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Name Docetaxol;Docetaxel;XRP-6976L;NSC-628503;RP-56976;Taxotere
Chemical Name N-Debenzoyl-N-tert-butoxycarbonyl-10-deacetyltaxol
      [2aR-[2aalpha,4beta,4abeta,6beta,9alpha(alphaR*,betaS*),11beta,12alpha,12aalpha,12balpha]]-beta-(tert-Butoxycarbonylamino)-alpha-hydroxybenzenepropanoic acid 12b-(acetyloxy)-12-(benzyloxy)-1,2,3,4,4a,6,9,10,11,12,12a,12b-dodecahydro-4,6,11-trihydroxy-4a,8,13,13-tetramethyl-5-oxo-7,11-methano-5H-cyclodeca[3,4]benz[1,2-b]oxet-9-yl ester
      (2R,3S)-N-Carboxy-3-phenylisoserine,N-tert-butyl ester,13-ester with 5beta,20-epoxy-1,2alpha,4,7beta,10beta,13alpha-hexahydrotax-11-en-9-one 4-acetate 2-benzoate
      (2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-12b-(Acetoxy)-12-(benzoyloxy)-9-[3(S)-(tert-butoxycarbonylamino)-2(R)-hydroxy-3-phenylpropionyloxy]-4,6,11-trihydroxy-4a,8,13,13-tetramethyl-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benz[1,2-b]oxet-5-one
CAS 114977-28-5
Related CAS 148408-66-6 (trihydrate)
Formula C43H53NO14
Structure
Formula Weight 807.90016
Stage 上市-1995
Company Aventis Pharma (Originator), Chugai (Licensee)
Activity/Mechanism Breast Cancer Therapy, Gastric Cancer Therapy, Head and Neck Cancer Therapy, Lung Cancer Therapy, Non-Small Cell Lung Cancer Therapy, Oncolytic Drugs, Ovarian Cancer Therapy, Prostate Cancer Therapy, Solid Tumors Therapy, Squamous Cell Carcinoma Therapy, Antimitotic Drugs, Microtubule-Stabilizing Agents, Taxanes
Syn. Route 5
Route 1
docetaxel is a synthetic derivative of 10-deacetylbaccatin iii (10-dab; rp 61387). the crystalline active ingredient is synthesized by a sequence of more than 10 chemical steps. the optically active side-chain (rpr 108278) is first fully synthesized and coupled with suitably protected 10-dab. the resulting intermediate is then deprotected to give docetaxel which is crystallized.
List of intermediates No.
3-amino-4-fluorophenylamine (i)
ethyl 7-(acetamido)-6-fluoro-4-hydroxy-3-quinolinecarboxylate (ii)
Reference 1:
    locci-tonelli, d.; spiridonidis, c.h.; fabre, j.l.; docetaxel. drugs fut 1995, 20, 5, 464.
Reference 2:
    colin, m.; guenard, d.; gueritte-voegelein, f.; potier, p. (aventis sa); process for preparing derivs. of baccatine iii and of 10-deacetyl baccatine iii. us 4924012 .

Route 2
a new method for the synthesis of the docetaxel side-chain has been reported:the esterification of (s)-phenylglycine (i) with socl2 and methanol gives the corresponding methyl ester (ii), which is acylated with tert-butoxycarbonyl anhydride to the tert-butoxycarbonyl derivative (iii). the reduction of (iii) with dibutylaluminum hydride (dibal) in toluene yields the corresponding aldehyde (iv), which is condensed with 2-(trimethylsilyl)thiazole (v) by means of tetrabutylammonium fluoride (tbaf) to afford the (1r,2s)-n-[2-hydroxy-1-phenyl-2-(2-thiazolyl)ethyl]carbamic acid tert-butyl ester (vi) with 88% enantiomeric purity. the cyclization of (vi) with 2,2-dimethoxypropane (vii) catalyzed by camphosulfonic acid (csa) gives (4s,5r)-3-(tert-butoxycarbonyl)-2,3-dimethyl-4-phenyl-5-(2-thiazolyl)ox azolidine (viii), which is treated with methyl trifluoromethanesulfonate to afford (4s,5r)-3-(tert-butoxycarbonyl)-2,2-dimethyl-4-phenyloxazolidine-5-carb aldehyde (ix). finally, this compound is oxidized with kmno4 in tert-butanol/aqueous potassium phosphate buffer to yield the corresponding carboxylic acid, the (4s,5r)-3-(tert-butoxycarbonyl)-2,2-dimethyl-4-phenyloxazolidine-5-carb oxylic acid (x), the side-chain of taxotere suitably protected.
List of intermediates No.
(2r,3r,4s,5r)-2-(6-amino-2-sulfanyl-9h-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol (i)
3-chloro-1,1,1-trifluoropropane (ii)
1-iodo-2-(methylsulfanyl)ethane; 2-iodoethyl methyl sulfide (v)
(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 (vii)
ethyl 3-[[3-methyl-5-(methylamino)-1h-pyrazol-4-yl]amino]-3-oxopropanoate (iii)
1,1-bis(methylsulfanyl)-2-nitroethane (vi)
7-amino-3-[(5-methyl-2h-1,2,3,4-tetraazol-2-yl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (viii)
2-diazopropane (ix)
benzyl 7-amino-3-[(5-methyl-2h-1,2,3,4-tetraazol-2-yl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (x)
ethyl 3-(1,3-benzodioxol-5-yl)-2-bromopropanoate
2-({[amino(imino)methyl]sulfanyl}methyl)-5-(tert-butyl)-1,3-oxazole (iv)
Reference 1:
    semola, t.; dondoni, a.; perrone, d.; synthesis of taxol and taxotere side chains by 2-(trimethylsilyl)thiazole based homologation of l-phenylglycine. synthesis 1995, 2, 2, 181.

Route 3
several partial syntheses of docetaxel have been described:the selective hydrolysis of taxol a (i, r = ph), taxol b (i, r = c(me)=chme) or taxol c (i, r = c5h11) with nahco3 in thf/water gives the corresponding 10-deacetyl derivatives (ii), which by selective silylation with triethylsilyl chloride in pyridine are converted into the 10-deacetyl-2,7-bis(triethylsilyl) compounds (iii). the reaction of compounds (iii) with zirconocene chloride hydride [bis(cyclopentadienyl)zirconium chloride hydride] in thf afford the corresponding imino derivatives (iv), which, without isolation are hydrolyzed and desilylated by a treatment with concentrated aqueous hcl in ethanol giving 10-deacetyltaxolamine (v). finally, this compound is acylated at the amino group by a treatment by di-tert-butyl dicarbonate and nahco3 in ethyl acetate/water.
List of intermediates No.
2,3-dihydro-1,4-benzodioxin-5-amine; 2,3-dihydro-1,4-benzodioxin-5-ylamine; 5-amino-1,4-benzodioxane (iia)
methyl 2-methyl-1-azulenecarboxylate (ia)
2-(2-hydroxyphenyl)acetic acid (ib)
tert-butyl 2-iodoacetate (iiia)
[(2,2-dimethylpropanoyl)oxy]methyl 7-amino-3-[(5-methyl-2h-1,2,3,4-tetraazol-2-yl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (iva)
2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetic acid (v)
1-azepanecarbonyl chloride
6-chloro-4-methyl-3,4-dihydro-2(1h)-quinolinone (ic)
tert-butyl 6-chloro-4-methyl-2-oxo-3,4-dihydro-1(2h)-quinolinecarboxylate (iib)
tert-butyl 6-chloro-2-ethoxy-4-methyl-3,4-dihydro-1(2h)-quinolinecarboxylate (iic)
1-(tert-butoxycarbonyl)-6-chloro-4-methyl-3,4-dihydroquinolinium (iiib)
8-chloro-6-methyl-1,2,4,4a,5,6-hexahydro-3h-pyrido[1,2-a]quinolin-3-one (iiic)
[4-(4-nitrobenzoyl)-1-piperazinyl](4-nitrophenyl)methanone (ivb)
2-(4-nitrophenyl)acetonitrile (ivc)
Reference 1:
    young, t.h. (hauser, inc.); preparation of taxol and docetaxel through primary amines. ep 0852581; wo 9623780 .

Route 4
a new synthesis of docetaxel has been developed:the stereoselective dihydroxylation of methyl cinnamate (i) by the sharpless ad process gives the enantiopure diol (ii), which was treated first with tosyl chloride/triethylamine and then with k2co3 in dmf yielding epoxide (iii). hydrolysis of the ester group of (iii) with lioh in methanol/water affords the epoxy-acid (iv), which is coupled with 7,10-bis(2,2,2-trichloroethoxycarbonyl)-10-deacetylbaccatin iii (v) by means of dicyclohexylcarbodiimide (cdd) and dimethylaminopyridine in hot toluene to give the ester (vi). regioselective cleavage of the epoxide ring of (vi) with nan3 in aqueous methanol yielded the azide derivative (vii), which was treated with triphenylphosphine in the presence of tert-butoxycarbonyl anhydride and k2co3 in dichloromethane affording the tert-butoxycarbonylamino derivative (viii). finally, (viii) was submitted to a reductive deprotection with zinc powder in acetic acid.
List of intermediates No.
diacetyl [7-[(3s,4s)-3-amino-4-(fluoromethyl)pyrrolidinyl]-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinyl]carbonyl borate (i)
1,4-benzoxazepine-3,5(2h,4h)-dione (ii)
4-(4-chlorobutyl)-1,4-benzoxazepine-3,5(2h,4h)-dione (iii)
3-chloro-4-(4-chlorobutyl)-1,4-benzoxazepin-5(4h)-one (iv)
4-(2-pyridinyl)-1,2,3,6-tetrahydropyridine (v)
(vi)
1-[4-[3-chloro-5-oxo-1,4-benzoxazepin-4(5h)-yl]butyl]-4-(2-pyridinyl)pyridinium chloride (vii)
6-amino-9h-purin-1-ium-1-olate (viii)
Reference 1:
    harada, n.; yamaguchi, t.; hashiyama, t.; ozaki, k.; synthesis of taxoids 3. a novel and efficient method for preparation of taxoids employing cis-glycidic acid. tetrahedron lett 1998, 39, 5575.

Route 5
the acylation of 10-deacetylbaccatin iii (i) with cdi in chloroform gives the 7,10-bis-o-(imidazolylcarbonyl) derivative (ii), which is condensed with the chiral oxazolidinecarboxylic acid (iii) by means of dcc and dmap in hot toluene to yield the corresponding ester (iv). the hydrolysis of (iv) with aqueous tfa affords compound (v), which is finally treated with (boc)2o and nahco3 in thf to provide the target docetaxel.
List of intermediates No.
ethyl 3-[(2,5-dimethoxybenzyl)[2-(4-methoxybenzoyl)-1-benzofuran-3-yl]amino]-3-oxopropanoate (i)
1-cyclopropyl-6-fluoro-4-oxo-7-(1-piperazinyl)-1,4-dihydro-3-quinolinecarboxylic acid (iii)
2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetic acid (v)
Reference 1:
    duvvuri, s.; puranik, r. (dr. reddys research foundation); an improved process for the preparation of docetaxel. wo 0212216 .

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多西他賽;英文名Docetaxol;Docetaxel;XRP-6976L;NSC-628503;RP-56976;Taxotere;CAS[114977-28-5]

 
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