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Name Temozolomide;Sch-52365;CCRG-81045;NSC-362856;M&B-39831;Temodar;Temodal
Chemical Name 8-Carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one
      3-Methyl-4-oxo-3,4-dihydroimidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide
CAS 85622-93-1
Related CAS
Formula C6H6N6O2
Structure
Formula Weight 194.15372
Stage 上市-1999
Company Cancer Research UK (Originator), Antigenics (Not Determined), M.D. Anderson Cancer Center (Not Determined), Schering-Plough (Licensee), National Cancer Institute (Codevelopment)
Activity/Mechanism Astrocytoma Therapy, Brain Cancer Therapy, Glioblastoma MultiformeTherapy, Lymphoma Therapy, Melanoma Therapy, Oncolytic Drugs, Solid Tumors Therapy, Antimitotic Drugs, DNA Alkylating Drugs
Syn. Route 6
Route 1
by reaction of 5-diazoimidazole-4-carboxamide (ii), prepared by diazotization of 5-aminoimidazole-4-carboxamide (i) with nitrous acid, with methylisocyanate (iii) either alone or in dichloromethane.
List of intermediates No.
benzhydryl (e)-2-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3.2.0]hept-2-en-6-yl)-3-hydroxy-2-butenoate (i)
benzhydryl (e)-2-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3.2.0]hept-2-en-6-yl)-3-(4-morpholinyl)-2-butenoate (ii)
Reference 1:
    stevens, m.f.g.; baig, g.u.; triazines and related products, part 22. synthesis and reactions of imidazo[5,1-c][1,2,4]triazines. j chem soc perkin trans i. j chem soc - perkins trans i 1981, 1424.
Reference 2:
    lunt, e.; stevens, m.f.g.; stone, r.; woolbridge, k.r.h. (cancer research campaign technology ltd.); tetrazine derivs., process for their preparation and pharmaceutical compsns. containing them. be 894175; de 3231255; fr 2511679; gb 2104522; jp 1983043975; us 5260291 .
Reference 3:
    prous, j.; castaner, j.; graul, a.; temozolomide. drugs fut 1994, 19, 8, 746.
Reference 4:
    stevens, m.f.g.; hickman, j.a.; stone, r.; gibson, n.w.; baig, g.u.; lunt, e.; newton, c.g.; antitumor imidazotetrazinones. 1. synthesis and chemistry of 8-carbamoyl-3-(2-chloroethyl)imidazo[5,1-d]-1,2,3,5-tetrazin-4(3h)-one, a novel broad-spectrum antitumor agent. j med chem 1984, 27, 196-201, 196.

Route 2
the synthesis of several forms of [13c]- and [15n]-labeled temozolomide has been reported:1) the diazotation of 3-aminopyrazole-4-carboxamide (i) with [15n]-labeled sodium nitrite and hcl gives the corresponding labeled diazonium salt (ii), which is cyclized with methyl isocyanate (ii) at room temperature, yielding temozolomide labeled at the n in the 2-position.
List of intermediates No.
benzhydryl (e)-2-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3.2.0]hept-2-en-6-yl)-3-hydroxy-2-butenoate (i)
benzhydryl (7r)-3-hydroxy-8-oxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (ii)
benzhydryl (7r)-3-hydroxy-8-oxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (iii)
toluene-4-sulfonic acid tetrahydrofuran-2-ylmethyl ester (ii)
Reference 1:
    wilman, d.e.v.; thomson, w.; wheelhouse, r.t.; stevens, m.f.g.; antitumour imidazotetrazines. 31. the synthesis of isotopically labelled temozolomide and a multinuclear (h-1, c-13, n-15) magnetic resonance investigation of temozolomide and mitozolomide. j chem soc - perkins trans i 1995, 3, 3, 249.

Route 3
2) the condensation of n,n-diphenylcarbamoyl chloride (iv) with [13c]-labeled methylamine (v) gives the corresponding urea (vi), which by heating at 240 c is converted to the [13c]-labeled methyl isocyanate (vii). finally, this compound is cyclized with the diazonium salt (viii) (obtained by diazotation of 3-aminopyrazole-4-carbonitrile with nano2-hcl in the usual way) to afford temozolomide labeled at the methyl in the 3-position.3) the preceding sequence performed with [15n]-labeled methylamine (x) gives urea (xi), isocyanate (xii) and finally temozolomide labeled at the n in the 3-position.
List of intermediates No.
benzhydryl (e)-2-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3.2.0]hept-2-en-6-yl)-3-hydroxy-2-butenoate (ix)
benzhydryl (e)-2-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3.2.0]hept-2-en-6-yl)-3-(4-morpholinyl)-2-butenoate (viii)
benzhydryl (7r)-3-hydroxy-8-oxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (vii)
benzhydryl (2r,3r,7r)-7-amino-3-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-8-oxo-5-thia-1-azabicyclo[4.2.0]octane-2-carboxylate (xii)
benzhydryl (7r)-7-amino-3-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (iv)
methyl 2-cyano-3,3-bis(methylsulfanyl)acrylate (v)
2-tetrahydro-2-furanylacetonitrile (x)
2-tetrahydro-2-furanylacetic acid (vi)
methyl 2-tetrahydro-2-furanylacetate (xi)
2-[(2r)tetrahydro-2-furanyl]acetic acid (v)
methyl 2-[(2s)tetrahydro-2-furanyl]acetate (vi)
2-[(2s)tetrahydro-2-furanyl]-1-ethanol (vii)
Reference 1:
    wilman, d.e.v.; thomson, w.; wheelhouse, r.t.; stevens, m.f.g.; antitumour imidazotetrazines. 31. the synthesis of isotopically labelled temozolomide and a multinuclear (h-1, c-13, n-15) magnetic resonance investigation of temozolomide and mitozolomide. j chem soc - perkins trans i 1995, 3, 3, 249.

Route 4
this compound has been obtained by two related ways:1. the reaction of 5-diazoimidazole (i) with methylamine gives the triazene (ii), which is then cyclized with 11c-phosgene (iii) to yield the target 11c-carbonyl labeled compound.2. the cyclization of 5-diazoimidazole-4-carboxamide (i) with 11c-carbonyl labeled methyl isocyanate (iv) gives the target 11c carbonyl labeled compound.
List of intermediates No.
benzhydryl (7r)-3-hydroxy-8-oxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (iv)
Reference 1:
    brock, c.s.; brady, f.; stevens, m.f.g.; brown, g.d.; price, p.m.; luthra, s.k.; antitumor imidazotetrazines. 40.(1) radiosyntheses of [4-11c-carbonyl]- and 3-n-11c-methyl]-8-carbamoyl-3- methylimidazo[5,1-d]-1,2,3,5-tetrazin-4(3h)-one (temozolomide) for positron emission tomography (pet) studies. j med chem 2002, 45, 25, 5448.

Route 5
the cyclization of 5-diazoimidazole-4-carboxamide (i) with 11c-methyl isocyanate (ii) gives the target 11c methyl labelled compound.
List of intermediates No.
benzhydryl (7r)-3-hydroxy-8-oxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (ii)
Reference 1:
    brock, c.s.; brady, f.; stevens, m.f.g.; brown, g.d.; price, p.m.; luthra, s.k.; antitumor imidazotetrazines. 40.(1) radiosyntheses of [4-11c-carbonyl]- and 3-n-11c-methyl]-8-carbamoyl-3- methylimidazo[5,1-d]-1,2,3,5-tetrazin-4(3h)-one (temozolomide) for positron emission tomography (pet) studies. j med chem 2002, 45, 25, 5448.

Route 6
further nitration of the nitroimidazole (i) with hno3, ac2o gives the 1,4-dinitroimidazole (ii), which is treated with kcn and nahco3 in methanol/water to yield 5-nitro-1h-imidazole-4-carbonitrile (iii). the reaction of (iii) with dihydropyran and ts-oh in ethyl acetate affords the n-protected imidazole (iv). the reduction of (iv) with h2 over pt/c in ethyl acetate provides the hydroxylamine (v), which is oxidized with naio4 in ethyl acetate/water to give the nitroso derivative (vi). the condensation of (vi) with phenyl 2-methylcarbazate (vii) by means of hoac and tfa yields the triazene (viii), which is treated with conc. hcl in ethyl acetate to afford the carboxamide (ix). finally, this compound is cyclized to the target imidazo-tetrazinone by irradiation with daylight in acetone/meoh, most probably through the non isolated cis intermediate (x).
List of intermediates No.
Reference 1:
    wanner, m.j.; koomen, g.j.; a new synthesis of temozolomide. j chem soc - perkins trans i 2002, 16, 1877.

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替莫唑胺;英文名Temozolomide;Sch-52365;CCRG-81045;NSC-362856;M&B-39831;Temodar;Temodal;CAS[85622-93-1]

 
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