【结 构 式】 |
【分子编号】22845 【品名】5-Amino-4,6-dichloropyrimidine; 4,6-dichloro-5-pyrimidinylamine; 4,6-dichloro-5-pyrimidinamine 【CA登记号】5413-85-4 |
【 分 子 式 】C4H3Cl2N3 【 分 子 量 】163.99344 【元素组成】C 29.3% H 1.84% Cl 43.24% N 25.62% |
合成路线1
该中间体在本合成路线中的序号:(VI)This compound can be obtained by two related ways: 1) The condensation of 2-aminooctanoic acid (I) with acetic anhydride in pyridine at 100 C gives 3-acetamidononan-2-one (III), which is hydrolyzed with refluxing aqueous concentrated HCl yielding 3-aminononan-2-one hydrochloride (IV). The reduction of (IV) with NaBH4 in methanol affords 3-amino-2-nonanol (V), which is condensed with 4,6-dichloro-5-aminopyrimidine (VI) by means of tributylamine in refluxing pentanol giving 5-amino-6-(2-hydroxy-3-nonylamino)-4-chloropyrimidine (VII). The cyclization of (VII) with ethyl orthoformate (A) by means of ethanesulfonic acid in refluxing CHCl3 affords 9-(2-hydroxy-3-nonyl)-6-chloropurine (VIII), which is finally hydrolyzed with refluxing aqueous 0.5 N NaOH. 2) The chloropurine (VIII) is treated with methanolic NH3 at 80-100 C in a pressure vessel to give 9-(2-hydroxy-3-nonyl)adenine (IX), which is then treated with NaNO2 in acetic acid aqueous HCl.
【1】 Giner-Sorolla, A. (Newport Pharmaceuticals International Inc.; Sloan-Kettering Institute); 9-(Hydroxy alkyl)purines. US 4221910 . |
【2】 Simon, L.N.; Hadden, J.W. (Newport Pharmaceuticals International Inc.; Sloan-Kettering Institute); Method of imparting immunomodulating and antiviral activity. US 4221794 . |
【3】 Serradell, M.N.; Blancafort, P.; Castaner, J.; Arrigoni-Martelli, E.; NPT-15,392. Drugs Fut 1983, 8, 5, 420. |
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) | 21304 | Triethyl orthoformate; 1-(Diethoxymethoxy)ethane; Diethoxymethyl ethyl ether | 122-51-0 | C7H16O3 | 详情 | 详情 |
(I) | 36045 | 2-aminooctanoic acid | C8H17NO2 | 详情 | 详情 | |
(III) | 36046 | N-(1-acetylheptyl)acetamide | C11H21NO2 | 详情 | 详情 | |
(IV) | 36047 | 3-amino-2-nonanone | C9H19NO | 详情 | 详情 | |
(V) | 36048 | 3-amino-2-nonanol | C9H21NO | 详情 | 详情 | |
(VI) | 22845 | 5-Amino-4,6-dichloropyrimidine; 4,6-dichloro-5-pyrimidinylamine; 4,6-dichloro-5-pyrimidinamine | 5413-85-4 | C4H3Cl2N3 | 详情 | 详情 |
(VII) | 36049 | 3-[(5-amino-6-chloro-4-pyrimidinyl)amino]-2-nonanol | C13H23ClN4O | 详情 | 详情 | |
(VIII) | 36050 | 3-(6-chloro-9H-purin-9-yl)-2-nonanol | C14H21ClN4O | 详情 | 详情 | |
(IX) | 36051 | 3-(6-amino-9H-purin-9-yl)-2-nonanol | C14H23N5O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(C)The reaction of (-)-5-O-benzyl-2,3-O-isopropylidene-D-ribolactonle (I) with lithium dimethylmethylphosphonate in THF gives the hemiketal (II) in quantitative yield. Benzoylation of (II) with benzoyl chloride in pyridine leads to the acyclic dibenzoate (III), which is debenzoylated with methanolic sodium methoxide to afford the beta-ketophosphonate (IV). Oxidation of (IV) with the modified Collins' reagent (CrO3 - 2Py) in dichloromethane gives diketophosphonate (V). The reaction of (V) with powdered anhydrous potassium carbonate and 18-crown-6-ether in benzene under high dilution gives the 2-cyclopentenone (VI) (50% yield). Reduction of (VI) with sodium borohydride in a 0.4-M CeCl3 - 7H2O- methanol solution affords the allylic alcohol (VII) (85% yield), which is mesylated to give (VIII). The mesyl group on (VIII) is displaced by lithium azide to give the beta-azide (IX) (84% yield). Reduction of (IX) with 1,3-propanedithiol and triethylamine in absolute methanol gives the 2-cyclopentenylamine (X) (85% yield). Condensation of (X) with 5-amino-4,6-dichloropyrimidine in the presence of triethylamine (n-BuOH, reflux, 45 h) gives (XI) (52% yield). Ring closure with triethyl orthoformate and Ac2O or HCl gives (XII), which is treated with methanolic ammonia to afford (XIII) (overall yield 58%). Debenzylation of (XIII) with boron trichloride in dichloromethane leads to removal of the isopropylidene group (61% yield). Another method to obtain neplanocin A is also available, in which an enantioselective synthesis of neplanocin A is performed by a chemoenzymatic approach starting from the Diels-Alder adduct of cyclopentadiene and dimethyl acetylene-dicarboxylate.
【1】 Arita, M.; Ito, Y.; Sawai, H.; Ohno, M.; Adachi, K.; Enantioselective synthesis of the carbocyclic nucleosides (-)-aristeromycin and (-)-neplanocin A by a chemicoenzymatic approach. J Am Chem Soc 1983, 105, 4049. |
【2】 Lim, M.I.; Maquez, V.E.; Total synthesis of (-)-neplanocin A. Tetrahedron Lett 1981, 34, 4, 359-366. |
【3】 Hayashi, M.; Yoshioka, H.; Yaginuma, S.; Nakatsu, K.; Studies on neplanocin A, new antitumor antibiotic. II. Structure determination. J Antibiot 1981, 34, 6, 675-680. |
【4】 Fujimoto, S.; Neplanocin A. Drugs Fut 1985, 10, 10, 822. |
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) | 29720 | [(dimethoxyphosphoryl)methyl]lithium | C3H8LiO3P | 详情 | 详情 | |
(B) | 29729 | 1,3-propanedithiol; 3-sulfanylpropylhydrosulfide | 109-80-8 | C3H8S2 | 详情 | 详情 |
(I) | 29719 | 6-(benzyloxy)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-4(3aH)-one | C14H16O5 | 详情 | 详情 | |
(II) | 29721 | dimethyl [6-(benzyloxy)-4-hydroxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methylphosphonate | C17H25O8P | 详情 | 详情 | |
(III) | 29722 | (1R)-1-[(4S,5S)-5-[(E)-1-(benzoyloxy)-2-(dimethoxyphosphoryl)ethenyl]-2,2-dimethyl-1,3-dioxolan-4-yl]-2-(benzyloxy)ethyl benzoate | C32H35O10P | 详情 | 详情 | |
(IV) | 29723 | dimethyl 2-[(4R,5R)-5-[(1R)-2-(benzyloxy)-1-hydroxyethyl]-2,2-dimethyl-1,3-dioxolan-4-yl]-2-oxoethylphosphonate | C18H27O8P | 详情 | 详情 | |
(V) | 29724 | dimethyl 2-[(4R,5S)-5-[2-(benzyloxy)acetyl]-2,2-dimethyl-1,3-dioxolan-4-yl]-2-oxoethylphosphonate | C18H25O8P | 详情 | 详情 | |
(VI) | 29725 | 6-(benzyloxy)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-one | C15H16O4 | 详情 | 详情 | |
(VII) | 29726 | (4S)-6-(benzyloxy)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol | C15H18O4 | 详情 | 详情 | |
(VIII) | 29727 | (4S)-6-(benzyloxy)-2,2-dimethyl-4-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxole; benzyl (6S)-2,2-dimethyl-6-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl ether | C18H24O4S | 详情 | 详情 | |
(IX) | 29728 | (6R)-6-azido-2,2-dimethyl-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl benzyl ether; (4R)-4-azido-6-(benzyloxy)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxole | C15H17N3O3 | 详情 | 详情 | |
(X) | 29730 | (4R)-6-(benzyloxy)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ylamine; (4R)-6-(benzyloxy)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-amine | C15H19NO3 | 详情 | 详情 | |
(XI) | 29731 | N-(5-amino-6-chloro-4-pyrimidinyl)-N-[6-(benzyloxy)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]amine; N(4)-[6-(benzyloxy)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-6-chloro-4,5-pyrimidinediamine | C19H21ClN4O3 | 详情 | 详情 | |
(XII) | 29732 | 9-[6-(benzyloxy)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-6-chloro-9H-purine; benzyl 6-(6-chloro-9H-purin-9-yl)-2,2-dimethyl-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl ether | C20H19ClN4O3 | 详情 | 详情 | |
(XIII) | 29733 | 9-[6-(benzyloxy)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-9H-purin-6-amine; 9-[6-(benzyloxy)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-9H-purin-6-ylamine | C20H21N5O3 | 详情 | 详情 | |
(C) | 22845 | 5-Amino-4,6-dichloropyrimidine; 4,6-dichloro-5-pyrimidinylamine; 4,6-dichloro-5-pyrimidinamine | 5413-85-4 | C4H3Cl2N3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(I)The reaction of 4,6-dichloropyrimidin-5-amine (I) with 5-aminopentanol (I) gives 4-chloro-6-(5-hydroxypentylamino)pyrimidin-5 amine (III), which is cyclized with triethyl orthoformate (IV) yielding 6-chloro-9-(5-hydroxypentyl)purine (V). The hydrolysis of (V) with formic acid affords 9-(5-hydroxypentyl) hypoxanthine (VI), which is treated with phosgene (VII) to give 9-[5-(chlorocarbonyloxy)pentyl]hypoxanthine (VIII). Finally, this compound is condensed with arginine (IX).
【1】 Stradi, R.; Cornaglia-Ferraris, P.; Perezzani, L.S.; Forni, G.; Riccardi, C.; PCF-39. Drugs Fut 1987, 12, 2, 134. |
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) | 22845 | 5-Amino-4,6-dichloropyrimidine; 4,6-dichloro-5-pyrimidinylamine; 4,6-dichloro-5-pyrimidinamine | 5413-85-4 | C4H3Cl2N3 | 详情 | 详情 |
(II) | 22846 | 5-amino-1-pentanol | 2508-29-4 | C5H13NO | 详情 | 详情 |
(III) | 22847 | 5-[(5-amino-6-chloro-4-pyrimidinyl)amino]-1-pentanol | C9H15ClN4O | 详情 | 详情 | |
(IV) | 21304 | Triethyl orthoformate; 1-(Diethoxymethoxy)ethane; Diethoxymethyl ethyl ether | 122-51-0 | C7H16O3 | 详情 | 详情 |
(V) | 22849 | 5-(6-chloro-9H-purin-9-yl)-1-pentanol | C10H13ClN4O | 详情 | 详情 | |
(VI) | 22850 | 9-(5-hydroxypentyl)-9H-purin-6-ol | C10H14N4O2 | 详情 | 详情 | |
(VIII) | 22852 | 9-[5-[(chlorocarbonyl)oxy]pentyl]-6-hydroxy-9H-purine | C11H13ClN4O3 | 详情 | 详情 | |
(IX) | 22853 | Arginine; 2-Amino-5-guanidinopentanoic acid | C6H14N4O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号:(II)The overall synthetic approach to N-0861 is described in Scheme 17807901a: Reduction of 4,6-dichloro-5-nitropyrimidine (I) followed by reaction with methylamine gives 5-amino-6-chloro-4-methylaminopyrimidine (III). Cyclization with triethylorthoformate under acidic conditions results in 9-methyl-6-chloropurine (IV). Reaction of (±)-endo-2-aminonorbornane (V) with 9-methyl-6-chloropurine (IV) provides N-0861.
【1】 van Galen, P.; Williams, M.; Jacobson, K.; Adenosine receptors: Pharmacology, structure-activity relationships, and therapeutic potential. J Med Chem 1992, 35, 3, 407-22. |
【2】 Hong, O.; Jacobson, K.; Daly, J.; Shamim, M.; Padgett, W.; Ukena, D.; Non-xanthine heterocycles: Activity as antagonists of A1- and A2-adenosine receptors. Biochem Pharmacol 1988, 37, 4, 655-54. |
【3】 Peck, J.V.; Cusack, N.J.; N-0861. Drugs Fut 1993, 18, 5, 433. |
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) | 15284 | 4,6-dichloro-5-nitropyrimidine | 4316-93-2 | C4HCl2N3O2 | 详情 | 详情 |
(II) | 22845 | 5-Amino-4,6-dichloropyrimidine; 4,6-dichloro-5-pyrimidinylamine; 4,6-dichloro-5-pyrimidinamine | 5413-85-4 | C4H3Cl2N3 | 详情 | 详情 |
(III) | 15285 | 6-chloro-N(4)-methyl-4,5-pyrimidinediamine; N-(5-amino-6-chloro-4-pyrimidinyl)-N-methylamine | C5H7ClN4 | 详情 | 详情 | |
(IV) | 15286 | 6-chloro-9-methyl-9H-purine | 2346-74-9 | C6H5ClN4 | 详情 | 详情 |
(V) | 63964 | (1R,2S,4S)bicyclo[2.2.1]hept-2-ylamine; (1R,2S,4S)bicyclo[2.2.1]heptan-2-amine | C7H13N | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号:(I)Condensation of 5-amino-4,6-dichloropyrimidine (I) with benzylamine afforded diamine (III). Subsequent reaction of (III) with triethyl orthopropionate in the presence of HCl produced imidate (IV), which was cyclized to purine (V) upon heating in diphenyl ether in the presence of p-toluenesulfonic acid. Palladium catalyzed coupling of (IV) with the organozinc derivative generated from Grignard reagent (V) and ZnCl2 produced the corresponding 6-aryl purine (VI). The N-benzyl group of (VI) was then deprotected by hydrogenation in the presence of palladium catalyst and trifluoroacetic acid to furnish (VII). Finally, condensation with dicyclopropylcarbinol (VIII) under Mitsunobu conditions yielded the title compound.
【1】 Beck, J.P.; Arvanitis, A.G.; Bakthavatchalam, R.; Wilde, R.G. (DuPont Pharmaceuticals Co.); Imidazopyrimidines and imidazopyridines for the treatment of neurological disorders. EP 0994877; WO 9901454 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 | |
(I) | 22845 | 5-Amino-4,6-dichloropyrimidine; 4,6-dichloro-5-pyrimidinylamine; 4,6-dichloro-5-pyrimidinamine | 5413-85-4 | C4H3Cl2N3 | 详情 | 详情 |
(II) | 38817 | N(4)-benzyl-6-chloro-4,5-pyrimidinediamine; N-(5-amino-6-chloro-4-pyrimidinyl)-N-benzylamine | C11H11ClN4 | 详情 | 详情 | |
(III) | 38818 | ethyl N-[4-(benzylamino)-6-chloro-5-pyrimidinyl]propanimidoate | C16H19ClN4O | 详情 | 详情 | |
(IV) | 38819 | 9-benzyl-6-chloro-8-ethyl-9H-purine | C14H13ClN4 | 详情 | 详情 | |
(V) | 38820 | bromo[2-chloro-4-(trifluoromethyl)phenyl]magnesium | C7H3BrClF3Mg | 详情 | 详情 | |
(VI) | 38821 | 9-benzyl-6-[2-chloro-4-(trifluoromethyl)phenyl]-8-ethyl-9H-purine | C21H16ClF3N4 | 详情 | 详情 | |
(VII) | 38822 | 6-[2-chloro-4-(trifluoromethyl)phenyl]-8-ethyl-9H-purine | C14H10ClF3N4 | 详情 | 详情 | |
(VIII) | 38823 | dicyclopropylmethanol | 14300-33-5 | C7H12O | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号:(VI)Iodination of 5-amino-4,6-dichloropyrimidine (VI) by means of NaI in concentrated HI affords the diiodopyridine (VII). Sequential alkylation of aminopyrimidine (VII) with 2-chlorobenzyl bromide (VIII) to produce (IX), and further N-methylation with iodomethane and NaH, lead to the tertiary amine (X). Ammonolysis of the diiodopyrimidine (X) with ethanolic ammonia in a sealed tube at 80 C yields amine (XI). Finally, Sonogashira coupling between acetylene (V) and iodopyrimidine (XI) in the presence of Pd(PPh3)2Cl2 and CuI furnishes the target diaryl acetylene
【1】 Gomtsyan, A.; et al.; Design, synthesis, and structure-activity relationship of 6-alkynylpyrimidines as potent adenosine kinase inhibitors. J Med Chem 2002, 45, 17, 3639. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(V) | 60888 | 4-(5-ethynyl-2-pyridinyl)morpholine | C11H12N2O | 详情 | 详情 | |
(VI) | 22845 | 5-Amino-4,6-dichloropyrimidine; 4,6-dichloro-5-pyrimidinylamine; 4,6-dichloro-5-pyrimidinamine | 5413-85-4 | C4H3Cl2N3 | 详情 | 详情 |
(VII) | 60889 | 4,6-diiodo-5-pyrimidinamine; 4,6-diiodo-5-pyrimidinylamine | C4H3I2N3 | 详情 | 详情 | |
(VIII) | 53082 | 1-(Bromomethyl)-2-chlorobenzene; 2-Chloro-alpha-bromotoluene; 2-Chlorobenzyl bromide; Alpha-Bromo-2-chlorotoluene; o-Chlorobenzyl bromide | 611-17-6 | C7H6BrCl | 详情 | 详情 |
(IX) | 60890 | N-(2-chlorobenzyl)-4,6-diiodo-5-pyrimidinamine; N-(2-chlorobenzyl)-N-(4,6-diiodo-5-pyrimidinyl)amine | C11H8ClI2N3 | 详情 | 详情 | |
(X) | 60891 | N-(2-chlorobenzyl)-4,6-diiodo-N-methyl-5-pyrimidinamine; N-(2-chlorobenzyl)-N-(4,6-diiodo-5-pyrimidinyl)-N-methylamine | C12H10ClI2N3 | 详情 | 详情 | |
(XI) | 60892 | N-(4-amino-6-iodo-5-pyrimidinyl)-N-(2-chlorobenzyl)-N-methylamine; N~5~-(2-chlorobenzyl)-6-iodo-N~5~-methyl-4,5-pyrimidinediamine | C12H12ClIN4 | 详情 | 详情 |