1,3,5-triisopropylbenzene -Drug Synthesis Database

【结构式】

【分子编号】14888

【品名】1,3,5-triisopropylbenzene

【CA登记号】717-74-8

【分子式】C₁₅H₂₄

【分子量】204.35556

【元素组成】C 88.16% H 11.84%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(VIII)

SR 27417 (N-(2-dimethylaminoethyl)-N-(3-pyridinylmethyl)[4-(2,4,6-triisopropylphenyl)thiazol-2-yl]amine difumarate) was prepared via a convergent route. Reductive amination of N,N-dimethylaminoethanamine (I) and pyridyl-3-carboxaldehyde (II) by sodium borohydride gave the amine (III). Eaction of pivaloyl chloride (IV) and potassium thiocyanate in anhydrous acetone provided the pivaloyl isothiocyanate (V), which was condensed in situ with the amine (III) to afford the protected thiourea (VI). Chlorhydric hydrolysis of (IV) gave the thiourea (VII) with the bromoketene (IX) in refluxing ethanol led to SR 27417.

参考文献中间体

合成目标

【1】 Herbert, J.M.; Valette, G.; Bernat, A.; Savi, P.; Maffrand, J.P.; Le Fur, G.; SR 27417, a highly potent, selective and long-acting antagonist of the PAF receptor. Drugs Fut 1992, 17, 11, 1011.

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)	14881	N-(2-aminoethyl)-N,N-dimethylamine; N(1),N(1)-dimethyl-1,2-ethanediamine; 2-Dimethylaminoethylamine	108-00-9	C₄H₁₂N₂	详情	详情
(II)	12849	Nicotinaldehyde; 3-Pyridinecarboxaldehyde	500-22-1	C₆H₅NO	详情	详情
(III)	14883	N-[2-(dimethylamino)ethyl]-N-(3-pyridinylmethyl)amine; N(1),N(1)-dimethyl-N(2)-(3-pyridinylmethyl)-1,2-ethanediamine		C₁₀H₁₇N₃	详情	详情
(IV)	13597	2,2-Dimethylpropanoyl chloride; Pivaloyl chloride	3282-30-2	C₅H₉ClO	详情	详情
(V)	14885	2,2-dimethylpropanoyl isothiocyanate		C₆H₉NOS	详情	详情
(VI)	14886	N-[2-(dimethylamino)ethyl]-N'-(2,2-dimethylpropanoyl)-N-(3-pyridinylmethyl)thiourea		C₁₆H₂₆N₄OS	详情	详情
(VII)	14887	N-[2-(dimethylamino)ethyl]-N-(3-pyridinylmethyl)thiourea		C₁₁H₁₈N₄S	详情	详情
(VIII)	14888	1,3,5-triisopropylbenzene	717-74-8	C₁₅H₂₄	详情	详情
(IX)	14889	2-bromo-1-(2,4,6-triisopropylphenyl)-1-ethanone		C₁₇H₂₅BrO	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XI)

1) Synthesis of intermediate (V): The reduction of 2,4,6-triisopropylbenzoyl chloride (I) with LiAlH4 in ethyl ether gives 2,4,6-triisopropylbenzyl alcohol (II) (1-4), which by reaction with SOCl2 in toluene is converted into 2,4,6-triisopropylbenzyl chloride (III). The reaction of (III) with NaCN or KCN in DMSO affords 2,4,6-triisopropylphenylacetonitrile (IV), which is hydrolyzed with aqueous H2SO4 or KOH in diethylene glycol/water, yielding the phenylacetic acid (V). 2) Synthesis of intermediate (III): The intermediate benzyl chloride (III) can also be obtained by direct chloromethylation of 1,3,5-triisopropylbenzene (XI) with paraformaldehyde/HCl in acetic acid. 3) Synthesis of intermediate (V): Phenylacetic acid (V) can also be obtained by condensation of 1,3,5-triisopropylbenzene (XI) with glyoxylic acid (XIV) by means of H2SO4 in refluxing acetic acid, yielding a mixture of acetoxyacetic acid (XV) and hydroxyacetic acid (XVI). This mixture is finally reduced with HI in acetic acid to the phenylacetic acid (V). 4) Synthesis of intermediate (IV): The acetonitrile (IV) can also be obtained by reaction of benzyl bromide (XII) with KCN in DMSO. 5) Synthesis of intermediate (XIII): Avasimibe can also be obtained by reaction of benzyl alcohol (II) with PBr3 in ether to give the benzyl bromide (XII), which is treated with Mg in THF to yield the corresponding Grignard reagent (XIII).

参考文献中间体

合成目标

【1】 Sliskovic, D.R.; CI-1011: An atypical ACAT inhibitor with antiatherosclerotic activity. Int Symp Med Chem 1996, Abst SR-06.2.
【2】 Lee, H.T.; Sliskovic, D.R.; Picard, J.A.; et al.; Inhibitors of acyl-CoA:cholesterol O-acyl transferase (ACAT) as hypocholesterolemic agents. CI-1011: An acyl sulfamate with unique cholesterol-lowering activity in animals fed noncholesterol-supplemented diets. J Med Chem 1996, 39, 26, 5031.
【3】 Sorbera, L.A.; Rabasseda, X.; Castañer, J.; Avasimibe . Drugs Fut 1999, 24, 1, 9.
【4】 Lee, H.T.; Picad, J.A.; Sliskovic, D.R.; Wierenga, W. (Pfizer Inc.); N-Acyl sulfamic acid esters (or thioesters), N-acyl sulfonamides, and N-sulfonyl carbamic acid esters (or thioesters) as hypercholesterolemic agents. EP 0698010; JP 1996510256; US 5491172; WO 9426702 .
【5】 Dozeman, G.J.; et al.; Chemical development of a pilot scale process for the ACAT inhibitor 2,6-diisopropylphenyl [(2,4,6-triisopropylphenyl)acetyl]sulfamate. Org Process Res Dev 1997, 1, 2, 137-48.

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)	20236	2,4,6-triisopropylbenzoyl chloride	57199-00-5	C₁₆H₂₃ClO	详情	详情
(II)	20237	(2,4,6-triisopropylphenyl)methanol		C₁₆H₂₆O	详情	详情
(III)	20238	2-(chloromethyl)-1,3,5-triisopropylbenzene		C₁₆H₂₅Cl	详情	详情
(IV)	20239	2-(2,4,6-triisopropylphenyl)acetonitrile		C₁₇H₂₅N	详情	详情
(V)	20240	2-(2,4,6-triisopropylphenyl)acetic acid		C₁₇H₂₆O₂	详情	详情
(XI)	14888	1,3,5-triisopropylbenzene	717-74-8	C₁₅H₂₄	详情	详情
(XII)	20242	2-(bromomethyl)-1,3,5-triisopropylbenzene		C₁₆H₂₅Br	详情	详情
(XIII)	20243	bromo(2,4,6-triisopropylbenzyl)magnesium		C₁₆H₂₅BrMg	详情	详情
(XIV)	15168	methyl 2-chloro-2-fluorocyclopropanecarboxylate		C₅H₆ClFO₂	详情	详情
(XV)	20245	2-(acetoxy)-2-(2,4,6-triisopropylphenyl)acetic acid		C₁₉H₂₈O₄	详情	详情
(XVI)	20246	2-hydroxy-2-(2,4,6-triisopropylphenyl)acetic acid		C₁₇H₂₆O₃	详情	详情

Extended Information