1-(Chloromethyl)naphthalene -Drug Synthesis Database

【结构式】

【分子编号】27408

【品名】1-(Chloromethyl)naphthalene

【CA登记号】86-52-2

【分子式】C₁₁H₉Cl

【分子量】176.64516

【元素组成】C 74.79% H 5.14% Cl 20.07%

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)

By condensation of 1-(chloromethyl)naphthalene (I) with N-(4-tert-butylbenzyl)-N-methylamine (II) by means of sodium carbonate in hot DMF.

参考文献中间体

合成目标

【1】 Maeda, T.; Koshikawa, S.; Yamamoto, T.; Sasaki, K.; Yokoo, M.; Amemiya, K.; Hashimoto, R.; Arika, T.; Takase, M. (Kaken Pharmaceutical Co., Ltd.); Amine derivs. and fungicides containing the same. US 5021458 .

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)	27408	1-(Chloromethyl)naphthalene	86-52-2	C₁₁H₉Cl	详情	详情
(II)	40524	[4-(tert-butyl)phenyl]-N-methylmethanamine; N-[4-(tert-butyl)benzyl]-N-methylamine		C₁₂H₁₉N	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IX)

The esterification of (2R,4R)-4-hydroxypyrrolidine-2-carboxylic acid (I) with ethanol and sulfuric acid gives the expected ethyl ester (II), which is N-protected with benzyl bromide and DIEA in dichloromethane to the N-benzyl derivative (III). The oxidation of (III) with oxalyl chloride in DMSO affords the pyrrolidinone (IV), which is cyclized with ammonium carbamate and KCN in hot ethanol/water to afford the spiro imidazolidinedione (V). Opening of the imidazolidinedione ring of (V) with refluxing 3N NaOH, followed by esterification with ethanol/SOCl2 provides (2R,4R)-4-amino-1-benzylpyrrolidine-2,4-dicarboxylic acid diethyl ester (VI), which is protected at the amino group with tert-butoxycarbonyl anhydride giving the carbamate (VII) (1). Hydrogenolysis of the N-benzyl group of (VII) in the presence of Pd/C yields (VIII) with a free imino group, which is alkylated with 1-(chloromethyl)naphthalene (IX) by means of DIEA and Bu4NI affording the naphthylmethyl derivative (X). Removal of the Boc protecting group of (X) with HCl in ethyl ether gives (2R,4R)-4-amino-1-(1-naphthylmethyl)pyrrolidine-2,4-dicarboxylic acid diethyl ester (XI), which is finally hydrolyzed with NaOH to the target diacid (2).

参考文献中间体

合成目标

【1】 Valli, M.J.; Schoepp, D.D.; Wright, R.A.; Johnson, B.G.; Kingston, A.E.; Tomlinson, R.; Monn, J.A.; Synthesis and metabotropic glutamate receptor antagonist activity of N'-substituted analogs of 2R,4R-4-aminopyrrolidine-2,4-dicarboxylic acid. Bioorg Med Chem Lett 1998, 8, 15, 1985.
【2】 Monn, J.A.; et al.; Synthesis of the four isomers of 4-aminopyrrolidine-2,4-dicarboxylate: Identification of a potent, highly selective, and systemically-active agonist for metabotropic glutamate receptors negatively coupled to adenylate cyclase. J Med Chem 1996, 39, 15, 2990.

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)	27400	(2R,4R)-4-hydroxy-2-pyrrolidinecarboxylic acid		C₅H₉NO₃	详情	详情
(II)	27401	ethyl (2R,4R)-4-hydroxy-2-pyrrolidinecarboxylate		C₇H₁₃NO₃	详情	详情
(III)	27402	ethyl (2R,4R)-1-benzyl-4-hydroxy-2-pyrrolidinecarboxylate		C₁₄H₁₉NO₃	详情	详情
(IV)	27403	ethyl (2R)-1-benzyl-4-oxo-2-pyrrolidinecarboxylate		C₁₄H₁₇NO₃	详情	详情
(V)	27404	ethyl (8R)-7-benzyl-2,4-dioxo-1,3,7-triazaspiro[4.4]nonane-8-carboxylate		C₁₆H₁₉N₃O₄	详情	详情
(VI)	27405	diethyl (2R,4R)-4-amino-1-benzyl-2,4-pyrrolidinedicarboxylate		C₁₇H₂₄N₂O₄	详情	详情
(VII)	27406	diethyl (2R,4R)-1-benzyl-4-[(tert-butoxycarbonyl)amino]-2,4-pyrrolidinedicarboxylate		C₂₂H₃₂N₂O₆	详情	详情
(VIII)	27407	diethyl (2R,4R)-4-[(tert-butoxycarbonyl)amino]-2,4-pyrrolidinedicarboxylate		C₁₅H₂₆N₂O₆	详情	详情
(IX)	27408	1-(Chloromethyl)naphthalene	86-52-2	C₁₁H₉Cl	详情	详情
(X)	27409	diethyl (2R,4R)-4-[(tert-butoxycarbonyl)amino]-1-(1-naphthylmethyl)-2,4-pyrrolidinedicarboxylate		C₂₆H₃₄N₂O₆	详情	详情
(XI)	27410	diethyl (2R,4R)-4-amino-1-(1-naphthylmethyl)-2,4-pyrrolidinedicarboxylate		C₂₁H₂₆N₂O₄	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VIII)

Solution synthesis: In this case the target product is obtained by alkylation of 1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one (VII) with 1-(chloromethyl)naphthalene (VIII) by means of K2CO3 and NaI in refluxing 2-butanone, followed by acylation with methyl bromoacetate (X) in DMF by means of NaH.

参考文献中间体

合成目标

【1】 Watson, B.; Thomsen, C.; Hohlweg, R. (Novo Nordisk A/S); Novel 1,3,8-triazaspiro[4.5]decanones with high affinity for opioid receptor subtypes. EP 1080091; WO 9959997 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VII)	18116	1-Phenyl-1,3,8-triazaspiro[4.5]decan-4-one	1021-25-6	C₁₃H₁₇N₃O	详情	详情
(VIII)	27408	1-(Chloromethyl)naphthalene	86-52-2	C₁₁H₉Cl	详情	详情
(IX)	47326	8-(1-naphthylmethyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one		C₂₄H₂₅N₃O	详情	详情
(X)	12309	methyl 2-bromoacetate; methyl bromoacetate	96-32-2	C₃H₅BrO₂	详情	详情

Extended Information