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【结 构 式】 
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【分子编号】18831 【品名】tritylhydrosulfide; triphenylmethanethiol 【CA登记号】3695-77-0 |
【 分 子 式 】C19H16S 【 分 子 量 】276.40204 【元素组成】C 82.56% H 5.83% S 11.6% |
合成路线1
该中间体在本合成路线中的序号：(V)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 |
合成路线2
该中间体在本合成路线中的序号：(III)Conversion of 4-hydroxy-L-proline (I) into the corresponding cis-N-Boc-4-hydroxy-L-proline methyl ester (II) is performed as follows: Treatment of (I) with SOCl2 in MeOH followed by reaction with Boc2O and Et3N in EtOAc affords the corresponding protected acid chloride; then the methyl ester moiety is formed under Mitsunobu conditions with formic acid, DIAD and PPh3 in THF followed by treatment with NaOH in MeOH. The OH group of (II) is converted into thioether (IV) by first mesylation with MsCl and Et3N in toluene followed by reaction with triphenylmethanethiol (III) in THF in the presence of NaH. Reduction of the methyl ester of (IV) with LiBH4 in THF provides alcohol (V), which is mesylated with MsCl and Et3N in THF and then treated with NaN3 and HMPA to furnish azide (VI). Boc removal in (VI) is performed by treatment with HCl in EtOAc to give derivative (VII), which is then converted into compound (VIII) by condensation with 2-(2,4-difluorobenzoyl)benzoic acid (XI) by means of water-soluble carbodiimide (WSC) and HOBt in DMF (compound (XI) can be obtained by Friedel-Crafts reaction between phthalic anhydride (IX) and 1,3-difluorobenzene (X) in the presence of AlCl3). Reduction of the azido moiety of (VIII) by means of SnCl2 and NaOH in EtOH furnishes amine (XII), which is finally converted into the desired product by condensation with carboxylic acid (XIII) by means of WSC and HOBt (derivative (XIII) can be obtained by Knoevenagel reaction between 4-formyl-benzoic acid (XIV) and 2,4-thiazolidinedione (XV) in refluxing 2-methoxyethanol in the presence of piperidine).
| 【1】 Nishi, K.; Seno, K.; Ono, T.; Yamada, K.; Murakami, Y.; Nakamoto, S.; Okuno, T.; Pyrrolidine inhibitors of human cytosolic phospholipase A2. Part 2: Synthesis of potent and crystallized 4-triphenylmethylthio derivative "pyrrophenone". Bioorg Med Chem Lett 2001, 11, 4, 587. |
| 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) | 14489 | (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline | 51-35-4 | C5H9NO3 | 详情 | 详情 |
| (II) | 15783 | 1-(tert-butyl) 2-methyl (2S,4S)-4-hydroxytetrahydro-1H-pyrrole-1,2-dicarboxylate | C11H19NO5 | 详情 | 详情 | |
| (III) | 18831 | tritylhydrosulfide; triphenylmethanethiol | 3695-77-0 | C19H16S | 详情 | 详情 |
| (IV) | 50070 | 1-(tert-butyl) 2-methyl (2S,4R)-4-(tritylsulfanyl)-1,2-pyrrolidinedicarboxylate | C30H33NO4S | 详情 | 详情 | |
| (V) | 50071 | tert-butyl (2S,4R)-2-(hydroxymethyl)-4-(tritylsulfanyl)-1-pyrrolidinecarboxylate | C29H33NO3S | 详情 | 详情 | |
| (VI) | 50072 | tert-butyl (2S,4R)-2-(azidomethyl)-4-(tritylsulfanyl)-1-pyrrolidinecarboxylate | C29H32N4O2S | 详情 | 详情 | |
| (VII) | 50073 | (2S,4R)-2-(azidomethyl)-4-(tritylsulfanyl)pyrrolidine; (3R,5S)-5-(azidomethyl)pyrrolidinyl trityl sulfide | C24H24N4S | 详情 | 详情 | |
| (VIII) | 50074 | [(2S,4R)-2-(azidomethyl)-4-(tritylsulfanyl)pyrrolidinyl][2-(2,4-difluorobenzoyl)phenyl]methanone | C38H30F2N4O2S | 详情 | 详情 | |
| (IX) | 11900 | 2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride | 85-44-9 | C8H4O3 | 详情 | 详情 |
| (X) | 13095 | m-Difluorobenzene; 1,3-Difluorobenzene | 372-18-9 | C6H4F2 | 详情 | 详情 |
| (XI) | 41002 | 2-(2,4-difluorobenzoyl)benzoic acid | C14H8F2O3 | 详情 | 详情 | |
| (XII) | 50075 | [(2S,4R)-2-(aminomethyl)-4-(tritylsulfanyl)pyrrolidinyl][2-(2,4-difluorobenzoyl)phenyl]methanone | C38H32F2N2O2S | 详情 | 详情 | |
| (XIII) | 50076 | 4-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]benzoic acid | C11H7NO4S | 详情 | 详情 | |
| (XIV) | 18922 | 4-formylbenzoic acid | 619-66-9 | C8H6O3 | 详情 | 详情 |
| (XV) | 10883 | 1,3-Thiazolane-2,4-dione; 2,4-Thiazolidinedione | 2295-31-0 | C3H3NO2S | 详情 | 详情 |