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药物详细合成路线

Name Ganirelix acetate;Org-37462;RS-26306;Antagon;Orgalutran
Chemical Name N-Acetyl-3-(2-naphthyl)-D-alanyl-4-chloro-D-phenylalanyl-3-(3-pyridinyl)-D-alanyl-L-seryl-L-tyrosyl-N6-[(ethylamino)(ethylimino)methyl]-D-lysyl-L-leucyl-N6-[(ethylamino)(ethylimino)methyl]-L-lysyl-L-prolyl-D-alaninamide diacetate
      N-Acetyl-3-(2-naphthyl)-D-alanyl-4-chloro-D-phenylalanyl-3-(3-pyridyl)-D-alanyl-L-seryl-L-tyrosyl-Nomega,Nomega-diethyl-D-homoarginyl-L-leucyl-Nomega,Nomega-diethyl-L-homoarginyl-L-prolyl-D-alaninamide diacetate
CAS 129311-55-3
Related CAS 124904-93-4 (free base)
Formula C84H121ClN18O17
Structure
Formula Weight 1690.46437
Stage 上市-2000
Company Roche (Originator), Organon (Licensee)
Activity/Mechanism Disorders of Sexual Function and Reproduction, Treatment of, ENDOCRINE DRUGS, Female Infertility, Agents for, GnRH (LHRH) Antagonists
Syn. Route 3
Route 1
the synthesis of ganirelix was performed using usual solid-state peptide synthesis with a beckman 990 or a 5.0 l vega 296 automated solid-phase peptide synthesizer. the synthesis was initiated by condensation of chloromethylated polystyrene/divinylbenzene resin (merrifieled resin) (ii) with boc-d-alanine (i) by means of cesium carbonate, giving boc-d-ala-resin (iii), which was submitted to successive cycles of deprotection with tfa or hcl and addition of a new protected amino acid by means of dcc or hobt. the following amino acids were added successively: boc-l-proline (iv), nalpha-boc-nomega,nomega-diethyl-l-homoarginine (vi), boc-l-leucine (viii), nalpha-boc-nomega,nomega-diethyl-d-homoarginine (x) and boc-l-tyrosine (xii), yielding successively the peptide resins (v), (vii), (ix), (xi) and (xiii).
List of intermediates No.
2,2,2-trifluoro-n-[(3r)-2-oxopyrrolidinyl]acetamide (i)
4-[4-(4-[[(2s,4r)-2-(2,4-dichlorophenyl)-2-(1h-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl)-1-piperazinyl]aniline (iv)
(2s)-2-[(1s,2r,3r)-4-(benzyloxy)-1,3-dihydroxy-2-methylbutyl]-5-hexenyl pivalate (v)
[(4s,6s)-3-[(benzyloxy)methyl]-1,4-dimethyl-2,9-dioxabicyclo[3.3.1]non-6-yl]methyl pivalate (vi)
[(4s,6s)-3-(hydroxymethyl)-1,4-dimethyl-2,9-dioxabicyclo[3.3.1]non-6-yl]methyl pivalate (vii)
[(4s,6s)-3-ethynyl-1,4-dimethyl-2,9-dioxabicyclo[3.3.1]non-6-yl]methanol (ix)
(4s,6r)-1,4-dimethyl-3-[(e)-2-(tributylstannyl)ethenyl]-2,9-dioxabicyclo[3.3.1]nonane-6-carboxylic acid (x)
3-(triethylsilyl)-2-propynal (xi)
(3r,4r)-4-methyl-1-(triethylsilyl)-5-hexen-1-yn-3-ol (xii)
((3r,4r)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-hexen-1-ynyl)(triethyl)silane; tert-butyl(dimethyl)silyl (1r,2r)-2-methyl-1-[2-(triethylsilyl)ethynyl]-3-butenyl ether (xiii)
(4ar,4bs,6as,7s,9as,9bs,11ar)-n-ethyl-1,4a,6a-trimethyl-2-oxohexadecahydro-1h-indeno[5,4-f]quinoline-7-carboxamide (viii)
Reference 1:
    robinson, j.3rd; morgans, d.j.; bingenheimer, w.; arzeno, h.b.; temporary serine protection in solid phase synthesis of lh-rh analogs. int j pept protein res 1993, 41, 4, 342.
Reference 2:
    castaner, j.; leeson, p.; rabasseda, x.; ganirelix acetate. drugs fut 1999, 24, 4, 393.
Reference 3:
    nestor, j.j. jr.; mcclure, n.l. (syntex (usa), inc.); temporary minimal protection synthesis of lh-rh analogs. ep 0443532; jp 1992211096; us 5212288 .
Reference 4:
    nestor, j.j. jr.; vickery, b.h. (syntex (usa), inc.); nonapeptide and decapeptide analogs of lhrh as lhrh antagonists. ep 0277829; jp 1988201199; us 4801577 .
Reference 5:
    vickery, b.h. (syntex (usa), inc.); lhrh antagonist analogs and 19-nor-progestational steroids for therapy. ep 0301850 .

Route 2
the synthesis of ganirelix was performed using usual solid-state peptide synthesis with a the following amino acids were added successively to intermediate (xiii): n-boc-o-benzyl-l-serine (xiv), boc-(3-pyridyl)-d-alanine (xvi) and boc-4-chloro-d-phenylalanine (xviii), yielding successively the peptide resins (xv), (xvii) and (xix).
List of intermediates No.
3,3-diphenyl-1-propanamine (xiv)
((3r,4r)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-hexen-1-ynyl)(triethyl)silane; tert-butyl(dimethyl)silyl (1r,2r)-2-methyl-1-[2-(triethylsilyl)ethynyl]-3-butenyl ether (xiii)
ethyl 3-(diethoxyphosphoryl)propanoate (xv)
ethyl (e,4r,5r)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-7-(triethylsilyl)-2-hepten-6-ynoate (xvi)
(e,4r,5r)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-7-(triethylsilyl)-2-hepten-6-yn-1-ol (xvii)
[3-[(1r,2r)-2-[[tert-butyl(dimethyl)silyl]oxy]-1-methyl-4-(triethylsilyl)-3-butynyl]-2-oxiranyl]methanol (xviii)
bromo[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]magnesium (xix)
Reference 1:
    robinson, j.3rd; morgans, d.j.; bingenheimer, w.; arzeno, h.b.; temporary serine protection in solid phase synthesis of lh-rh analogs. int j pept protein res 1993, 41, 4, 342.
Reference 2:
    castaner, j.; leeson, p.; rabasseda, x.; ganirelix acetate. drugs fut 1999, 24, 4, 393.
Reference 3:
    nestor, j.j. jr.; vickery, b.h. (syntex (usa), inc.); nonapeptide and decapeptide analogs of lhrh as lhrh antagonists. ep 0277829; jp 1988201199; us 4801577 .
Reference 4:
    vickery, b.h. (syntex (usa), inc.); lhrh antagonist analogs and 19-nor-progestational steroids for therapy. ep 0301850 .
Reference 5:
    nestor, j.j. jr.; mcclure, n.l. (syntex (usa), inc.); temporary minimal protection synthesis of lh-rh analogs. ep 0443532; jp 1992211096; us 5212288 .

Route 3
the amino acid boc-(2-naphthyl)-d-alanine (xx) were added to intermediate (xix), yielding the peptide resin (xxi). when the integration of amino acids was completed, the peptide resin (xxi) was deprotected with tfa, acetylated with acetic anhydride and finally treated with ammonia in methanol in order to eliminate the resin matrix and form the final amide group.
List of intermediates No.
bromo[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]magnesium (xix)
(2s,3s,4r,5r)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-2-[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]-7-(triethylsilyl)-6-heptyne-1,3-diol (xx)
(2s,3s,4r,5r)-5-[[tert-butyl(dimethyl)silyl]oxy]-3-hydroxy-4-methyl-2-[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]-7-(triethylsilyl)-6-heptynyl pivalate (xxi)
Reference 1:
    robinson, j.3rd; morgans, d.j.; bingenheimer, w.; arzeno, h.b.; temporary serine protection in solid phase synthesis of lh-rh analogs. int j pept protein res 1993, 41, 4, 342.
Reference 2:
    castaner, j.; leeson, p.; rabasseda, x.; ganirelix acetate. drugs fut 1999, 24, 4, 393.
Reference 3:
    nestor, j.j. jr.; mcclure, n.l. (syntex (usa), inc.); temporary minimal protection synthesis of lh-rh analogs. ep 0443532; jp 1992211096; us 5212288 .
Reference 4:
    vickery, b.h. (syntex (usa), inc.); lhrh antagonist analogs and 19-nor-progestational steroids for therapy. ep 0301850 .
Reference 5:
    nestor, j.j. jr.; vickery, b.h. (syntex (usa), inc.); nonapeptide and decapeptide analogs of lhrh as lhrh antagonists. ep 0277829; jp 1988201199; us 4801577 .

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加尼瑞克;英文名Ganirelix acetate;Org-37462;RS-26306;Antagon;Orgalutran;CAS[129311-55-3]

 
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