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【结 构 式】 
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【分子编号】16170 【品名】1,2-dichloroethane 【CA登记号】107-06-2 |
【 分 子 式 】C2H4Cl2 【 分 子 量 】98.95916 【元素组成】C 24.27% H 4.07% Cl 71.65% |
合成路线1
该中间体在本合成路线中的序号：(II)By condensation of ethylenediamine (I) with 1,2-dichloroethane (II).
| 【1】 Langsjoen, A.; Jones, G.D.; Zomlefer, J.; Neumann, N.M.C.; Polymerization of ethyleneimine. J Org Chem 1944, 9, 125-147. |
| 【2】 Von Hoffmann, A.W.; Zur geschichte der aethylenbasen. Ber 1890, 23, 3711-18. |
| 【3】 Walshe, J.M.; Dixon, H.B.F.; Gibbs, K.; Preparation of triethylenetetraamine dihydrochloride for the treatment of Wilson's disease. Lancet 1972, 1, 7755, 853. |
| 【4】 Castaner, J.; Serradell, M.N.; Hopkins, S.J.; Blancafort, P.; Trientine. Drugs Fut 1983, 8, 8, 697. |
合成路线2
该中间体在本合成路线中的序号：(B)The synthesis of RFCNU from 2,3-O-isopropylidene-5-O-p-nitrobenzoyl-beta-D-ribosyl bromide (III) has been described, as well as the preparation of 2,3-O-isopropylidene-5-O-p-nitrobenzoyl-beta-D-ribosyl bromide from 2,3-O-isopropylidene-D-ribosyl-furanose (I). Briefly, the synthesis is as follows: A cold solution of 2,3-O-isopropylidene-D-ribofuranose (I) in dry pyridine is stirred and treated with p-nitrobenzoyl chloride (A). Workup gives 2,3-O-isopropylene-1,5-di-O-p-nitrobenzoyl-D-ribofuranose (II), which is crystallized from methylene chloride/ether. (II) is added in portions to a dry solution of methylene chloride saturated with HBr at 0 C and stirred for 0.5 h. It is warmed to room temperature, the precipitated p-nitrobenzoic acid removed by filtration (under argon) and the filtrate concentrated. Addition of petroleum ether/diethyl ether and partial concentration by vacuum gives crystals of 2,3-isopropylidene-5-O-p-nitrobenzoyl-beta-ribosyl bromide (III). (III), dissolved in toluene, is reacted with silver isocyanate and refluxed under nitrogen. Silver bromide is filtered off and the filtrate concentrated by evaporation, yielding an oil. Dissolution of the oil in acetonitrile and cooling to -40 C yields crystals of isocyanato-1-O-isopropylidene-2,3-O-p-nitrobenzoyl-5-D-ribofuranose (IV). (IV) is reacted with an aqueous solution of 2-chloroethylamine (B) and the solution extracted with benzene. The organic base is separated, dried and refrigerated. Warming gives a yellow oil, which is treated with ethanol to give crystalline (chloro-2-ethyl)-1-(ribofuranosylisopropylidene-2',3'-p-nitrobenzoate-5')-3-urea (V). (V) is dissolved in methylene chloride, cooled to -40 C and an excess of liquid nitrosyl chloride (NOCl) is added with stirring. Addition of a mixture of chloroform and petroleum ether gives crystals of (chloro-2-ethyl)-1-(ribofuranosylisopropylidene-2',3'-p-nitrobenzoate-5')-3-nitrosourea (RFCNU). The synthesis may be modified to yield either the alpha or beta anomer. Both anomeric forms have shown the same antitumor activity.
| 【1】 Weigele, M.; De Bernado, S.; A synthesis of pyrazomycins. J Org Chem 1976, 41, 287-290. |
| 【2】 Imbach, J.L.; Montero, J.L.; Rodriguez, M.; Sur une nouvelle voie de synthese de la R.F.C.N.U. Eur J Med Chem - Chim Ther 1977, 12, 408-412. |
| 【3】 Eastland, G.; Bofumustine. Drugs Fut 1984, 9, 9, 641. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 16170 | 1,2-dichloroethane | 107-06-2 | C2H4Cl2 | 详情 | 详情 |
| (A) | 18941 | p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride | 122-04-3 | C7H4ClNO3 | 详情 | 详情 |
| (I) | 17718 | (3aR,6R,6aR)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-ol | C8H14O5 | 详情 | 详情 | |
| (II) | 34287 | [(3aR,4R,6aR)-2,2-dimethyl-6-[(4-nitrobenzoyl)oxy]tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl 4-nitrobenzoate | C22H20N2O11 | 详情 | 详情 | |
| (III) | 34288 | [(3aS,4R,6aR)-6-bromo-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl 4-nitrobenzoate | C15H16BrNO7 | 详情 | 详情 | |
| (IV) | 34289 | [(3aR,4R,6aR)-6-isocyanato-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl 4-nitrobenzoate | C16H16N2O8 | 详情 | 详情 | |
| (V) | 34290 | [(3aR,4R,6aR)-6-([[(2-chloroethyl)amino]carbonyl]amino)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl 4-nitrobenzoate | C18H22ClN3O8 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(D)Pyridine-3-carboxaldehyde O-methyloxime (I) is prepared either by methylation of 3-pyridinealdoxime sodium salt or by condensation of 3-pyridinecarboxaldehyde with methoxylamine in water. Quaternization of (I) with ethyl iodide gives 3-(methoxyiminomethyl)-1-ethylpyridinium iodide (II), which is reduced by means of sodium borohydride in methanol to 1-ethyl-1,2,5,6-tetrahydropyridine-3-carboxaldehyde O-methyloxime (III). Cleavage of the ethyl group is obtained by reaction with 4-chlorophenylchloroformate in refluxing dichloroethane to yield RU 47213. Ru 47213 is obtained as pure (E)-isomer. Under UV irradiation in toluene it is partially converted into the sterically unfavored (Z)-isomer.
| 【1】 Barzaghi, F.; Galliani, G.; Toja, E.; RU 47213. Drugs Fut 1994, 19, 5, 454. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 12849 | Nicotinaldehyde; 3-Pyridinecarboxaldehyde | 500-22-1 | C6H5NO | 详情 | 详情 |
| (D) | 16170 | 1,2-dichloroethane | 107-06-2 | C2H4Cl2 | 详情 | 详情 |
| (B) | 31260 | nicotinaldehyde oxime | 1193-92-6 | C6H6N2O | 详情 | 详情 |
| (I) | 12850 | Nicotinaldehyde O-methyloxime | C7H8N2O | 详情 | 详情 | |
| (II) | 31259 | 1-ethyl-3-[(methoxyimino)methyl]pyridinium iodide | C9H13IN2O | 详情 | 详情 | |
| (III) | 31261 | 1-ethyl-1,2,5,6-tetrahydro-3-pyridinecarbaldehyde O-methyloxime | C9H16N2O | 详情 | 详情 | |
| (C) | 17779 | 1-chloro-4-[(chlorocarbonyl)oxy]benzene | 7693-45-0 | C7H4Cl2O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)Flibanserin may be prepared by reacting 1-(phenylvinyl)-2,3-dihydro-1H-benzimidazol-2-one (I) with 1,2-dichloroethane (II) in the presence of NaH in warm dimethylformamide. The resulting 1-(2-chloroethyl)-2,3-dihydro-1H-benzimidazol-one (III) is in turn coupled with commercially available m-trifluoromethylphenylpiperazine hydrochloride (IV) in the presence of sodium carbonate and catalytic potassium iodide in refluxing ethanol. The crude flibanserin hydrochloride (V) is then dissolved in aqueous ethanol and the pure base is precipitated upon addition of sodium hydroxide.
| 【1】 Cesana, R.; Borsini, F.; Ladinsky, H.; Ceci, A.; Giraldo, E.; Turconi, M.; Brambilla, A.; Monferini, E.; Flibanserin. Drugs Fut 1998, 23, 1, 9. |
| 【2】 Turconi, M.; Bietti, G.; Giraldo, E.; Borsini, F.; Bignotti, M. (Boehringer Ingelheim GmbH); Benzimidazolone derivatives as 5-HT1A agonists and 5-HT2 antagonists. EP 0526434; JP 1994509575; US 5576318; WO 9303016 . |
| 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) | 16169 | 1-(1-phenylvinyl)-1,3-dihydro-2H-benzimidazol-2-one | C15H12N2O | 详情 | 详情 | |
| (II) | 16170 | 1,2-dichloroethane | 107-06-2 | C2H4Cl2 | 详情 | 详情 |
| (III) | 16171 | 1-(2-chloroethyl)-1,3-dihydro-2H-benzimidazol-2-one | C9H9ClN2O | 详情 | 详情 | |
| (IV) | 16172 | 1-[3-(trifluoromethyl)phenyl]piperazine; N-[3-(trifluoromethyl)phenyl]piperazine | 15532-75-9 | C11H13F3N2 | 详情 | 详情 |
| (V) | 16173 | 1-(2-[4-[3-(trifluoromethyl)phenyl]piperazino]ethyl)-1,3-dihydro-2H-benzimidazol-2-one | C20H21F3N4O | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(III)The aminoacid building block (VIII) can be prepared by two different ways. The oxidative cleavage of 7-octene-1,2-diol (I) by means of NaIO4 yields aldehyde (II). Partial hydrolysis of diethyl 2-acetamidomalonate (III) provides monoacid (IV), which is subjected to Knoevenagel-type condensation with 6-heptenal (II) in the presence of Ac2O and pyridine to afford enamide (V). Enantioselective hydrogenation of the enamide double bond to the (S)-amidoester (VI) is then achieved by using the Burk's method. In order to replace the N-acetyl protecting group of (VI), the acetamide nitrogen is protected with Boc2O, and the resulting imide (VII) is further hydrolyzed to the target N-Boc aminoacid (VIII) under standard basic conditions.
| 【1】 Halmos, T.; Llinas-Brunet, M.; Faucher, A.-M.; Ghiro, E.; Goudreau, N.; Tsantrizos, Y.S.; Cameron, D.R. (Boehringer Ingelheim (Canada) Ltd.); Macrocyclic peptides active against the hepatitis C virus. EP 1169339; JP 2002542160; WO 0059929 . |
| 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) | 58933 | 7-Octene-1,2-diol | C8H16O2 | 详情 | 详情 | |
| (II) | 27179 | 6-heptenal | C7H12O | 详情 | 详情 | |
| (III) | 16170 | 1,2-dichloroethane | 107-06-2 | C2H4Cl2 | 详情 | 详情 |
| (IV) | 58934 | Ethyl 2-acetamidomalonate | C7H11NO5 | 详情 | 详情 | |
| (V) | 58935 | ethyl (2Z)-2-(acetylamino)-2,8-nonadienoate | C13H21NO3 | 详情 | 详情 | |
| (VI) | 58936 | ethyl (2S)-2-(acetylamino)-8-nonenoate | C13H23NO3 | 详情 | 详情 | |
| (VII) | 58937 | (2S)-2-[acetyl(tert-butoxycarbonyl)amino]-8-nonenoic acid | C16H27NO5 | 详情 | 详情 | |
| (VIII) | 58938 | (2S)-2-[(tert-butoxycarbonyl)amino]-8-nonenoic acid | C14H25NO4 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IIa)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 |