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【结 构 式】

【药物名称】Celiprolol hydrochloride, ST-1396, Cordiax, Selectol, Celectol

【化学名称】3-[3-Acetyl-4-(1,1-dimethylethylamino-2-hydroxypropoxy)phenyl]-1,1-diethylurea hydrochloride

【CA登记号】57470-78-7, 56980-93-9 (free base)

【 分 子 式 】C20H34ClN3O4

【 分 子 量 】415.96468

【开发单位】Aventis Pharma (Originator), Crinos (Not Determined), Nippon Shinyaku (Licensee)

【药理作用】Angina pectoris, Treatment of, CARDIOVASCULAR DRUGS, Hypertension, Treatment of, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, beta-Adrenoceptor Antagonists

合成路线1

The condensation of 3-acetyl-4-hydroxyaniline (I) with N,N-diethylcarbamoyl chloride (II) in pyridine gives the urea (II), which is treated with epichlorohydrin (IV) and NaOH to yield N-[3-acetyl-4-(2,3-epoxypropoxy)phenyl]-N',N'-diethylurea (V). Finally, the epoxy ring of (V) is opened with tert-butylamine (VI).

1 Stormann-Menninger-Lerchenthal, H.; Pittner, H.; Zolss, G. (CL Pharma); 4-Ureido-2-acyl phenoxypropanolamine. DE 2458624; US 4034009 .
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) 33815 1-(5-amino-2-hydroxyphenyl)-1-ethanone C8H9NO2 详情 详情
(II) 33816 N,N'-Diethylcarbamoyl chloride; 1-[(chlorocarbonyl)(ethyl)amino]ethane 88-10-8 C5H10ClNO 详情 详情
(III) 33817 N'-(3-acetyl-4-hydroxyphenyl)-N,N-diethylurea C13H18N2O3 详情 详情
(IV) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(V) 33818 N'-[3-acetyl-4-(2-oxiranylmethoxy)phenyl]-N,N-diethylurea C16H22N2O4 详情 详情
(VI) 17895 2-Amino-2-methylpropane; tert-butylamine; 2-methyl-2-propanamine 75-64-9 C4H11N 详情 详情

合成路线2

The reaction of 3-acetyl-4-[3-(tert-butylamino)-2-hydroxypropoxy)aniline (VII) with phenyl carbamate (VIII) in pyridine gives the N-[3-acetyl-4-[3-(tert-butylamino)-2-hydroxypropoxy]phenylcarbamic acid phenyl ester (IX), which is tretated with diethylamine (X) in ethanol/water. By reaction of N-[3-acetyl-4-(3-chloro-2-hydroxypropoxy)phenyl]-N',N'-diethylurea (XI) with tert-butylamine (VI).

1 Stormann-Menninger-Lerchenthal, H.; Pittner, H.; Zolss, G. (CL Pharma); 4-Ureido-2-acyl phenoxypropanolamine. DE 2458624; US 4034009 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VI) 17895 2-Amino-2-methylpropane; tert-butylamine; 2-methyl-2-propanamine 75-64-9 C4H11N 详情 详情
(VII) 33819 1-[5-amino-2-[3-(tert-butylamino)-2-hydroxypropoxy]phenyl]-1-ethanone C15H24N2O3 详情 详情
(VIII) 33820 phenyl carbamate 622-46-8 C7H7NO2 详情 详情
(IX) 33821 phenyl 3-acetyl-4-[3-(tert-butylamino)-2-hydroxypropoxy]phenylcarbamate C22H28N2O5 详情 详情
(X) 24486 Diethylamine; N,N-Diethylamine 109-89-7 C4H11N 详情 详情
(XI) 33822 N'-[3-acetyl-4-(3-chloro-2-hydroxypropoxy)phenyl]-N,N-diethylurea C16H23ClN2O4 详情 详情

合成路线3

There are several pathways for the preparation of the title compound according to the patent literature.

1 Zoelss, G.; AT 335464 .
2 Koch, H.; Celiprolol hydrocloride. Drugs Fut 1979, 4, 3, 181.
3 Zoelss, G.; AT 335467 .
4 Zoelss, G.; AT 335465 .
5 Zoelss, G.; et al.; AT 334385 .
6 Celiprolol - ein kardioselektiver beta-rezeptorblocker. Chemie Linz Ag (Kurzinformation), UL/2007, (Nov. 1978) 1978.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 17895 2-Amino-2-methylpropane; tert-butylamine; 2-methyl-2-propanamine 75-64-9 C4H11N 详情 详情
(D) 24486 Diethylamine; N,N-Diethylamine 109-89-7 C4H11N 详情 详情
(B) 33816 N,N'-Diethylcarbamoyl chloride; 1-[(chlorocarbonyl)(ethyl)amino]ethane 88-10-8 C5H10ClNO 详情 详情
(I) 33818 N'-[3-acetyl-4-(2-oxiranylmethoxy)phenyl]-N,N-diethylurea C16H22N2O4 详情 详情
(II) 33819 1-[5-amino-2-[3-(tert-butylamino)-2-hydroxypropoxy]phenyl]-1-ethanone C15H24N2O3 详情 详情
(III) 33817 N'-(3-acetyl-4-hydroxyphenyl)-N,N-diethylurea C13H18N2O3 详情 详情
(IV) 39491 N-[3-acetyl-4-[3-(tert-butylamino)-2-hydroxypropoxy]phenyl]urea C16H25N3O4 详情 详情
(V) 33821 phenyl 3-acetyl-4-[3-(tert-butylamino)-2-hydroxypropoxy]phenylcarbamate C22H28N2O5 详情 详情
(C) 31720 1-(tert-butylamino)-3-chloro-2-propanol C7H16ClNO 详情 详情

合成路线4

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.

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5

The reaction of D-mannitol (I) with acetone and ZnCl2 gives the diacetonide (II), which is oxidized with Pb(OAc)4 to yield the acetonide of (R)-glyceraldehyde (III). The reduction of (III) with H2 over Pd/C affords the (S)-glycerin acetonide (IV), which is treated with TsCl in pyridine to provide the corresponding tosylate (V). The condensation of (V) with the urea derivative (VI) by means of KOH in DMSO gives the adduct (VII), which is deprotected with HCl in acetone to yield the diol (VIII). Monotosylation of (VIII) with TsCl in pyridine affords the primary tosylate (IX), which is treated with Na in methanol to provide the epoxide (X). Finally this compound is treated with tert-butylamine to furnish the target (R)-enantiomer.

1 Hofer, O.; Schlogl, K.; Absolute configuration and enantiomeric purity of celiprolol. Arzneim-Forsch Drug Res 1986, 36, 8, 1157.
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) 45943 (2R,3R,4R,5R)-1,2,3,4,5-heptanepentol C7H16O5 详情 详情
(II) 45944 (1S,2S)-1,2-bis[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-1,2-ethanediol 1707-77-3 C12H22O6 详情 详情
(III) 36759 (4R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde 15186-48-8 C6H10O3 详情 详情
(IV) 12698 [(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]methanol 14347-78-5 C6H12O3 详情 详情
(V) 15208 (S)-(+)-2,2-Dimethyl-4-(hydroxymethyl)-1,3-dioxolane-p-toluenesulfonate; [(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl 4-methylbenzenesulfonate 23735-43-5 C13H18O5S 详情 详情
(VI) 33817 N'-(3-acetyl-4-hydroxyphenyl)-N,N-diethylurea C13H18N2O3 详情 详情
(VII) 45945 N'-(3-acetyl-4-[[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy]phenyl)-N,N-diethylurea C19H28N2O5 详情 详情
(VIII) 45946 N'-(3-acetyl-4-[[(2R)-2,3-dihydroxypropyl]oxy]phenyl)-N,N-diethylurea C16H24N2O5 详情 详情
(IX) 45947 (2S)-3-(2-acetyl-4-[[(diethylamino)carbonyl]amino]phenoxy)-2-hydroxypropyl 4-methylbenzenesulfonate C23H30N2O7S 详情 详情
(X) 45948 N'-[3-acetyl-4-[(2R)oxiranylmethoxy]phenyl]-N,N-diethylurea C16H22N2O4 详情 详情
(XI) 17895 2-Amino-2-methylpropane; tert-butylamine; 2-methyl-2-propanamine 75-64-9 C4H11N 详情 详情

合成路线6

The reaction of 4-nitrophenol (I) with acetic anhydride in aqueous NaOH gives the corresponding acetate (II), which is submitted to a Fries migration with AlCl3 in nitrobenzene at 140 C to yield the acetophenone (III). The condensation of (III) with epichlorohydrin (IV) by means of K2CO3 affords the adduct (V), which is treated with tert-butylamine (VI) in water to obtain the aminoisopropanol derivative (VII). The reduction of the nitro group of (VII) with H2 over Pd/C in methanol gives the corresponding amino derivative (VIII), which is finally condensed with N,N-diethylcarbamoyl chloride (IX) by means of TEA in THF to yield the target urea.

1 Joshi, R.A.; et al.; A new and improved process for celiprolol hydrochloride. Org Process Res Dev 2001, 5, 2, 176.
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) 11236 4-Nitrophenol; p-Nitrophenol 100-02-7 C6H5NO3 详情 详情
(II) 50841 4-Nitrophenyl acetate; Acetic acid 4-nitrophenyl ester; p-Nitrophenyl acetate 830-03-5 C8H7NO4 详情 详情
(III) 50842 1-(2-hydroxy-5-nitrophenyl)-1-ethanone C8H7NO4 详情 详情
(IV) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(V) 50843 1-[5-nitro-2-(2-oxiranylmethoxy)phenyl]-1-ethanone C11H11NO5 详情 详情
(VI) 17895 2-Amino-2-methylpropane; tert-butylamine; 2-methyl-2-propanamine 75-64-9 C4H11N 详情 详情
(VII) 50844 1-[2-[3-(tert-butylamino)-2-hydroxypropoxy]-5-nitrophenyl]-1-ethanone C15H22N2O5 详情 详情
(VIII) 33819 1-[5-amino-2-[3-(tert-butylamino)-2-hydroxypropoxy]phenyl]-1-ethanone C15H24N2O3 详情 详情
(IX) 33816 N,N'-Diethylcarbamoyl chloride; 1-[(chlorocarbonyl)(ethyl)amino]ethane 88-10-8 C5H10ClNO 详情 详情
Extended Information