1-(chloromethyl)cyclopropane -Drug Synthesis Database

【结构式】

【分子编号】29776

【品名】1-(chloromethyl)cyclopropane

【CA登记号】5911-08-0

【分子式】C₄H₇Cl

【分子量】90.55228

【元素组成】C 53.06% H 7.79% Cl 39.15%

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：(V)

The alkylation of 4-benzyloxyphenol (I) with 2-(cyclopropylmethoxy)ethyl mesylate (II) by means of NaOCH3 in refluxing methanol gives 4-[2-(cyclopropylmethoxy)-1-ethoxy]phenylmethoxybenzene (III), which is debenzylated by hydrogenolysis with H2 over PdC in methanol yielding 4-[2-(cyclopropylmethoxy)-1-ethoxy]phenol (IV). The treatment of (IV) with epichlorohydrin (V) in aqueous NaOH affords 1-[4-[2-(cyclopropylmethoxy)ethoxyphenoxy]-2,3-epoxy]propane (VI). Finally, this compound is treated with an excess of isopropylamine at room temperature to yield cicloprolol.

参考文献中间体

合成目标

【1】 Leclerc, G.; Cicloprolol Hydrocloride. Drugs Fut 1985, 10, 12, 975.

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)	29332	(6E,10E)-3,7,11,15-tetramethyl-6,10,14-hexadecatrienoic acid		C₂₀H₃₄O₂	详情	详情
(II)	18956	4-(Benzyloxy)phenol; 4-Benzyloxyphenol	103-16-2	C₁₃H₁₂O₂	详情	详情
(III)	29833	benzyl 4-[2-(cyclopropylmethoxy)ethoxy]phenyl ether; 1-(benzyloxy)-4-[2-(cyclopropylmethoxy)ethoxy]benzene		C₁₉H₂₂O₃	详情	详情
(IV)	29834	4-[2-(cyclopropylmethoxy)ethoxy]phenol		C₁₂H₁₆O₃	详情	详情
(V)	29776	1-(chloromethyl)cyclopropane	5911-08-0	C₄H₇Cl	详情	详情
(VI)	29835	2-([4-[2-(cyclopropylmethoxy)ethoxy]phenoxy]methyl)oxirane; 4-[2-(cyclopropylmethoxy)ethoxy]phenyl 2-oxiranylmethyl ether		C₁₅H₂₀O₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(Ia)

The reaction of cyclopropylmethyl chloride or cyclopropylmethyl bromide (Ia-b) with piperazine (II) by means of Na2CO3 in anhydrous DMF gives N,N-dicyclopropylmethylpiperazine.

参考文献中间体

合成目标

【1】 Robba, M.F.; Aurousseau, M.E. (Laboratoire Innothera SA); Cyclopropylmethyl piperazines, the process for preparing the same and their use in therapeutics. CA 1171085; EP 81401516; FR 8021527; JP 163681; US 4474783 .
【2】 Leclerc, G.; INO-2628 CZ. Drugs Fut 1985, 10, 11, 907.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(Ib)	22277	Cyclopropyl bromide; 1-(Bromomethyl)cyclopropane	7051-34-5	C₄H₇Br	详情	详情
(Ia)	29776	1-(chloromethyl)cyclopropane	5911-08-0	C₄H₇Cl	详情	详情
(II)	10355	Diethylenediamine; Piperazine	110-85-0	C₄H₁₀N₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(V)

The condensation of 4-ethoxyaniline (II) with N,N-diethylcarbamoyl chloride (II) by means of KHCO3 gives the urea (III), which is acylated with acetyl chloride and AlCl3 to yield N-(3-acetyl-4-hydroxyphenyl)-N',N'-diethylurea (IV). The alkylation of (IV) with epichlorohydrin (V) affords the adduct (VI), which is treated with HBr providing the bromoalcohol (VII). Finally this compound is treated with tert-butylamine to furnish the target urea.

参考文献中间体

合成目标

【1】 Zolss, G.; On the synthesis of the cardioselective beta-adrenergic receptor blocking agent celiprolol. Arzneim-Forsch Drug Res 1983, 33, 1a, 2.

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)	45939	4-Aminophenetole; 1-Amino-4-ethoxybenzene; 4-Aminoethoxybenzene; 4-Ethoxyphenylamine; p-Phenetidine; 4-Ethoxyaniline	156-43-4	C₈H₁₁NO	详情	详情
(II)	33816	N,N'-Diethylcarbamoyl chloride; 1-[(chlorocarbonyl)(ethyl)amino]ethane	88-10-8	C₅H₁₀ClNO	详情	详情
(III)	45940	N'-(4-ethoxyphenyl)-N,N-diethylurea		C₁₃H₂₀N₂O₂	详情	详情
(IV)	33817	N'-(3-acetyl-4-hydroxyphenyl)-N,N-diethylurea		C₁₃H₁₈N₂O₃	详情	详情
(V)	29776	1-(chloromethyl)cyclopropane	5911-08-0	C₄H₇Cl	详情	详情
(VI)	45941	N'-[3-acetyl-4-(cyclopropylmethoxy)phenyl]-N,N-diethylurea		C₁₇H₂₄N₂O₃	详情	详情
(VII)	45942	N'-[3-acetyl-4-(3-bromo-2-hydroxypropoxy)phenyl]-N,N-diethylurea		C₁₆H₂₃BrN₂O₄	详情	详情
(VIII)	17895	2-Amino-2-methylpropane; tert-butylamine; 2-methyl-2-propanamine	75-64-9	C₄H₁₁N	详情	详情

合成路线4

该中间体在本合成路线中的序号：(VII)

Treatment of ethyl cyanoacetate derivative (I) with cyanoacetamide (II) in EtOH in the presence of NaOEt provides dicyano derivative (III), which is then converted into diimide (IV) by treatment with refluxing sulfuric acid. Alternatively, (IV) can also be obtained by reaction between cyclopentanone (V), cyanoacetamide (II) and piperidine by means of KOH or NaOH in H2O (or H2O/EtOH) to provide mononitrile derivative (VI), which is then refluxed with H2SO4. Double N-alkylation of compound (IV) with chloride (VII) by heating with NaH or alkaline carbonate in DMF yields dialkylated compound (VIII), which is reduced with LiAlH4 or Red-Al in refluxing THF/toluene to furnish the free base (IX). Finally, (IX) is converted into the desired dihydrochloride by treatment with HCl in isopropanol.

参考文献中间体

合成目标

【1】 McElvain, S.M.; Clemens, D.H.; Piperidine derivatives. XXX. 1,4-Dialkyl-4-arylpiperidines. J Am Chem Soc 1958, 80, 3915.
【2】 Thole, F.B.; Thorpe, J.F.; The formation and reactions of imino-compounds. Part XV. The production of imino-derivatives of piperidine leading to the formation of the betabeta-disubstituted glutaric acids. J Chem Soc 1911, 99, 422.
【3】 Schon, U.; et al.; Synthesis, pharmacological characterization, and quantitative structure-activity relationship analyses of 3,7,9,9-tetraalkylbispidines: Derivatives with specific bradycardic activity. J Med Chem 1998, 41, 3, 318.
【4】 Shon, U.; Hachmeister, B.; Kehrbach, W.; Kuhl, U.; Buschmann, G. (Kali-Chemie AG); New 3,7-diazabicylo[3.3.1]nonanes. DE 3234697; EP 0103833; JP 1993247039 .
【5】 Schon, U.; Heitmann, W.; Matzel, U. (Kali-Chemie AG); Medicament containing crystalline fumaric acid salts or 9,9-alkylen-3-7-diazabicyclononane cpds.. DE 4139763; EP 0550383; JP 1993247040 .

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)	43191	ethyl 2-cyano-2-cyclopentylideneacetate	5407-83-0	C₁₀H₁₃NO₂	详情	详情
(II)	12122	Cyanoacetamide; 2-Cyanoacetamide	107-91-5	C₃H₄N₂O	详情	详情
(III)	49455	7,9-Dioxo-8-azaspiro[4.5]decane-6,10-dicarbonitrile		C₁₁H₁₁N₃O₂	详情	详情
(IV)	49456			C₁₁H₁₂N₂O₄	详情	详情
(V)	15113	cyclopentanone	120-92-3	C₅H₈O	详情	详情
(VI)	49457	10-cyano-7-imino-9-oxo-8-azaspiro[4.5]decane-6-carboxamide		C₁₁H₁₄N₄O₂	详情	详情
(VII)	29776	1-(chloromethyl)cyclopropane	5911-08-0	C₄H₇Cl	详情	详情
(VIII)	49458			C₁₉H₂₄N₂O₄	详情	详情
(IX)	49459			C₁₉H₃₂N₂	详情	详情

Extended Information