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【结 构 式】 
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【分子编号】68052 【品名】4-[3-(allyloxymethyl)phenyl]-2-chloropyrimidine 【CA登记号】 |
【 分 子 式 】C14H13ClN2O 【 分 子 量 】260.7228 【元素组成】C 64.5% H 5.03% Cl 13.6% N 10.74% O 6.14% |
合成路线1
该中间体在本合成路线中的序号：(VIII)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 |
合成路线2
该中间体在本合成路线中的序号：(V)condensation of 2-(allyloxymethyl)-1-(2-chloroethoxy)-4-nitrobenzene (VI) with pyrrolidine (XI) in dimethylacetamide at 60 °c affords 1-[2-[2-(allyloxymethyl)-4-nitrophenoxy]ethyl]pyrrolidine (XII), which by reduction with SnCl2 in MeoH/cH2cl2 or with Fe and NH4Cl provides the corresponding aniline (XIII). coupling of amine (XIII) with 4-[3-(allyloxymethyl)phenyl]-2-chloropyrimidine (VIII) In the presence of HCl in BuOH at 100 °c gives the diallyl derivative (XIV), which finally undergoes ring-closing metathesIs In the presence of Grubbs’ second-generation catalyst and TFA in CH2Cl2 at 50 °c or in the presence of the Zhan-1B catalyst .
| 【1】 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. |
| 【2】 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. |
| 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) | 68050 | 2-((allyloxy)methyl)-1-(2-chloroethoxy)-4-nitrobenzene | C12H14ClNO4 | 详情 | 详情 | |
| (II) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (III) | 68057 | 1-(2-(2-((allyloxy)methyl)-4-nitrophenoxy)ethyl)pyrrolidine | C16H22N2O4 | 详情 | 详情 | |
| (IV) | 68058 | 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline | C16H24N2O2 | 详情 | 详情 | |
| (V) | 68052 | 4-[3-(allyloxymethyl)phenyl]-2-chloropyrimidine | C14H13ClN2O | 详情 | 详情 | |
| (VI) | 68059 | N-(3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5-(3-((allyloxy)methyl)phenyl)pyrimidin-2-amine | C30H36N4O3 | 详情 | 详情 |