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【结 构 式】 
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【分子编号】42307 【品名】2-hydroxy-5-nitrobenzaldehyde；5-nitrosalicylaldehyde 【CA登记号】97-51-8 |
【 分 子 式 】C7H5NO4 【 分 子 量 】167.12104 【元素组成】C 50.31% H 3.02% N 8.38% O 38.29% |
合成路线1
该中间体在本合成路线中的序号：(I)5-Nitrosalicylaldehyde (I) was condensed with diethyl bromomalonate (II) to give ethyl 5-nitrobenzofuran-2-carboxylate (III), which was converted into the corresponding primary amide (IV) by reaction with ethanolic ammonia. Dehydration of amide (IV) to the nitrile (V) was effected by treatment with POCl3. After formation of imidate (VI) with HCl/MeOH, cyclization with ethylenediamine produced the imidazoline (VII). The nitro group of (VII) was then reduced to amine (VIII) using Fe and HCl. This was finally converted to the title isothiocyanate by reaction with thiophosgene.
| 【1】 Hudson, A.L.; Nutt, D.J.; Grundt, P.; Coates, P.A.; Husbands, S.M.; Tyacke, R.; Robinson, E.S.J.; Lewis, J.W.; Probes for imidazole binding sites: Synthesis and evaluation of a selective, irreversible I2 ligand. Bioorg Med Chem Lett 2000, 10, 6, 605. |
| 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) | 42307 | 2-hydroxy-5-nitrobenzaldehyde；5-nitrosalicylaldehyde | 97-51-8 | C7H5NO4 | 详情 | 详情 |
| (II) | 35647 | diethyl 2-bromomalonate | 685-87-0 | C7H11BrO4 | 详情 | 详情 |
| (III) | 42308 | ethyl 5-nitro-1-benzofuran-2-carboxylate | 69404-00-8 | C11H9NO5 | 详情 | 详情 |
| (IV) | 42309 | 5-nitro-1-benzofuran-2-carboxamide | C9H6N2O4 | 详情 | 详情 | |
| (V) | 42310 | 5-nitro-1-benzofuran-2-carbonitrile | C9H4N2O3 | 详情 | 详情 | |
| (VI) | 42311 | methyl 5-nitro-1-benzofuran-2-carboximidoate | C10H8N2O4 | 详情 | 详情 | |
| (VII) | 42312 | 2-(5-nitro-1-benzofuran-2-yl)-4,5-dihydro-1H-imidazole | C11H9N3O3 | 详情 | 详情 | |
| (VIII) | 42313 | 2-(4,5-dihydro-1H-imidazol-2-yl)-1-benzofuran-5-amine; 2-(4,5-dihydro-1H-imidazol-2-yl)-1-benzofuran-5-ylamine | C11H11N3O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)Coupling of decanoylchloride (I) with D-serine (II) under Schotten-Baumann conditions (with Na2CO3 in H2O/THF) provides N-decanoyl-D-serine (III). Separately, aldehyde (IV) is reduced by means of NaBH4 in EtOH to yield alcohol (V), whose nitro group is reduced by means of In and NH4Cl in EtOH to afford substituted aniline (VI). Coupling of 5-amino-2-hydroxybenzyl alcohol (VI) with serine (III) by means of dicyclohexylcarbodiimide (DCC) and 1-hydroxybenzotriazole (HOBt) in DMF furnishes compound (VII), which is finally oxidized with NaIO4 in MeOH/H2O to yield the desired spiroepoxide.
| 【1】 Giannis, A.; Arenz, C.; Synthesis of the first selective irreversible inhibitor of neutral sphingomyelinase. Angew Chem. Int Ed Engl 2000, 39, 8, 1440. |
| 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) | 28271 | decanoyl chloride | 112-13-0 | C10H19ClO | 详情 | 详情 |
| (II) | 15728 | (+)-2-Amino-3-hydroxypropionic acid; D-(+)-Serine; D-serine | 312-84-5 | C3H7NO3 | 详情 | 详情 |
| (III) | 47198 | (2R)-2-(decanoylamino)-3-hydroxypropionic acid | C13H25NO4 | 详情 | 详情 | |
| (IV) | 42307 | 2-hydroxy-5-nitrobenzaldehyde；5-nitrosalicylaldehyde | 97-51-8 | C7H5NO4 | 详情 | 详情 |
| (V) | 47199 | 2-(hydroxymethyl)-4-nitrophenol | C7H7NO4 | 详情 | 详情 | |
| (VI) | 47200 | 4-amino-2-(hydroxymethyl)phenol | C7H9NO2 | 详情 | 详情 | |
| (VII) | 47201 | N-[(1R)-2-[4-hydroxy-3-(hydroxymethyl)anilino]-1-(hydroxymethyl)-2-oxoethyl]decanamide | C20H32N2O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)Coupling of N-Boc-phenylalanine (I) with amine (II) by means of HBTU and DIEA provides amide (III), whose Boc group is removed by treatment with HCl in dioxane to afford amine hydrochloride (IV). Finally, the target compound is obtained by reductive amination between amine (IV) and aldehyde (V) in MeOH in the presence of NaCNBH3.
| 【1】 Harriman, G.C.B.; Cochran, N.A.; Gallant, D.; Briskin, M.J.; Schwender, C.F.; Cell adhesion antagonists: Synthesis and evaluation of a novel series of phenylalanine based inhibitors. Bioorg Med Chem Lett 2000, 10, 14, 1497. |
| 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) | 12874 | (2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine | 13734-34-4 | C14H19NO4 | 详情 | 详情 |
| (II) | 46226 | isopentylamine; 3-methyl-1-butanamine | C5H13N | 详情 | 详情 | |
| (III) | 46225 | tert-butyl (1S)-1-benzyl-2-(isopentylamino)-2-oxoethylcarbamate | C19H30N2O3 | 详情 | 详情 | |
| (IV) | 46227 | (2S)-2-amino-N-isopentyl-3-phenylpropanamide | C14H22N2O | 详情 | 详情 | |
| (V) | 42307 | 2-hydroxy-5-nitrobenzaldehyde；5-nitrosalicylaldehyde | 97-51-8 | C7H5NO4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)O-Alkylation of 5-nitrosalicylaldehyde (I) with 1,2-dichloroethane (IIa) or 1-bromo-2-chloroethane (IIb) (3) by means of K2CO3 in DMF at 100-5 °c or 60 °c affords 2-(2-chloroethoxy)-5-nitrobenzaldehyde (III), which by reduction with nabH4 in THF or MeoH yields the corresponding alcohol (IV). O-Alkylation of alcohol (IV) with allyl bromide (V) and KoH and Bu4NHSo4 or Bu4Ni at 40 °c gives 2-(allyloxymethyl)-1-(2-chloroethoxy)-4-nitrobenzene (VI), which is then reduced with Fe in the presence of nH4cl in EtoH to yield the corresponding aniline (VII). condensation of amine (VII) with 4-[3-(allyloxymethyl)phenyl]-2-chloropyrimidine (VIII) by means of Hcl in buoH at 80 °c affords the 2-anilinopyrimidine derivative (IX), which then undergoes ring-closing metathesis in the presence of Grubbs’ second-generation catalyst and HCl in CH2Cl2 at 40-45 °c to yield macrocycle (X). Finally, compound (X) is submitted to microwave-assisted condensation with pyrrolidine (XI) in dimethylacetamide at 80 °c .
intermediate (VIII) can be prepared by Suzuki coupling of 2,4-dichloropyrimidine (XII) with 3-(hydroxymethyl)phenylboronic acid (XIII) in the presence of Pd(OAc)2, PPh3 and na2co3 in THF at 70 °c or Pd(PPh3)4 and Na2CO3 in DME at 80-5 °c to give [3-(2-chloropyrimidin-4-yl)phenyl]methanol (XIV), which is finally O-alkylated with allyl bromide (V) and KOH and Bu4NHSO4 or Cs2CO3 in DMF at 40 °c .
| 【1】 William, A.D., Lee, A.c., blanchard, S. et al. Discovery of the macrocycle 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (SB1518), a potent Janus kinase 2/fms-like tyrosine kinase-3 (JAK2/FLT3) inhibitor for the treatment of myelofibrosis and lymphoma. J Med chem 2011, 54(13): 4638-58. |
| 【2】 Lee, A., William, A., Poulsen, A. et al. Design, synthesis and SAR studies leading to SB1518, a novel macrocyclic JAK2/FLT3 inhibitor in phase 2 clinical trials for myelofibrosis and lymphoma. 102nd Annu Meet Am Assoc cancer Res (AAcR) (April 2-6, orlando) 2011, Abst 3564. |
| 【3】 blanchard, S., Lee, c.H.A., nagaraj, H.K.M., Poulsen, A., Sun, E.t., tan, Y.L.E., William, A.D. (S*bio Pte. Ltd.). EP 1951729, JP 2009515954, US 8153632, Wo 2007058627. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IIa) | 16170 | 1,2-dichloroethane | 107-06-2 | C2H4Cl2 | 详情 | 详情 |
| (IIb) | 24271 | 1-bromo-2-chloroethane | 107-04-0 | C2H4BrCl | 详情 | 详情 |
| (IX) | 68053 | N-(3-((allyloxy)methyl)-4-(2-chloroethoxy)phenyl)-4-(3-((allyloxy)methyl)phenyl)pyrimidin-2-amine | C26H28ClN3O3 | 详情 | 详情 | |
| (I) | 42307 | 2-hydroxy-5-nitrobenzaldehyde；5-nitrosalicylaldehyde | 97-51-8 | C7H5NO4 | 详情 | 详情 |
| (III) | 68048 | 2-(2-chloroethoxy)-5-nitrobenzaldehyde | C9H8ClNO4 | 详情 | 详情 | |
| (IV) | 68049 | (2-(2-chloroethoxy)-5-nitrophenyl)methanol | C9H10ClNO4 | 详情 | 详情 | |
| (V) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (VI) | 68050 | 2-((allyloxy)methyl)-1-(2-chloroethoxy)-4-nitrobenzene | C12H14ClNO4 | 详情 | 详情 | |
| (VII) | 68051 | 3-((allyloxy)methyl)-4-(2-chloroethoxy)aniline | C12H16ClNO2 | 详情 | 详情 | |
| (VIII) | 68052 | 4-[3-(allyloxymethyl)phenyl]-2-chloropyrimidine | C14H13ClN2O | 详情 | 详情 | |
| (X) | 68054 | C24H24ClN3O3 | 详情 | 详情 | ||
| (XI) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (XII) | 54377 | 2,4-Dichloropyrimidine | 3934-20-1 | C4H2Cl2N2 | 详情 | 详情 |
| (XIII) | 68055 | 3-(hydroxymethyl)phenylboronic acid；(3-Hydroxymethyl)phenylboronic acid;(m-Hydroxymethyl)phenylboronic acid;3-Hydroxymethylbenzeneboronic acid | 87199-15-3 | C7H9BO3 | 详情 | 详情 |
| (XIV) | 68056 | [3-(2-chloropyrimidin-4-yl)phenyl]methanol | C11H9ClN2O | 详情 | 详情 |