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Name Tirofiban hydrochloride;MK-383;L-700462;Aggrastat
Chemical Name N-(Butylsulfonyl)-4-O-[4-(4-piperidyl)butyl]-L-tyrosine monohydrochloride
CAS 142373-60-2
Related CAS 144494-65-5 (free base), 150915-40-5 (monoH2O)
Formula C22H37ClN2O5S
Structure
Formula Weight 477.06759
Stage 上市-1998
Company Merck & Co. (Originator), Banyu (Licensee), Guilford Pharmaceuticals (Licensee)
Activity/Mechanism Acute Myocardial Infarction, Treatment of, Angina pectoris, Treatment of, Antiplatelet Therapy, CARDIOVASCULAR DRUGS, Cerebrovascular Diseases, Treatment of, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, NEUROLOGIC DRUGS, Stroke, Treatment of, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, Integrin alphaIIbbeta3 (Fibrinogen gpIIb/IIIa) Antagonists
Syn. Route 6
Route 1
4-pyridineacetic acid (i) was hydrogenated to the corresponding piperidine (ii) in the presence of pto2. after protection of (ii) as the n-boc derivative (iii), reduction of its carboxylate group with borane in thf provided alcohol (iv). subsequent swern oxidation of alcohol (iv) furnished aldehyde (v). this was then subjected to a wittig condensation with carbomethoxytriphenylphosphorane to yield the unsaturated ester (vi), which was further hydrogenated to (vii) in the presence of pd/c. after saponification of the methyl ester function of (vii), the resultant carboxylic acid was reduced to alcohol (viii) by means of borane in thf. conversion of alcohol (viii) into the alkyl bromide (ix) was accomplished by treatment with carbon tetrabromide and triphenylphosphine. then, alkylation of the phenolic hydroxyl of n-cbz-l-tyrosine (x) with bromide (ix) in the presence of nah in dmf afforded adduct (xi).
List of intermediates No.
methyl (1s,4s,6r,10r)-15-oxo-5-oxatetracyclo[8.4.1.0(1,6).0(4,6)]pentadec-7-ene-8-carboxylate (i)
(2r)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-(dibenzylamino)-1-propanol (iii)
(x)
methyl (e)-3-[4-(acetyloxy)phenyl]-2-propenoate (iv)
(4s,7s,13r,16r,22r)-13-ethyl-4-(1h-indol-3-ylmethyl)-7-[(4-methoxy-1h-indol-3-yl)methyl]-18,22-dimethyl-16-[(phenylseleninyl)methyl]-24-thia-3,6,9,12,15,18,21,26-octaazabicyclo[21.2.1]hexacosa-1(25),23(26)-diene-2,5,8,11,14,17,20-heptone (ii)
4,8-dimethyl-7-hydroxycoumarin (vi)
4,8-dimethyl-7-(1-methyl-2-oxopropoxy)-2h-chromen-2-one (vii)
Reference 1:
    egbertson, m.s.; laswell, w.l.; hartman, g.d.; duggan, m.e.; halczenko, w. (merck & co., inc.); novel sulfonamide fibrinogen receptor antagonists. ep 0478363; ep 0743302; jp 1992288051; us 5292756 .
Reference 2:
    egbertson, m.s.; hartman, g.d.; halczenko, w.; laswell, w.l.; duggan, m.e. (merck & co., inc.); novel sulfonamide fibrinogen receptor antagonists. wo 9319046 .
Reference 3:
    egbertson, m.s.; chang, c.t.c.; duggan, m.e.; et al.; non-peptide fibrinogen receptor antagonists. 2. optimization of a tyrosine template as a mimic for arg-gly-asp. j med chem 1994, 37, 16, 2537.

Route 2
acid (xi) was converted to the methyl ester (xii) by alkylation with iodomethane in the presence of cs2co3. after removal of the n-cbz group of (xii) by catalytic hydrogenolysis, the resultant amine (xiii) was acylated by butanesulfonyl chloride (xiv) producing sulfonamide (xv). saponification of the ester group of (xv) with lioh gave acid (xvi). the n-boc group of (xvi) was finally cleaved by treatment with hcl in etoac.
List of intermediates No.
2-[(4s)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]acetic acid (xiv)
Reference 1:
    egbertson, m.s.; hartman, g.d.; halczenko, w.; laswell, w.l.; duggan, m.e. (merck & co., inc.); novel sulfonamide fibrinogen receptor antagonists. wo 9319046 .
Reference 2:
    egbertson, m.s.; laswell, w.l.; hartman, g.d.; duggan, m.e.; halczenko, w. (merck & co., inc.); novel sulfonamide fibrinogen receptor antagonists. ep 0478363; ep 0743302; jp 1992288051; us 5292756 .
Reference 3:
    egbertson, m.s.; chang, c.t.c.; duggan, m.e.; et al.; non-peptide fibrinogen receptor antagonists. 2. optimization of a tyrosine template as a mimic for arg-gly-asp. j med chem 1994, 37, 16, 2537.

Route 3
intermediate (xi) was converted to the title compound by an alternative method, reported to provide a higher enantiomeric excess. hydrogenolysis of the n-cbz group of (xi) in the presence of pd/c gave the aminoacid (xv). subsequent acylation of (xv) with butanesulfonyl chloride (xiv) under schotten-baumann conditions furnished sulfonamide (xvi), which was then treated with hcl in etoac to remove the n-boc protecting group.
List of intermediates No.
2-[(4s)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]acetic acid (xiv)
Reference 1:
    egbertson, m.s.; chang, c.t.c.; duggan, m.e.; et al.; non-peptide fibrinogen receptor antagonists. 2. optimization of a tyrosine template as a mimic for arg-gly-asp. j med chem 1994, 37, 16, 2537.

Route 4
in a different strategy, the lithium derivative of 4-picoline (xvii) was alkylated with 2-(3-bromopropoxy)tetrahydropyran (xviii) to afford (xix). acidic hydrolysis of the tetrahydropyranyl protecting group furnished 4-(4-pyridinyl)butanol (xx). alternatively, lithiation of 4-picoline (xvii), followed by alkylation with 1-bromo-3-chloropropane (xxi) gave rise to 4-(4-pyridinyl)butyl chloride (xxii).
List of intermediates No.
ethyl 2-(3,4-dimethoxyphenyl)-3-[[2-(3,4-dimethoxyphenyl)acetyl]amino]propanoate (xxi)
ethyl (e)-3-[(3ar,6r,6ar)-2,2,6-trimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]-4-(benzyloxy)-2-butenoate (xvii)
tert-butyl 2-(benzylamino)acetate (xviii)
Reference 1:
    chung, j.y.l.; zhao, d.; hughes, d.l. (merck & co., inc.); process for preparing fibrinogen receptor antagonists. us 5312923; wo 9316994 .
Reference 2:
    chung, j.y.l.; zhao, d.; hughes, d.l. (merck & co., inc.); process for preparing fibrinogen receptor antagonists. wo 9316995 .
Reference 3:
    chung, j.y.l.; zhao, d.; hughes, d.l.; grabowski, e.e.; a practical synthesis of fibrinogen receptor antagonist mk-383 - selective functionalization of (s)-tyrosine. tetrahedron 1993, 49, 26, 5767.

Route 5
tyrosine methyl ester (xxiii) was acylated with butanesulfonyl chloride (xiv) in the presence of pyridine to produce sulfonamide (xxiv). mitsunobu coupling of pyridinyl butanol (xx) with the phenolic compound (xxiv) furnished ether (xxv). subsequent hydrolysis of the methyl ester group of (xxv) employing lioh afforded acid (xxvi). the title piperidine compound was then obtained by catalytic hydrogenation of the pyridine ring of (xxvi) in the presence of pd/c.
List of intermediates No.
disodium 4-amino-4-[[4,6-bis(3-[[bis(3-amino-3-oxopropyl)amino]sulfonyl]anilino)-1,3,5-triazin-2-yl]amino][1,1-biphenyl]-2,2-disulfonate (xxiii)
2-[(4s)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]acetic acid (xiv)
Reference 1:
    chung, j.y.l.; zhao, d.; hughes, d.l. (merck & co., inc.); process for preparing fibrinogen receptor antagonists. us 5312923; wo 9316994 .

Route 6
in a variation of this process, l-tyrosine (xxvii) was initially protected as the bis-o-silylated derivative (xxviii) employing n,o-bis(trimethylsilyl) trifluoroacetamide. acylation of (xxviii) with butanesulfonyl chloride (xiv), followed by hydrolysis of the silyl groups, gave rise to n-butanesulfonyl tyrosine (xxix). the phenolic hydroxyl of (xxix) was then alkylated by 4-(4-pyridinyl)butyl chloride (xxii) to produce ether (xxvi). finally, hydrogenation of the pyridine ring furnished the target piperidine derivative, which was isolated as the corresponding hydrochloride salt.
List of intermediates No.
2-[(4s)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]acetic acid (xiv)
2-hydroxy-6-pentadecylbenzoic acid (xxvii)
Reference 1:
    chung, j.y.l.; zhao, d.; hughes, d.l. (merck & co., inc.); process for preparing fibrinogen receptor antagonists. wo 9316995 .
Reference 2:
    chung, j.y.l.; zhao, d.; hughes, d.l.; grabowski, e.e.; a practical synthesis of fibrinogen receptor antagonist mk-383 - selective functionalization of (s)-tyrosine. tetrahedron 1993, 49, 26, 5767.

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鹽酸替羅非班;英文名Tirofiban hydrochloride;MK-383;L-700462;Aggrastat;CAS[142373-60-2]

 
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