|
【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 |