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药物详细合成路线

Name Tasosartan;WAY-126756;WAY-ANA-756;ANA-756;Verdia
Chemical Name 2,4-Dimethyl-8-[2-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-7-one
CAS 145733-36-4
Related CAS
Formula C23H21N7O
Structure
Formula Weight 411.47012
Stage III 期临床
Company Wyeth Pharmaceuticals (Originator)
Activity/Mechanism CARDIOVASCULAR DRUGS, Hypertension, Treatment of, Angiotensin AT1 Antagonists
Syn. Route 5
Route 1
1) the cyclization of 2-acetylglutaric acid diethyl ester (i) with acetamidine (ii) by means of sodium ethoxide in refluxing ethyl ether gives the pyrimidinone derivative (iii), which by treatment with refluxing phosphorus oxychloride is converted into the chloropyrimidine (iv). the cyclization of (iv) with 4-bromobenzylamine (v) by means of nahco3 in refluxing butanol affords 8-(4-bromobenzyl)-2,4-dimethyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-7-one (vi), which is condensed with 2-(2-tert-butyltetrazol-5-yl)phenylboronic acid (vii) by means of tetrakis(triphenylphosphine)palladium in refluxing toluene/ethanol to give 8-[2-(2-tert-butyltetrazol-5-yl)biphenyl-4-ylmethyl]-2,4-dimethyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-7-one (viii). finally, this compound is deprotected with methanesulfonic acid in refluxing toluene. (1,2)2) the boronic acid (vii) has been obtained as follows: the cyclization of 2-bromobenzonitrile (ix) with sodium azide in hot dmf, followed by protection with tert-butanol in trifluoroacetic acid/h2so4 gives 5-(2-bromophenyl)-2-tertbutyltetrazole (x), which is finally condensed with triisopropyl borate by means of butyllithium in thf and hydrolyzed with hcl. (1,2)
List of intermediates No.
tert-butyl (e)-7-[3-(4-fluorophenyl)-1-isopropyl-1h-indol-2-yl]-5-hydroxy-3-oxo-6-heptenoate (ix)
ethyl 3-[3-(benzyloxy)-2-pyridinyl]propanoate (i)
ethyl 3-(3-hydroxy-2-pyridinyl)propanoate (ii)
3-(3-hydroxy-2-pyridinyl)propanamide (iii)
3-[3-(benzyloxy)-2-pyridinyl]propanamide (iv)
1-bromo-2-butanone (v)
2-[8-(benzyloxy)-2-ethyl-1-indolizinyl]acetamide (vi)
2-[3-benzoyl-8-(benzyloxy)-2-ethyl-1-indolizinyl]acetamide (vii)
2-[3-benzyl-8-(benzyloxy)-2-ethyl-1-indolizinyl]acetamide (viii)
methyl 2-[[1-(2-amino-2-oxoethyl)-3-benzyl-2-ethyl-8-indolizinyl]oxy]acetate (x)
Reference 1:
    merlos, m.; casas, a.; castaner, j.; tasosartan. drugs fut 1997, 22, 8, 850.
Reference 2:
    ellingboe, j.w.; nikaido, m.; bagli, j. (american home products corp.); substd. pyridopyrimidines useful as angiotensin ii antagonists. ep 0539086; us 5149699; us 5256654 .
Reference 3:
    ellingboe, j.w.; antane, m.; nguyen, t.t.; et al.; pyrido[2,3-p]pyrimidine angiotensin ii antagonists. j med chem 1994, 37, 4, 542-50.

Route 2
3) the 8-[2-(2-tert-butyltetrazol-5-yl)biphenyl-4-ylmethyl]-2,4-dimethyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-7-one (viii) can also be obtained as follows: the reaction of the previously described 5-(2-bromophenyl)-2-tertbutyltetrazole (x) with mg in thf catalyzed with 1,2-dibromoethane gives the corresponding grignard reagent, which is treated with zncl2 yielding the organozinc derivative (xi). finally, this compound is condensed with the previously described intermediate 8-(4-bromobenzyl)-2,4-dimethyl-5,6,7,8-tetrahydropyrido-[2,3-d]pyrimidin-7-one (vi) catalyzed by bis(triphenylphosphine)palladium and diisobutylaluminum hydride in thf.
List of intermediates No.
2-[8-(benzyloxy)-2-ethyl-1-indolizinyl]acetamide (vi)
2-[3-benzyl-8-(benzyloxy)-2-ethyl-1-indolizinyl]acetamide (viii)
methyl 2-[[1-(2-amino-2-oxoethyl)-3-benzyl-2-ethyl-8-indolizinyl]oxy]acetate (x)
(1s,5r,13r,17r)-10-methoxy-4-methyl-12-oxa-4-azapentacyclo[9.6.1.0(1,13).0(5,17).0(7,18)]octadeca-7(18),8,10-trien-14-one (xi)
Reference 1:
    merlos, m.; casas, a.; castaner, j.; tasosartan. drugs fut 1997, 22, 8, 850.
Reference 2:
    giguere, p.; iera, s.; bernatchez, m.; barreca, g.; castaldi, g.; cannata, v. (american home products corp.); process for preparation of biphenyl derivs. wo 9640684 .

Route 3
1) the oxidation of tasosartan (v) with kmno4 and naoh in water gives metabolite (i).2) the condensation of tasosartan (v) with 2,3,4-tri-o-acetyl-1alpha-bromo-1-deoxy-d-glucopyranosyluronic acid methyl ester (vi) by means of koh in refluxing acetone gives the acetylated glucuronide methyl ester (vii), which is deacetylated with kcn in methanol yielding glucuronide methyl ester (viii). finally, this compound is hydrolyzed with naoh in methanol to afford metabolite (ii).
List of intermediates No.
5-methyl-6-(1h-[1,2,3]triazolo[4,5-c]pyridin-1-yl)-1-isoquinolinol (vi)
methyl (2r,3r)-3-amino-2-(3-cyanobenzyl)butanoate (i)
methyl (2r,3r)-3-[[(benzyloxy)carbonyl]amino]-2-(3-cyanobenzyl)butanoate (ii)
methyl (2r,3r)-2-(3-cyanobenzyl)-3-[[(3,4-dimethoxy[1,1-biphenyl]-4-yl)carbonyl]amino]butanoate (v)
6-fluoro-2-methyl-4h-3,1-benzoxazin-4-one (vii)
3-(2-chlorophenyl)-6-fluoro-2-methyl-4(3h)-quinazolinone (viii)
Reference 1:
    ellingboe, j.w.; collini, m.d.; quagliato, d.; chen, j.; antane, m.; schmid, j.; hartupee, d.; white, v.; park, c.h.; tanikella, t.; bagli, j.f.; metabolites of the angiotensin ii antagonist tasosartan: the importance of a second acidic group. j med chem 1998, 41, 22, 4251.

Route 4
3) the iodination of 2,6-dimethylpyrimidin-4-ol (ix) with i2/naoh in refluxing water gives 5-iodo-2,6-dimethylpyrimidin-4-ol (x), which is treated with pocl3 in refluxig toluene yielding 4-chloro-5-iodo-2,6-dimethylpyrimidine (xi). the reaction of (xi) with (1-ethoxyvinyl)tributyltin (xii) catalyzed by tetrakis(triphenylphosphine)palladium in refluxing dioxane affords 4-chloro-5-(1-ethoxyvinyl)-2,6-dimethylpyrimidine (xiii), which is condensed with 4-bromobenzylamine (xiv) by means of nahco3 in refluxing butanol giving 4-(4-bromobenzylamino)-5-(1-ethoxyvinyl)-2,6-dimethylpyrimidine (xv). the hydrolysis of (xv) with hcl in refluxing acetone yields the corresponding acetyl derivative (xvi), which is condensed with 2-(2-tert-butyl-2h-tetrazol-5-yl)phenylboronic acid (xvii) by means of tetrakis(triphenylphosphine)palladium to afford the biphenyl derivative (xviii). the cyclization of (xviii) with diethyl carbonate and nah in hot thf gives 8-[2-(2-tert-butyl-2h-tetrazol-5-yl)biphenyl-4-ylmethyl]-5-hydroxy-2,4-dimethylpyrido[2,3-d]pyrimidin-7(8h)-one (xix), which is finally deprotected with trifluoromethanesulfonic acid in refluxing toluene to give metabolite (iii).
List of intermediates No.
1-bromo-2-butanone (xiv)
2-[3-benzoyl-8-(benzyloxy)-2-ethyl-1-indolizinyl]acetamide (xvii)
diisopropyl dichloro(diisopropoxyphosphoryl)methylphosphonate (xii)
2,6-pyridinedicarbaldehyde (iii)
6-[(e)-2-[3-(2-chlorophenyl)-6-fluoro-4-oxo-3,4-dihydro-2-quinazolinyl]ethenyl]-2-pyridinecarbaldehyde (ix)
2-thienyl-n-(2-thienylmethyl)methanamine; n,n-bis(2-thienylmethyl)amine (x)
tert-butyl (1s)-1-[[bis(2-thienylmethyl)amino]carbonyl]pentylcarbamate (xi)
(2s)-2-amino-n,n-bis(2-thienylmethyl)hexanamide (xiii)
ethyl (e)-3-(1,3-benzodioxol-5-yl)-2-propenoate (xv)
(1s)-n-benzyl-1-phenyl-1-ethanamine; n-benzyl-n-[(1s)-1-phenylethyl]amine (xvi)
ethyl (3s)-3-(1,3-benzodioxol-5-yl)-3-[benzyl[(1s)-1-phenylethyl]amino]propanoate (xviii)
ethyl (3s)-3-amino-3-(1,3-benzodioxol-5-yl)propanoate (xix)
Reference 1:
    ellingboe, j.w.; collini, m.d.; quagliato, d.; chen, j.; antane, m.; schmid, j.; hartupee, d.; white, v.; park, c.h.; tanikella, t.; bagli, j.f.; metabolites of the angiotensin ii antagonist tasosartan: the importance of a second acidic group. j med chem 1998, 41, 22, 4251.

Route 5
4) the condensation of 2,4-dimethylpyrido[2,3-d]pyrimidin-7(8h)-one (xx) with 4-(bromomethyl)biphenyl-2-carbonitrile (xxi) by means of nah in dmf gives 8-(2-cyanobiphenyl-4-ylmethyl)-2,4-dimethylpyrido[2,3-d]pyrimidin-7(8h)-one (xix), which is then cyclized with sodium azide in refluxing xylene to afford metabolite (iv).
List of intermediates No.
tert-butyl (3s)-2,6-dioxopiperidinylcarbamate (xxi)
ethyl (3s)-3-(1,3-benzodioxol-5-yl)-3-[[(4-nitrophenoxy)carbonyl]amino]propanoate (xx)
ethyl (3s)-3-(1,3-benzodioxol-5-yl)-3-([[((1s)-1-[[bis(2-thienylmethyl)amino]carbonyl]pentyl)amino]carbonyl]amino)propanoate (xxii)
2-bromoethylamine; 2-bromo-1-ethanamine (iv)
Reference 1:
    ellingboe, j.w.; collini, m.d.; quagliato, d.; chen, j.; antane, m.; schmid, j.; hartupee, d.; white, v.; park, c.h.; tanikella, t.; bagli, j.f.; metabolites of the angiotensin ii antagonist tasosartan: the importance of a second acidic group. j med chem 1998, 41, 22, 4251.

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他索沙坦;英文名Tasosartan;WAY-126756;WAY-ANA-756;ANA-756;Verdia;CAS[145733-36-4]

 
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