)amino]-1-[(2-fluorophenyl)methyl]-2-oxoethyl}amino)carbonyl]-1h-benzimidazole-5-carboxylic acid (xxix)
cycloheptylmethanamine; cycloheptylmethylamine (xxx)
bis(phenylmethyl) 5-{[2-{[(5-{[(cycloheptylmethyl)amino]carbonyl}-1h-benzimidazol-6-yl)carbonyl]amino}-3-(2-fluorophenyl)propanoyl]amino}-1,3-benzenedicarboxylate (xxxi)
3-nitro-2-pyridinol (xxxii)
3-amino-2-pyridinol (xxxiii)
n-(2-hydroxy-3-pyridinyl)-5-methyl-3-isoxazolecarboxamide (xxxiv)
n-{[(1,1-dimethylethyl)oxy]carbonyl}-3,4-difluorophenylalanine (xxxv)
Reference 1:
    mealy, n.e.; casta?er, r.m.; silvestre, j.s.; casta?er, j.; aliskiren fumarate. drugs fut 2001, 26, 12, 1139.
Reference 2:
    rüeger, h.; maibaum, j.; stutz, s.; spindler, f.; g?schke, r.; a convergent synthesis approach towards cgp60536b, a non-peptide orally potent renin inhibitor, via an enantiomerically pure ketolactone intermediate. tetrahedron lett 2000, 41, 51, 10085.

Route 5
alternatively, the chiral phenylpropyl chloride (xxx) can also be prepared as follows: reduction of the cinnamic acid (xxxvi) with h2 over pd/c in ethyl acetate gives the phenylpropionic acid (xxxvii), which is treated with oxalyl chloride to yield the acyl chloride (xxxviii). condensation of (xxxviii) with (+)-pseudoephedrine (xxxix) by means of naoh in toluene/water affords the chiral amide (xl), which is enantioselectively alkylated with 2-iodopropane (xli) by means of lda in thf to provide the adduct (xlii). reduction of the amide group of (xlii) with bh3/nh3 in thf gives the already reported primary alcohol (xxix), which is finally treated with pocl3 in hot toluene to afford the phenylpropyl chloride intermediate (xxx).
List of intermediates No.
(1s,2s)-2-amino-1-phenyl-1,3-propanediol (xli)
(2s,3r,4s)-3-(acetoxy)-2-methyl-3,4-dihydro-2h-pyran-4-yl acetate (xxxix)
6-[({2-[(3,5-bis{[(phenylmethyl)oxy]carbonyl}phenyl)amino]-1-[(2-fluorophenyl)methyl]-2-oxoethyl}amino)carbonyl]-1h-benzimidazole-5-carboxylic acid (xxix)
cycloheptylmethanamine; cycloheptylmethylamine (xxx)
3,4-difluorophenylalanine (xxxvi)
3-(3,4-difluorophenyl)-2-hydroxypropanoic acid (xxxvii)
methyl 3-(3,4-difluorophenyl)-2-hydroxypropanoate (xxxviii)
methyl 3-(3,4-difluorophenyl)-2-{[(trifluoromethyl)sulfonyl]oxy}propanoate (xl)
methyl 3-(3,4-difluorophenyl)-2-[3-{[(5-methyl-3-isoxazolyl)carbonyl]amino}-2-oxo-1(2h)-pyridinyl]propanoate (xlii)
Reference 1:
    mealy, n.e.; casta?er, r.m.; silvestre, j.s.; casta?er, j.; aliskiren fumarate. drugs fut 2001, 26, 12, 1139.
Reference 2:
    carey, j.s.; sandham, d.a.; taylor, r.j.; fassler, a.; a convergent synthesis of the renin inhibitor cgp60536b. tetrahedron lett 2000, 41, 51, 10091.

Route 6
the chiral azido intermediate (xxxiv) can also be obtained as follows: reaction of (+)-pseudoephedrine isovaleramide (xliii) with allyl bromide (xxi) by means of lda in thf gives the pentenoyl amide (xliv), which is treated with nbs in dme/water to yield the spiro compound (xlv). hydrolysis of the bromomethyl group of (xlv) with tetrabutylammonium acetate and k2co3 affords the carbinol (xlvi), which is oxidized to aldehyde (xlvii) with so3/pyridine and tea in dmso/dichloromethane. condensation of (xlvii) with the propyl chloride intermediate (xxx) by means of mg, dibromoethane and cecl3 in refluxing thf provides the already reported chiral hydroxylactone (xxxii), which is treated first with 4-bromobenzenesulfonyl chloride and then with nan3 to give the desired azido derivative (xxxiv).
List of intermediates No.
tert-butyl (2r)-2-[[(methylsulfonyl)oxy]methyl]-1-pyrrolidinecarboxylate (xxi)
cycloheptylmethanamine; cycloheptylmethylamine (xxx)
3-nitro-2-pyridinol (xxxii)
n-(2-hydroxy-3-pyridinyl)-5-methyl-3-isoxazolecarboxamide (xxxiv)
3-(3,4-difluorophenyl)-2-[3-{[(5-methyl-3-isoxazolyl)carbonyl]amino}-2-oxo-1(2h)-pyridinyl]propanoic acid (xliii)
3-(2-amino-3-hydroxypropyl)-2-pyrrolidinone (xliv)
n-{1-[1-[(3,4-difluorophenyl)methyl]-2-({2-hydroxy-1-[(2-oxo-3-pyrrolidinyl)methyl]ethyl}amino)-2-oxoethyl]-2-oxo-1,2-dihydro-3-pyridinyl}-5-methyl-3-isoxazolecarboxamide (xlv)
n-[1-(1-[(3,4-difluorophenyl)methyl]-2-{[1-formyl-2-(2-oxo-3-pyrrolidinyl)ethyl]amino}-2-oxoethyl)-2-oxo-1,2-dihydro-3-pyridinyl]-5-methyl-3-isoxazolecarboxamide (xlvi)
1-(1-benzyl-4-piperidinyl)-1h-indole (xlvii)
Reference 1:
    mealy, n.e.; casta?er, r.m.; silvestre, j.s.; casta?er, j.; aliskiren fumarate. drugs fut 2001, 26, 12, 1139.
Reference 2:
    carey, j.s.; sandham, d.a.; taylor, r.j.; fassler, a.; a convergent synthesis of the renin inhibitor cgp60536b. tetrahedron lett 2000, 41, 51, 10091.

Route 7
alternatively, the chiral azido intermediate (xxxiv) can also be synthesized as follows: alkylation of oxazolidinone (v) with 1-chloro-3-iodopropene (xlviii) by means of lihmds in thf gives compound (xlix), which is condensed with the magnesium derivative of the phenylpropyl chloride (xxx) to yield, after working up, amide (l). bromination of (l) with nbs and phosphoric acid affords the bromolactone (li), which by treatment with nan3 in tripropylene glycol/water provides the azido derivative (xxxiv).
List of intermediates No.
(v)
cycloheptylmethanamine; cycloheptylmethylamine (xxx)
n-(2-hydroxy-3-pyridinyl)-5-methyl-3-isoxazolecarboxamide (xxxiv)
1-(4-piperidinyl)-1h-indole (xlviii)
1-[1-(2-pyridinylmethyl)-4-piperidinyl]-1h-indole (xlix)
2-oxo-2-{1-[1-(2-pyridinylmethyl)-4-piperidinyl]-1h-indol-3-yl}acetyl chloride (l)
n-(3,5-dimethyltricyclo[3.3.1.1~3,7~]dec-1-yl)acetamide (li)
Reference 1:
    mealy, n.e.; casta?er, r.m.; silvestre, j.s.; casta?er, j.; aliskiren fumarate. drugs fut 2001, 26, 12, 1139.
Reference 2:
    stutz, s.; herold, p. (speedel pharma inc.); 2-alkyl-5-halogen-pent-4-ene carboxylic acids and their production. wo 0109079; wo 0109083 .

Route 8
alternatively, the spiro aldehyde (xlvii) is treated with n-benzylhydroxylamine in dichloromethane to give nitrone (lii), which is submitted to a grignard reaction with the magnesium derivative of intermediate (xxx) in thf to afford the adduct (liii) as a mixture of epimers at the amino group. simultaneous n-dehydroxylation and cleavage of the spiro function of (liii) by means of zn, cu(oac)2 in acoh/water gives lactone (liv), which is condensed with 3-amino-2,2-dimethylpropionamide (xix) by means of tea and 2-hydroxypyridine giving the adduct (lv). finally, the benzylamino group of (lv) is removed with h2 over pd/c in methanol to yield a mixture of two epimers at the amino group, from which aliskiren is separated.
List of intermediates No.
n-[tert-butyl(dimethyl)silyl]-2,2,2-trifluoro-n-methylacetamide (xix)
cycloheptylmethanamine; cycloheptylmethylamine (xxx)
1-(1-benzyl-4-piperidinyl)-1h-indole (xlvii)
3,5-dimethyltricyclo[3.3.1.1~3,7~]dec-1-ylamine; 3,5-dimethyltricyclo[3.3.1.1~3,7~]decan-1-amine (liii)
4-[(3,5-dimethyltricyclo[3.3.1.1~3,7~]dec-1-yl)amino]-4-oxo-2-butenoic acid (liv)
(lv)
(lii)
Reference 1:
    de lathauwer, g.; perrone, d.; dondoni, a.; a convergent synthesis of the renin inhibitor spp-100 using a nitrone intermediate. tetrahedron lett 2001, 42, 29, 4819.
Reference 2:
    mealy, n.e.; casta?er, r.m.; silvestre, j.s.; casta?er, j.; aliskiren fumarate. drugs fut 2001, 26, 12, 1139.

Route 9
the condensation of ethyl isovalerate (i) with 1,3-dichloropropene (ii) by means of buli and dia in thf gives 5-chloro-2-isopropyl-4-pentenoic acid ethyl ester (iii), which is hydrolyzed with naoh in ethanol to yield the corresponding racemic acid (iv). the optical resolution of (iv) is carried out by means of cinchonidine and tea in thf to afford 5-chloro-2(s)-isopropyl-4-pentenoic acid (v), which can also be obtained by asymmetric synthesis as follows: condensation of 4(s)-benzyl-3-(3-methylbutyryl)oxazolidin-2-one (vi) with 3-iodo-1-propenyl chloride (vii) by means of lihmds in thf gives 4(s)-benzyl-3-(2(s)-isopropyl-3-methylbutyryl)oxazolidin-2-one (viii), which is hydrolyzed with lioh in thf/water to afford the chiral pentanoic acid (v). the reaction of (v) with oxalyl chloride in toluene gives the corresponding acyl chloride (ix), which is treated with dimethylamine and pyridine in dichloromethane to yield the dimethylamide (x). the condensation of (x) with the chiral chloro derivative (xi) (obtained by reaction of the corresponding alcohol (xii) with ccl4 and trioctylphosphine) by means of mg and 1,2-dibromoethane in thf affords the octenamide (xiii). the cyclization of (xiii) by means of phosphoric acid and simultaneous bromination with nbs in thf provides the chiral bromolactone (xiv), which is opened by means of dimethylamine and et2alcl in dichloromethane to give the chiral 5-bromo-4-hydroxy-2,7-diisopropyloctanamide (xv). the reaction of (xv) with acetic anhydride and pyridine in dichloromethane yields the acetoxy derivative (xvi), which is treated with lin3 to afford the 5(s)-azido derivative (xvii).
List of intermediates No.
6-[({2-[(3,5-bis{[(phenylmethyl)oxy]carbonyl}phenyl)amino]-1-[(2-fluorophenyl)methyl]-2-oxoethyl}amino)carbonyl]-1h-benzimidazole-5-carboxylic acid (xii)
cycloheptylmethanamine; cycloheptylmethylamine (xi)
1-(4-piperidinyl)-1h-indole (vii)
1-[1-(2-pyridinylmethyl)-4-piperidinyl]-1h-indole (viii)
n-(3,5-dimethyltricyclo[3.3.1.1~3,7~]dec-1-yl)acetamide (xiv)
Reference 1:
    herold, p.; stutz, s. (speedel pharma inc.); process for the preparation of substd. octanoyl amides. wo 0208172 .

Route 10
the cyclization of (xvii) by means of tsoh in refluxing methanol gives the chiral lactone (xviii), which is condensed with 3-amino-2,2-dimethylpropionamide (xix) by means of tea and 2-hydroxypyridine at 90 c to yield the corresponding amide (xx). finally, the azido group of (xx) is reduced with h2 over pd/c in tert-butyl methyl ether to afford the target aliskiren.
List of intermediates No.
n-[tert-butyl(dimethyl)silyl]-2,2,2-trifluoro-n-methylacetamide (xix)
n-(2-hydroxy-3-pyridinyl)-5-methyl-3-isoxazolecarboxamide (xviii)
Reference 1:
    herold, p.; stutz, s. (speedel pharma inc.); process for the preparation of substd. octanoyl amides. wo 0208172 .

Route 11
the condensation of the chiral chloro derivative (i) with 5-chloro-[2(s)-isopropyl]-4-pentanoic acid methyl ester (ii) by means of mg and dibromoethane in thf gives the chiral octenoic ester (iii) which is converted to the corresponding acid (iv) by means of lioh in thf/methanol/water. the reaction of (iv) with nbs in dichloromethane yields the bromolactone (v), which is treated with lioh in isopropanol to yield the epoxide (vi). this compound, without isolation, is treated with hcl in the same solvent to afford the chiral hydroxylactone (vii). the reaction of the oh group of (vii) with mscl and pyridine in toluene provides the mesylate (viii), which is treated with nan3 in hot 1,3-dimethylperhydropyrimidin-2-one to give the azido derivative (ix). the condensation of (ix) with 3-amino-2,2-dimethylpropionamide (x) by means of 2-hydroxypyridine in hot tea yields the carboxamide (xi). finally, the azido group of (xi) is reduced with h2 over pd/c in tert-butyl methyl ether to provide the target aliskiren.
List of intermediates No.
n-[tert-butyl(dimethyl)silyl]-2,2,2-trifluoro-n-methylacetamide (x)
cycloheptylmethanamine; cycloheptylmethylamine (i)
3-nitro-2-pyridinol (vii)
n-(2-hydroxy-3-pyridinyl)-5-methyl-3-isoxazolecarboxamide (ix)
Reference 1:
    herold, p.; stutz, s.; spindler, f. (speedel pharma inc.); process for the preparation of substd. octanoyl amides. wo 0202508 .

Route 12
the condensation of benzaldehyde (i) with ethyl isovalerate (ii) by means of hexyl lithium and dia in thf gives the hydroxyester (iii), which is acylated with ac2o and dmap in thf to yield the acetoxy derivative (iv). the elimination reaction in (iv) by means of t-buok in thf affords the unsaturated ester (v), which is reduced with diisobutylaluminum hydride in toluene to provide the unsaturated alcohol (vi). finally, this compound is enantioselectively reduced with h2 over a chiral biphenylyl diphenylphosphine catalyst and a [rh(norbornadiene)cl]2 catalyst in toluene to give the target intermediate 2(r)-isopropyl-3-[4-methoxy-3-(3-methoxypropoxy)phenyl]-1-propanol (vii). (see scheme 26758001d, intermediate (xxix)).
List of intermediates No.
6-[({2-[(3,5-bis{[(phenylmethyl)oxy]carbonyl}phenyl)amino]-1-[(2-fluorophenyl)methyl]-2-oxoethyl}amino)carbonyl]-1h-benzimidazole-5-carboxylic acid (vii)
Reference 1:
    herold, p.; stutz, s.; spindler, f. (speedel pharma inc.); process for the preparation of (r)-2-alkyl-3-phenyl-1-propanols. wo 0202487 .

Route 13
the condensation of benzaldehyde (i) with ethyl isovalerate (ii) by means of hexyl lithium and dia in thf gives the hydroxyester (iii), which is acylated with ac2o and dmap in thf to yield the acetoxy derivate (iv). the elimination reaction in (iv) by means of t-buok in thf affords the unsaturated ester (v), which is hydrolyzed with koh in ethanol to provide the unsaturated free acid (vi). finally, this compound is enantioselectively reduced with h2 over several chiral rh catalysts {[rh(nbd)2bf4, [rh(nbd)(ococf3)2], [rh(nbd)cl2], etc} to give the target intermediate 2(r)-isopropyl-3-[4-methoxy-3-(3-methoxypropoxy)phenyl]propionic acid (vii). (see scheme 26758001a, intermediate (vii)).
List of intermediates No.
2-[(1s)-1-[[(benzyloxy)carbonyl]amino]-2-[(2-methoxyethoxy)methoxy]ethyl]-4,6-dimethylphenylboronic acid (vii)
Reference 1:
    herold, p.; stutz, s. (speedel pharma inc.); preparation of (r)-2-alkyl-3-phenylpropionic acids. wo 0202500 .

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阿利克仑半富马酸盐;英文名Aliskiren fumarate;CGP-60536(free base);SPP-100B;SPP-100(free base);CGP-60536B;Rasilez;CAS[173334-58-2]

 
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
山东地区醋酸价格
陕西地区醋酸价格
江苏地区醋酸价格
浙江地区醋酸价格
山东地区醋酸价格
华北地区醋酸价格
河北地区醋酸价格
华北地区BDO市场低位整理
华东地区BDO市场偏弱运行
江苏地区醋酸价格
华北地区顺酐市场行情整理
河南地区醋酸价格
华北地区醋酸价格
华北地区醋酸价格
江苏地区醋酸价格
华北地区BDO市场低位整理
河北地区醋酸价格
江苏地区醋酸价格
浙江地区醋酸价格
华南地区BDO市场走势偏弱
 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