【结 构 式】 |
【分子编号】18839 【品名】methyl 2-(tritylsulfanyl)acetate 【CA登记号】 |
【 分 子 式 】C22H20O2S 【 分 子 量 】348.4656 【元素组成】C 75.83% H 5.79% O 9.18% S 9.2% |
合成路线1
该中间体在本合成路线中的序号:(XIII)Title compound has been prepared by several related ways. Alkylation of methyl acetoacetate (I) with n-heptyl bromide (II) in the presence of NaOMe in refluxing MeOH yielded (III), which was brominated in CHCl3 at 0 C to give (IV). Subsequent reaction with triphenylmethyl mercaptan (V) and tetrabutyl ammonium hydroxide in toluene at r.t. provided (XI). Alternatively, beta-ketoester (XI) was prepared from a-mercaptoacetic acid (VI). Thus, protection as the S-trityl compound (VIII) by treatment with triphenylcarbinol (VII) and TFA, followed by condensation with N,O-dimethyl hydroxylamine in the presence of EDC and HOBt afforded N-methoxyamide (IX). Then, Claisen condensation with methyl nonanoate (X) using LDA as the base in THF at -78 C provided ketoester (XI). In order to avoid b-ketoacid decarboxylation, ketone (XI) was reduced to alcohol (XV) with NaBH4 in MeOH at 0 C. This hydroxyester was also prepared by a related route, consisting of protection of methyl mercaptoacetate (XII) as the S-trityl compound (XIII), followed by reduction to aldehyde (XIV) with DIBAL-H and condensation with methyl nonanoate (X). Saponification of methyl ester (XV) with KOH yielded hydroxyacid (XVI). Subsequent coupling with tert-butylglycine amide (XVII) using EDC and HOBt as the condensing agents produced amide (XVIII). Ketoamide (XX) was then obtained by oxidation with Dess-Martin periodinane (XIX). Finally, deprotection of the S-trityl group was effected by trifluoroacetic acid treatment under reducing conditions with triethyl silane to provide the target compound.
【1】 Campbell, D.A.; Xiao, X.Y.; Harris, D.; Ida, S.; Mortezaei, R.; Ngu, K.; Shi, L.; Tien, D.; Wang, Y.; Navre, M.; Patel, D.V.; Sharr, M.A.; DiJoseph, J.F.; Killar, L.M.; Leone, C.L.; Levin, J.I.; Skotnicki, J.S.; Malonyl alpha-mercaptoketones and alpha-mercaptoalcohols, a new class of matrix metalloproteinase inhibitors. Bioorg Med Chem Lett 1998, 8, 10, 1157. |
【2】 Campbell, D.A.; Patel, D.V.; Xiao, X.Y. (Affymax Technologies, NV); Novel inhibitors of collagenase-1 and stromelysin-I metalloproteases, pharmaceutical compsns. comprising same and methods of their use. WO 9640204 . |
【3】 Campbell, D.A.; Patel, D.V.; Xiao, X.Y. (Affymax Technologies, NV); Novel inhibitors of metalloproteases, pharmaceutical compsns. comprising same and methods of their use. WO 9640738 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(I) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
(II) | 18828 | 1-bromoheptane | 629-04-9 | C7H15Br | 详情 | 详情 |
(III) | 18829 | methyl 2-acetylnonanoate | C12H22O3 | 详情 | 详情 | |
(IV) | 18830 | methyl 2-(2-bromoacetyl)nonanoate | C12H21BrO3 | 详情 | 详情 | |
(V) | 18831 | tritylhydrosulfide; triphenylmethanethiol | 3695-77-0 | C19H16S | 详情 | 详情 |
(VI) | 18524 | 2-sulfanylacetic acid | 68-11-1 | C2H4O2S | 详情 | 详情 |
(VII) | 18833 | Trityl alcohol; triphenylmethanol | 76-84-6 | C19H16O | 详情 | 详情 |
(VIII) | 18834 | 2-(tritylsulfanyl)acetic acid | C21H18O2S | 详情 | 详情 | |
(IX) | 18835 | N-methoxy-N-methyl-2-(tritylsulfanyl)acetamide | C23H23NO2S | 详情 | 详情 | |
(X) | 18836 | methyl nonanoate | 1731-84-6 | C10H20O2 | 详情 | 详情 |
(XI) | 18837 | methyl 2-[2-(tritylsulfanyl)acetyl]nonanoate | C31H36O3S | 详情 | 详情 | |
(XII) | 18838 | methyl 2-sulfanylacetate | 2365-48-2 | C3H6O2S | 详情 | 详情 |
(XIII) | 18839 | methyl 2-(tritylsulfanyl)acetate | C22H20O2S | 详情 | 详情 | |
(XIV) | 18840 | 2-(tritylsulfanyl)acetaldehyde | C21H18OS | 详情 | 详情 | |
(XV) | 18841 | methyl 2-[1-hydroxy-2-(tritylsulfanyl)ethyl]nonanoate | C31H38O3S | 详情 | 详情 | |
(XVI) | 18842 | 2-[1-hydroxy-2-(tritylsulfanyl)ethyl]nonanoic acid | C30H36O3S | 详情 | 详情 | |
(XVII) | 18843 | (2S)-2-amino-N,3,3-trimethylbutanamide | 89226-12-0 | C7H16N2O | 详情 | 详情 |
(XVIII) | 18844 | N-[(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl]-2-[1-hydroxy-2-(tritylsulfanyl)ethyl]nonanamide | C37H50N2O3S | 详情 | 详情 | |
(XIX) | 18845 | Dess-Martin periodinane; 1,1,1-Triacetoxy-1,2-benziodoxol-3(1H)-one | 87413-09-0 | C13H13IO8 | 详情 | 详情 |
(XX) | 18846 | N-[(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl]-2-[2-(tritylsulfanyl)acetyl]nonanamide | C37H48N2O3S | 详情 | 详情 |