4-Benzyl-2-(chloromethyl)morpholine -Drug Synthesis Database

【结构式】

【分子编号】13396

【品名】4-Benzyl-2-(chloromethyl)morpholine

【CA登记号】

【分子式】C₁₂H₁₆ClNO

【分子量】225.71788

【元素组成】C 63.85% H 7.14% Cl 15.71% N 6.21% O 7.09%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(I)

A new synthesis for Y-26611 has been reported: The reaction of 4-benzyl-2-(chloromethyl)morpholine (I) with potassium phthalimide (II) in refluxing DMF gives 4-benzyl-2-(phthalimidomethyl)morpholine (III), which is treated with hydrazine hydrate in refluxing ethanol yielding 2-(aminomethyl)-4-benzylmorpholine (IV). The acetylation of (IV) with acetic anhydride in cool toluene affords 2-(acetamidomethyl)-4-benzylmorpholine (V), which is debenzylated by hydrogenation with hydrazine hydrate over Pd/C in isopropanol to give 2-(acetamidomethyl)morpholine (VI). The condensation of (VI) with 1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (VII) by means of triethylamine in refluxing acetonitrile yields 7-[2-(acetamidomethyl)morpholin-4-yl]-1-cyclopropyl-6,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (VIII), which is finally deacetylated with refluxing aqueous HCl.

参考文献中间体

合成目标

【1】 Hirayama, F.; Yokoyama, Y.; Moriguchi, A.; Ikeda, Y.; Araki, K.; Iwao, E.; Uemori, S.; Yakushiji, T.; Kuroda, T.; Quinolone antimicrobial agents substituted with morpholines at the 7-position. Syntheses and structure-activity relationships. J Med Chem 1993, 36, 10, 1356.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	13396	4-Benzyl-2-(chloromethyl)morpholine	C₁₂H₁₆ClNO	详情	详情
(II)	10926	(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)potassium	C₈H₄KNO₂	详情	详情
(III)	13398	2-[(4-Benzyl-2-morpholinyl)methyl]-1H-isoindole-1,3(2H)-dione	C₂₀H₂₀N₂O₃	详情	详情
(IV)	13399	(4-Benzyl-2-morpholinyl)methylamine; (4-Benzyl-2-morpholinyl)methanamine	C₁₂H₁₈N₂O	详情	详情
(V)	13400	N-[(4-Benzyl-2-morpholinyl)methyl]acetamide	C₁₄H₂₀N₂O₂	详情	详情
(VI)	13401	N-(2-Morpholinylmethyl)acetamide	C₇H₁₄N₂O₂	详情	详情
(VII)	13393	1-Cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid	C₁₃H₈F₃NO₃	详情	详情
(VIII)	13403	7-[2-[(Acetamido)methyl]-4-morpholinyl]-1-cyclopropyl-6,8-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid	C₂₀H₂₁F₂N₃O₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

The condensation of 4-benzyl-2-(chloromethyl)morpholine (I) with 8-hydroxy-1,2,3,4-tetrahydroquinoline (II) by means of NaH in hot DMF gives 8-(4-benzylmorpholin-2-ylmethoxy)-1,2,3,4-tetrahydroquinoline (III), which is methylated with methyl iodide and K2CO3 in refluxing acetone yielding the corresponding N-methyl derivative (IV). Finally, this compound is debenzylated by hydrogenolysis with H2 over Pd/C in ethanol.

参考文献中间体

合成目标

【1】 Tracy, M.; Ngo, J.; Castaner, J.; Dabelotine Mesylate. Drugs Fut 1996, 21, 9, 890.
【2】 Regnier, G.; Guillonneau, C.; Lepagnol, J. (ADIR et Cie.); Novel morpholine derivs., process for their preparation and pharmaceutical compsns. containing them. AU 8813520; EP 0286495; FR 2612926; JP 1988255279; US 4782054 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	13396	4-Benzyl-2-(chloromethyl)morpholine	C₁₂H₁₆ClNO	详情	详情
(II)	16022	1,2,3,4-tetrahydro-8-quinolinol	C₉H₁₁NO	详情	详情
(III)	16023	(4-benzyl-1,4-oxazinan-2-yl)methyl 1,2,3,4-tetrahydro-8-quinolinyl ether; 8-[(4-benzyl-1,4-oxazinan-2-yl)methoxy]-1,2,3,4-tetrahydroquinoline	C₂₁H₂₆N₂O₂	详情	详情
(IV)	16024	8-[(4-benzyl-1,4-oxazinan-2-yl)methoxy]-1-methyl-1,2,3,4-tetrahydroquinoline; (4-benzyl-1,4-oxazinan-2-yl)methyl 1-methyl-1,2,3,4-tetrahydro-8-quinolinyl ether	C₂₂H₂₈N₂O₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(III)

Condensation of epichlorohydrin (I) with N-benzylethanolamine (II) in the presence of sulfuric acid afforded the (chloromethyl)morpholine (III). Halogen displacement in (III) by potassium phthalimide (IV) provided the substituted phthalimide (V). Further hydrazinolysis of (V) furnished racemic (aminomethyl)morpholine (VI) (1). The desired (S) enantiomer (VII) was obtained by crystallization of (VI) as the dibenzoyl-D-tartaric acid salt, followed by liberation of the base with NaOH. Eschweiler-Clarke reductive methylation of (VII) with formaldehyde and formic acid produced the dimethylamino derivative (VIII). The N-benzyl groupof (VIII) was then cleaved by transfer hydrogenation in the presence of hydrazine and Pd/C yielding chiral morpholine (IX). Finally, coupling of this morpholine (IX) with the difluoroqyuinolone boron chelate (X) provided the title morpholino quinolone.

参考文献中间体

合成目标

【1】 Sakurai, N.; Sano, M.; Hirayama, F.; Kuroda, T.; Uemori, S.; Moriguchi, A.; Yamamoto, K.; Ikeda, Y.; Kawakita, T.; Synthesis and structure-activity relationships of 7-(2-aminoalkyl)morpholinoquinolones as anti-Helicobacter pylori agents. Bioorg Med Chem Lett 1998, 8, 16, 2185.
【2】 Uemori, S.; Hirayama, F.; Moriguchi, A.; Sano, M.; Yokoyama, Y.; Ikeda, Y.; Miyoshi, M.; Sakurai, N.; Yamamoto, K.; Kawakita, T.; Synthesis and anti-Helicobacter pylori activity of Y-34867, a new 7-morpholinoquinolone. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-85.

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)	10146	Epichlorohydrin; 2-(Chloromethyl)oxirane	106-89-8	C₃H₅ClO	详情	详情
(II)	25630	2-(benzylamino)-1-ethanol	104-63-2	C₉H₁₃NO	详情	详情
(III)	13396	4-Benzyl-2-(chloromethyl)morpholine		C₁₂H₁₆ClNO	详情	详情
(IV)	10926	(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)potassium		C₈H₄KNO₂	详情	详情
(V)	13398	2-[(4-Benzyl-2-morpholinyl)methyl]-1H-isoindole-1,3(2H)-dione		C₂₀H₂₀N₂O₃	详情	详情
(VI)	13399	(4-Benzyl-2-morpholinyl)methylamine; (4-Benzyl-2-morpholinyl)methanamine		C₁₂H₁₈N₂O	详情	详情
(VII)	25362	1,4,8,11-Tetraazacyclotetradecane	295-37-4	C₁₀H₂₄N₄	详情	详情
(VIII)	25633	N-[[(2S)-4-benzylmorpholinyl]methyl]-N,N-dimethylamine		C₁₄H₂₂N₂O	详情	详情
(IX)	25634	N,N-dimethyl-N-[(2R)morpholinylmethyl]amine		C₇H₁₆N₂O	详情	详情
(X)	25635	1-Cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid diacetoxyboron complex		C₁₈H₁₆BF₂NO₈	详情	详情

Extended Information