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【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%

与该中间体有关的原料药合成路线共 3 条

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
Extended Information