1,3-benzodioxol-5-ylmethylamine; 1,3-benzodioxol-5-ylmethanamine; 3,4-Methylendioxybenzylamine -Drug Synthesis Database

【结构式】

【分子编号】33669

【品名】1,3-benzodioxol-5-ylmethylamine; 1,3-benzodioxol-5-ylmethanamine; 3,4-Methylendioxybenzylamine

【CA登记号】2620-50-0

【分子式】C₈H₉NO₂

【分子量】151.165

【元素组成】C 63.56% H 6% N 9.27% O 21.17%

与该中间体有关的原料药合成路线共 4 条

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

该中间体在本合成路线中的序号：(I)

The condensation of piperonylamine (I) with dihydroxyacetone dimer (II) in the presence of potassium thiocyanate produced the mercaptoimidazole (III), which was desulfurized upon treatment with nitric acid and sodium nitrite. The resulting (hydroxymethyl)imidazole (IV) was then converted to the corresponding chloride (V) employing thionyl chloride in chloroform.

参考文献中间体

合成目标

【1】 Lee, J.; Lee, H.; Shin, Y.; et al.; Synthesis and structure-activity relationships of 1-(1(3)H-imidazole-5(4)-yl)-methylpyrroles as farnesyl protein transferase inhibitors (FTPI). 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 210.
【2】 Lee, J.H.; Yoo, J.K.; Koh, J.S.; Choi, T.S.; Shin, Y.S.; Kim, K.H.; Jung, W.H.; Kim, J.H.; Lee, S.H.; Ahn, I.A.; Ro, S.G.; Lee, H.I.; Kim, H.S.; Chung, H.H.; Jeong, S.W.; Kwak, T.H. (LG Chem Ltd.); Imidazole derivs. having an inhibitory activity for farnesyl transferase and process for preparation thereof. WO 9928315 .

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)	33669	1,3-benzodioxol-5-ylmethylamine; 1,3-benzodioxol-5-ylmethanamine; 3,4-Methylendioxybenzylamine	2620-50-0	C₈H₉NO₂	详情	详情
(II)	20067	2,5-bis(hydroxymethyl)-1,4-dioxane-2,5-diol	89727-88-8	C₆H₁₂O₆	详情	详情
(III)	33670	[1-(1,3-benzodioxol-5-ylmethyl)-2-sulfanyl-1H-imidazol-5-yl]methanol		C₁₂H₁₂N₂O₃S	详情	详情
(IV)	33671	[1-(1,3-benzodioxol-5-ylmethyl)-1H-imidazol-5-yl]methanol		C₁₂H₁₂N₂O₃	详情	详情
(V)	33672	1-(1,3-benzodioxol-5-ylmethyl)-5-(chloromethyl)-1H-imidazole		C₁₂H₁₁ClN₂O₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XXI)

Cyclohexylalanine (XIV) was protected as the Boc derivative (XV) and then coupled with N,O-dimethylhydroxylamine to produce the Weinreb amide (XVI). Reduction of (XVI) with LiAlH4 at -78 C gave aldehyde (XVII) and subsequent addition of tert-butyl isonitrile furnished hydroxy amide (XVIII). After acid hydrolysis of (XVIII), amino acid (XIX) was protected as the N-Boc derivative (XX). This was coupled with benzodioxolylmethyl amine (XXI) yielding amide (XXII). Acid deprotection of the Boc group of (XXII) gave (XXIII), which was further coupled with dipeptide (VII) to generate tripeptide amide (XXIV). Following hydrogenolytic deprotection of the N-nitro group of (XXIV), Swern oxidation of the alcohol group gave rise to the title compound.

参考文献中间体

合成目标

【1】 Semple, J.E.; et al.; Novel, potent, and selective factor Xa inhibitors featuring a hydrophobic P1-ketoamide moiety. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 193.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XXIII	39362	(3S)-3-amino-N-(1,3-benzodioxol-5-ylmethyl)-4-cyclohexyl-2-hydroxybutanamide		C₁₈H₂₆N₂O₄	详情	详情
(VII)	39350			C₁₆H₂₄N₆O₇S	详情	详情
(XIV)	39357	(2S)-2-amino-3-cyclohexylpropionic acid; L-Cyclohexylalanine	27527-05-5	C₉H₁₇NO₂	详情	详情
(XV)	23050	(2S)-2-[(tert-butoxycarbonyl)amino]-3-cyclohexylpropionic acid		C₁₄H₂₅NO₄	详情	详情
(XVI)	39358	tert-butyl (1S)-1-(cyclohexylmethyl)-2-[methoxy(methyl)amino]-2-oxoethylcarbamate		C₁₆H₃₀N₂O₄	详情	详情
(XVII)	15853	tert-butyl N-[(1S)-2-cyclohexyl-1-formylethyl]carbamate		C₁₄H₂₅NO₃	详情	详情
(XVIII)	39359	tert-butyl (1S)-3-(tert-butylamino)-1-(cyclohexylmethyl)-2-hydroxy-3-oxopropylcarbamate		C₁₉H₃₆N₂O₄	详情	详情
(XIX)	12329	(2R,3S)-3-Amino-4-cyclohexyl-2-hydroxybutyric acid		C₁₀H₁₉NO₃	详情	详情
(XX)	39360	(3S)-3-[(tert-butoxycarbonyl)amino]-4-cyclohexyl-2-hydroxybutyric acid		C₁₅H₂₇NO₅	详情	详情
(XXI)	33669	1,3-benzodioxol-5-ylmethylamine; 1,3-benzodioxol-5-ylmethanamine; 3,4-Methylendioxybenzylamine	2620-50-0	C₈H₉NO₂	详情	详情
(XXII)	39361	tert-butyl (1S)-3-[(1,3-benzodioxol-5-ylmethyl)amino]-1-(cyclohexylmethyl)-2-hydroxy-3-oxopropylcarbamate		C₂₃H₃₄N₂O₆	详情	详情
(XXIV)	39363			C₃₄H₄₈N₈O₁₀S	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VIII)

3-Hydroxy-4-methoxy-2-nitrobenzaldehyde (II) was prepared by nitration of isovanillin (I) with fuming nitric acid in cold HOAc. Subsequent alkylation of the phenolic hydroxyl of (II) with n-pentyl bromide yielded the corresponding pentyl ether (III). The nitro group of (III) was then reduced to amine (IV) employing tin chloride in EtOH. Condensation of amino aldehyde (IV) with dimethyl malonate under Knoevenagel conditions furnished the quinolinone derivative (V). Saponification of the ester group of (V), followed by activation of the resultant carboxylic acid (VI) with SOCl2, gave rise to the acid chloride (VII). This was then coupled with 3,4-(methylenedioxy)benzylamine (VIII) to provide the target amide.

参考文献中间体

合成目标

【1】 Inaba, T.; Kaya, T.; Iwamura, H. (Japan Tobacco Inc.); 2-Oxoquinoline cpds. and medicinal uses thereof. EP 1142877; JP 2000256323; WO 0040562 .

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)	18455	3-hydroxy-4-methoxybenzaldehyde; Isovanillin	621-59-0	C₈H₈O₃	详情	详情
(II)	56017	3-Hydroxy-4-methoxy-2-nitrobenzaldehyde	6284-92-0	C₈H₇NO₅	详情	详情
(III)	56018	4-methoxy-2-nitro-3-(pentyloxy)benzaldehyde		C₁₃H₁₇NO₅	详情	详情
(IV)	56019	2-amino-4-methoxy-3-(pentyloxy)benzaldehyde		C₁₃H₁₉NO₃	详情	详情
(V)	56020	methyl 7-methoxy-2-oxo-8-(pentyloxy)-1,2-dihydro-3-quinolinecarboxylate		C₁₇H₂₁NO₅	详情	详情
(VI)	56021	7-methoxy-2-oxo-8-(pentyloxy)-1,2-dihydro-3-quinolinecarboxylic acid		C₁₆H₁₉NO₅	详情	详情
(VII)	56022	7-methoxy-2-oxo-8-(pentyloxy)-1,2-dihydro-3-quinolinecarbonyl chloride		C₁₆H₁₈ClNO₄	详情	详情
(VIII)	33669	1,3-benzodioxol-5-ylmethylamine; 1,3-benzodioxol-5-ylmethanamine; 3,4-Methylendioxybenzylamine	2620-50-0	C₈H₉NO₂	详情	详情

合成路线4

该中间体在本合成路线中的序号：(I)

The reaction of 1,3-benzodioxol-5-ylmethylamine (I) with acryloyl chloride (II) by means of TEA gives the acrylamide (III), which is reductocondensed with perhydroazepine (IV) by means of LiAlH4 or BH3/THF in THF to yield the secondary amine (V). Finally this compound is condensed with 5-chloro-3-(3,5-difluorophenyl)isoxazole (VI) by means of BuLi in diethyl ether to afford the target tertiary amine. The intermediate 5-chloro-3-(3,5-difluorophenyl)isoxazole (VI) has been obtained by two related ways: The condensation of 3.5-difluorobenzoyl chloride (VII) with malonic acid monoethyl ester (VIII) by means of BuLi gives 2-(3,5-difluorobenzoyl)acetic acid ethyl ester (IX), which is cyclized with hydroxylamine in HOAc to yield 3-(3,5-difluorophenyl)isoxazol-5-ol (X). Finally this compound is treated with POCl3 to afford the desired 5-chloro-3-(3,5-difluorophenyl)isoxazole (VI) intermediate. Alternatively, the reaction of 3,5-difluoroacetophenone (XI) with diethyl carbonate (XII) by means of NaH yields also the already reported intermediate 2-(3,5-difluorobenzoyl)acetic acid ethyl ester (IX)

参考文献中间体

合成目标

【1】 Nantermet, P.G.; et al.; Discovery of a nonpeptide small molecule antagonist of the human platelet thrombin receptor (PAR-1). Bioorg Med Chem Lett 2002, 12, 3, 319.
【2】 Freidinger, R.M.; Selnick, H.G.; Connolly, T.; Barrow, J.C.; Nantermet, P.G. (Merck & Co., Inc.); Isoxazole thrombin receptor antagonists. GB 2356198 .

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)	33669	1,3-benzodioxol-5-ylmethylamine; 1,3-benzodioxol-5-ylmethanamine; 3,4-Methylendioxybenzylamine	2620-50-0	C₈H₉NO₂	详情	详情
(II)	11577	Acryloyl chloride; Acrylyl chloride;2-Propenoyl chloride	814-68-6	C₃H₃ClO	详情	详情
(III)	56910	N-(1,3-benzodioxol-5-ylmethyl)acrylamide		C₁₁H₁₁NO₃	详情	详情
(IV)	18672	azepane	111-49-9	C₆H₁₃N	详情	详情
(V)	56911	3-(1-azepanyl)-N-(1,3-benzodioxol-5-ylmethyl)-1-propanamine; N-[3-(1-azepanyl)propyl]-N-(1,3-benzodioxol-5-ylmethyl)amine		C₁₇H₂₆N₂O₂	详情	详情
(VI)	56912	5-chloro-3-(3,5-difluorophenyl)isoxazole		C₉H₄ClF₂NO	详情	详情
(VII)	56913	3,5-Difluorobenzoyl chloride	129714-97-2	C₇H₃ClF₂O	详情	详情
(VIII)	15086	3-ethoxy-3-oxopropionic acid	1071-46-1	C₅H₈O₄	详情	详情
(IX)	56914	ethyl 3-(3,5-difluorophenyl)-3-oxopropanoate		C₁₁H₁₀F₂O₃	详情	详情
(X)	56915	3-(3,5-difluorophenyl)-5-isoxazolol		C₉H₅F₂NO₂	详情	详情
(XI)	56916	3,5-Difluoroacetophenone	123577-99-1	C₈H₆F₂O	详情	详情
(XII)	17470	diethyl carbonate; diethylcarbonate	105-58-8	C₅H₁₀O₃	详情	详情

Extended Information