【结 构 式】 |
【分子编号】17643 【品名】(Chloromethylene)dimethylammonium chloride; N-(chloromethylene)-N-methylmethanaminium chloride 【CA登记号】3724-43-4 |
【 分 子 式 】C3H7Cl2N 【 分 子 量 】128.00072 【元素组成】C 28.15% H 5.51% Cl 55.39% N 10.94% |
合成路线1
该中间体在本合成路线中的序号:(II)1) The reaction of 4,6-dihydroxypyrimidine-2,5-diamine (I) with (chloromethylene)dimethylammonium chloride (II) in refluxing chloroform gives 4,6-dichloro-2,5-bis(dimethylaminomethyleneamino)pyrimidine (III), which by reaction with aqueous HCl in hot ethanol yields monoamine (IV). The reaction of (IV) with a refluxing phosphate buffer (pH 3.2) affords N-(2-amino-4,6-dichloropyrimidin-5-yl)formamide (V). The condensation of (V) with (1S,4R)-4-amino-2-cyclopentene-1-methanol (VI) (which was obtained by optical resolution of the cis-racemate (VII) with D-dibenzoyltartaric acid, and elimination of the acid with ion exchange resin Amberlite IA-400, by means of triethylamine and NaOH in refluxing ethanol) gives N-[2-amino-4-chloro-6-[4(S)-(hydroxymethyl)-2-cyclopenten-1(R)-ylamino]pyrimidin-5-yl]formamide (VIII). The cyclization of (VIII) with refluxing diethoxymethyl acetate or triethyl orthoformate yields the corresponding purine derivative (IX), which is finally treated with cyclopropylamine (X) in refluxing n-butanol. 2) The formylation of N-(5-amino-4,6-dichloropyrimidin-2-yl)acetamide (XI) with 95% formic acid in acetic anhydride gives the expected formamide (XII), which is condensed with (1S,4R)-4-amino-2-cyclopentene-1-methanol (VI) by means of triethylamine in hot ethanol to yield the substituted pyrimidine (XIII). Finally, the cyclization of (XIII) with diethoxymethyl acetate as before affords the purine intermediate (IX).
【1】 Graul, A.; Castaner, J.; Leeson, P.A.; Abacavir Sulfate. Drugs Fut 1998, 23, 11, 1155-1167. |
【2】 Daluge, S.M. (Glaxo Wellcome plc); Therapeutic nucleosides. EP 0434450; JP 1996092252; JP 1999158160; JP 1999343292 . |
【3】 Daluge, S.M. (Glaxo Wellcome plc); Therapeutic nucleosides. AU 8937025; EP 0349242; JP 1990045486; JP 1999139976; US 5034394; US 5089500 . |
【4】 Daluge, S.M.; Martin, M.T.; Fugett, M.J.F.; Chloropyrimide intermediates. WO 9521161 . |
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) | 17642 | 2,5-diamino-4,6-pyrimidinediol | C4H6N4O2 | 详情 | 详情 | |
(II) | 17643 | (Chloromethylene)dimethylammonium chloride; N-(chloromethylene)-N-methylmethanaminium chloride | 3724-43-4 | C3H7Cl2N | 详情 | 详情 |
(III) | 17644 | N'-(4,6-dichloro-2-[[(E)-(dimethylamino)methylidene]amino]-5-pyrimidinyl)-N,N-dimethyliminoformamide | C10H14Cl2N6 | 详情 | 详情 | |
(IV) | 17645 | N'-(2-amino-4,6-dichloro-5-pyrimidinyl)-N,N-dimethyliminoformamide | C7H9Cl2N5 | 详情 | 详情 | |
(V) | 17646 | 2-amino-4,6-dichloro-5-pyrimidinylformamide | C5H4Cl2N4O | 详情 | 详情 | |
(VI) | 17647 | [(1S,4R)-4-amino-2-cyclopenten-1-yl]methanol | C6H11NO | 详情 | 详情 | |
(VII) | 63843 | (rac)-[(1R*,4S*)-4-amino-2-cyclopenten-1-yl]methanol | C6H11NO | 详情 | 详情 | |
(VIII) | 17649 | 2-amino-4-chloro-6-[[(1R,4S)-4-(hydroxymethyl)-2-cyclopenten-1-yl]amino]-5-pyrimidinylformamide | C11H14ClN5O2 | 详情 | 详情 | |
(IX) | 17650 | [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol | C11H12ClN5O | 详情 | 详情 | |
(X) | 12263 | Cyclopropylamine; Cyclopropanamine | 765-30-0 | C3H7N | 详情 | 详情 |
(XI) | 17652 | N-(5-amino-4,6-dichloro-2-pyrimidinyl)acetamide | C6H6Cl2N4O | 详情 | 详情 | |
(XII) | 17653 | N-[4,6-dichloro-5-(formylamino)-2-pyrimidinyl]acetamide | C7H6Cl2N4O2 | 详情 | 详情 | |
(XIII) | 17654 | N-(4-chloro-5-(formylamino)-6-[[(1R,4S)-4-(hydroxymethyl)-2-cyclopenten-1-yl]amino]-2-pyrimidinyl)acetamide | C13H16ClN5O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(XIII)Addition of ethyl diazoacetate (II) to 2,3-dibromopropene (I) in the presence of dirhodium tetraacetate furnished ethyl 2-bromo-2-(bromomethyl)cyclopropane-1-carboxylate (III) as a mixture of cis- and trans-isomers. Subsequent condensation of the dibromo ester (III) with the sodium salt of adenine (IV) produced adduct (V) as a diastereomeric mixture. Then, elimination of HBr using potassium tert-butoxide gave olefin (VIa-b). Alternatively, a direct synthesis of (VIa-b) was carried out by reaction of adenine (IV) with dibromo ester (III) in the presence of K2CO3 in hot DMF. Reduction of ester (VIa-b) with diisobutylaluminum hydride afforded alcohol (VIIa-b) as a mixture of syn- and anti-isomers. Isolation of the desired syn-isomer (VIII) was achieved by conversion to the corresponding formamidines, followed by chromatographic separation. The formamidine function of (VIII) was then hydrolyzed with methanolic ammonia to yield the racemic synadenol (IX). Incubation of (IX) with adenosine deaminase converted the (S)-enantiomer to the hypoxanthine derivative (XI), which was separated from the unreacted (R)-synadenol (X) by column chromatography. Acetylation of alcohol (XI) with Ac2O in pyridine provided ester (XII). Chloropurine derivative (XIV) was then obtained by treatment of (XII) with N,N-dimethylamino(chloromethylene)ammonium chloride (XIII) in CHCl3. Finally, chloride displacement in (XIV) and simultaneous ester cleavage with methanolic ammonia in a pressure vessel gave rise to the title compound.
【1】 Drach, J.C.; Zemlicka, J.; Ptak, R.G.; Qiu, Y.-L. (University of Michigan; Wayne State University); 2-Hydroxy methylcyclopropylidenemethyl purines and -pyrimidines as antiviral agents. WO 0053603 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(VIa),(IX) | 21754 | ethyl 2-[(Z)-(6-amino-9H-purin-9-yl)methylidene]cyclopropanecarboxylate | C12H13N5O2 | 详情 | 详情 | |
(VIb) | 21755 | ethyl 2-[(E)-(6-amino-9H-purin-9-yl)methylidene]cyclopropanecarboxylate | C12H13N5O2 | 详情 | 详情 | |
(VIIa) | 21756 | [2-[(Z)-(6-amino-9H-purin-9-yl)methylidene]cyclopropyl]methanol | C10H11N5O | 详情 | 详情 | |
(VIIb) | 21757 | [2-[(E)-(6-amino-9H-purin-9-yl)methylidene]cyclopropyl]methanol | C10H11N5O | 详情 | 详情 | |
(I) | 21748 | 2,3-dibromo-1-propene | 513-31-5 | C3H4Br2 | 详情 | 详情 |
(II) | 15911 | Ethyldiazoacetate; ethyl 2-diazoacetate | 623-73-4 | C4H6N2O2 | 详情 | 详情 |
(III) | 42613 | ethyl 2-bromo-2-(bromomethyl)cyclopropanecarboxylate | C7H10Br2O2 | 详情 | 详情 | |
(IV) | 10343 | 9H-Purin-6-amine; 9H-Purin-6-ylamine; Adenine | 73-24-5 | C5H5N5 | 详情 | 详情 |
(V) | 48356 | ethyl 2-[(6-amino-9H-purin-9-yl)methyl]-2-bromocyclopropanecarboxylate | C12H14BrN5O2 | 详情 | 详情 | |
(VIII) | 21758 | N'-(9-[[2-(hydroxymethyl)cyclopropylidene]methyl]-9H-purin-6-yl)-N,N-dimethyliminoformamide | C13H16N6O | 详情 | 详情 | |
(X) | 21781 | [(1R)-2-[(E)-(6-amino-9H-purin-9-yl)methylidene]cyclopropyl]methanol | C10H11N5O | 详情 | 详情 | |
(XI) | 21759 | 9-[[(2S)-2-(hydroxymethyl)cyclopropylidene]methyl]-1,9-dihydro-6H-purin-6-one | C10H10N4O2 | 详情 | 详情 | |
(XII) | 48357 | [(1S)-2-[(Z)-(6-oxo-1,6-dihydro-9H-purin-9-yl)methylidene]cyclopropyl]methyl acetate | C12H12N4O3 | 详情 | 详情 | |
(XIII) | 17643 | (Chloromethylene)dimethylammonium chloride; N-(chloromethylene)-N-methylmethanaminium chloride | 3724-43-4 | C3H7Cl2N | 详情 | 详情 |
(XIV) | 48358 | [(1S)-2-[(Z)-(6-chloro-9H-purin-9-yl)methylidene]cyclopropyl]methyl acetate | C12H11ClN4O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(VII)
【1】 Jin QW, Mnuragis MA, May PD. 2003. Process for preparing aminocarbonylpyrrolylmethylideneindolinones from indolinones, imidazolcarbonylpyrrolecarboxaldehydes, and amines. W0 2003070725 |
【2】 Manley JM, Kalman MJ, Conway BG, et al. 2003. Early amidation approach to 3-[(4-anudo)pyrrol-2-yl]-2-indolinones. J Org Cbem, 68(16):6447~6450 |
【3】 Wang JQ, Miller KD, Sledge GW, et aL. 2005. Synthesis of [18F] SU11248, a new potential PET tracer for imaging cancer tyrosine kinase. Bioorg Med Chem lett, 15(19): 4380~4384 |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(IX) | 60384 | 5-fluoro-1,3-dihydro-2H-indol-2-one | 56341-41-4 | C8H6FNO | 详情 | 详情 |
(I) | 11367 | 4-Methylene-2-oxetanone; Acetyl ketene | 674-82-8 | C4H4O2 | 详情 | 详情 |
(II) | 66748 | N-(2-(diethylamino)ethyl)-3-oxobutanamide | C10H20N2O2 | 详情 | 详情 | |
(III) | 27907 | Acetoacetic acid tert-butyl ester;3-Oxo-butanoic acid 1,1-dimethylethyl estertert-butyl 3-oxobutanoate | 1694-31-1 | C8H14O3 | 详情 | 详情 |
(IV) | 63353 | 1,1-dimethylethyl 2-(hydroxyimino)-3-oxobutanoate | 14352-65-9 | C8H13NO4 | 详情 | 详情 |
(V) | 66749 | tert-butyl 4-((2-(diethylamino)ethyl)carbamoyl)-3,5-dimethyl-1H-pyrrole-2-carboxylate | C18H31N3O3 | 详情 | 详情 | |
(VI) | 66750 | N-(2-(diethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide | C13H23N3O | 详情 | 详情 | |
(VII) | 17643 | (Chloromethylene)dimethylammonium chloride; N-(chloromethylene)-N-methylmethanaminium chloride | 3724-43-4 | C3H7Cl2N | 详情 | 详情 |
(VIII) | 66751 | N-((4-((2-(diethylamino)ethyl)carbamoyl)-3,5-dimethyl-1H-pyrrol-2-yl)methylene)-N-methylmethanaminium chloride | C16H29ClN4O | 详情 | 详情 | |
(X) | 66752 | (Z)-N-[2-(Diethylamino)ethyl]-5-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide | 326914-13-0 | C22H27FN4O2 | 详情 | 详情 |