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【结 构 式】 
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【药物名称】Tecalcet hydrochloride, KRN-568, R-568, NPS-R-568, Norcalcin 【化学名称】3-(2-Chlorophenyl)-N-[1(R)-(3-methoxyphenyl)ethyl]propylamine hydrochloride 【CA登记号】177172-49-5, 148717-54-8 (free base) 【 分 子 式 】C18H23Cl2NO 【 分 子 量 】340.29611 |
【开发单位】NPS Pharmaceuticals (Originator), Amgen (Licensee), Kirin Brewery (Licensee) 【药理作用】ENDOCRINE DRUGS, Thyroid Disease Therapy, Treatment of Hyperparathyroidism |
合成路线1
The required (R)-3-methoxy-alpha-methylbenzylamine (III) was prepared from 3’-methoxyacetophenone (I) via Leuckart reaction, upon heating at 180 C with ammonium formate. The resultant formamide (II) was hydrolyzed with concentrated HCl to the racemic amine, which was then resolved using (R)-mandelic acid.
| 【1】 D'Ambra, T.E.; Vanwagenen, B.C.; Duff, S.R.; Nelson, W.A. (NPS Pharmaceuticals, Inc.); Method of making a benzylpropanamine. WO 9602492 . |
| 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) | 18792 | 3-methoxyacetophenone; 1-(3-methoxyphenyl)-1-ethanone | 586-37-8 | C9H10O2 | 详情 | 详情 |
| (II) | 56139 | 1-(3-methoxyphenyl)ethylformamide | C10H13NO2 | 详情 | 详情 | |
| (III) | 56140 | (R)-1-(3-Methoxyphenyl)ethylamine; (R)-3-Methoxy-alpha-methylbenzylamine; (R)-m-Methoxy-alpha-methylbenzylamine | 88196-70-7 | C9H13NO | 详情 | 详情 |
合成路线2
A new procedure for the asymmetric synthesis of amine (III) was reported. Mitsunobu coupling of N-hydroxyphthalimide (V) with the chiral auxiliary (R)-phenylglycol (IV) yielded the (S)-alkoxyphthalimide (VI). Hydrazinolysis of (VI) provided the free alkoxyamine (VII), which was condensed with 3-methoxybenzaldehyde (VIII) to afford oxime (IX). Diastereoselective addition of methyllithium to the oxime ether (IX) led to the methyl adduct (X) as the major isomer. Then, reductive N-O bond cleavage to furnish amine (III) was carried out by using zinc-acetic acid or, with an improved yield, using molybdenum hexacarbonyl.
| 【1】 Yamazaki, N.; et al.; Nucleophilic addition of methyllithium to chiral oxime ethers: Asymmetric preparation of 1-(aryl)ethylamines and application to a synthesis of calcimimetics (+)-NPS R-568 and its thio analogue. Tetrahedron Lett 2001, 42, 30, 5029. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 56140 | (R)-1-(3-Methoxyphenyl)ethylamine; (R)-3-Methoxy-alpha-methylbenzylamine; (R)-m-Methoxy-alpha-methylbenzylamine | 88196-70-7 | C9H13NO | 详情 | 详情 |
| (IV) | 56141 | (R)-(-)-1-Phenyl-1,2-ethanediol; (R)-(-)-alpha,beta-Dihydroxyethylbenzene; (R)-(-)-Phenyl-1,2-ethanediol; (R)-(-)-Styrene glycol; (-)-Styrene glycol | 16355-00-3 | C8H10O2 | 详情 | 详情 |
| (V) | 13505 | N-Hydroxyphthalimide; 2-Hydroxy-1H-isoindole-1,3(2H)-dione | 524-38-9 | C8H5NO3 | 详情 | 详情 |
| (VI) | 56142 | 2-{[(1S)-2-hydroxy-1-phenylethyl]oxy}-1H-isoindole-1,3(2H)-dione | C16H13NO4 | 详情 | 详情 | |
| (VII) | 56143 | (2S)-2-(aminooxy)-2-phenyl-1-ethanol | C8H11NO2 | 详情 | 详情 | |
| (VIII) | 20589 | 3-methoxybenzaldehyde; m-Anisaldehyde | 591-31-1 | C8H8O2 | 详情 | 详情 |
| (IX) | 56144 | 3-methoxybenzaldehyde O-[(1S)-2-hydroxy-1-phenylethyl]oxime | C16H17NO3 | 详情 | 详情 | |
| (X) | 56145 | (2S)-2-({[(1R)-1-(3-methoxyphenyl)ethyl]amino}oxy)-2-phenyl-1-ethanol | C17H21NO3 | 详情 | 详情 |
合成路线3
The title compound was prepared by one-pot reductive alkylation of the chiral amine (III) with 3-(2-chlorophenyl)propionitrile (XI). Reduction of nitrile (XI) by means of DIBAL at -78 C produced the intermediate diisobutylaluminium-imine complex (XII) which, after addition of (R)-3-methoxy-alpha-methylbenzylamine (III), generated imine (XIII). Subsequent reduction of imine (XIII) with NaBH4 afforded the target amine.
| 【1】 Barmore, R.M.; et al.; The addition of amines to diisobutylaluminum-imine complexes. Preparation of NPS R-568 hydrochloride. Tetrahedron Lett 1998, 39, 21, 3451. |
| 【2】 D'Ambra, T.E.; Vanwagenen, B.C.; Duff, S.R.; Nelson, W.A. (NPS Pharmaceuticals, Inc.); Method of making a benzylpropanamine. WO 9602492 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 56140 | (R)-1-(3-Methoxyphenyl)ethylamine; (R)-3-Methoxy-alpha-methylbenzylamine; (R)-m-Methoxy-alpha-methylbenzylamine | 88196-70-7 | C9H13NO | 详情 | 详情 |
| (XI) | 56146 | 3-(2-Chlorophenyl)propionitrile; 2-Chlorohydrocinnamonitrile | C9H8ClN | 详情 | 详情 | |
| (XII) | 56147 | C17H27AlClN | 详情 | 详情 | ||
| (XIII) | 56148 | (1R)-N-[(E)-3-(2-chlorophenyl)propylidene]-1-(3-methoxyphenyl)-1-ethanamine; N-[(E)-3-(2-chlorophenyl)propylidene]-N-[(1R)-1-(3-methoxyphenyl)ethyl]amine | C18H20ClNO | 详情 | 详情 |
合成路线4
In an alternative procedure, alkylation of diethyl malonate with 2-chlorobenzyl chloride (XIV) afforded malonate (XV), which underwent hydrolysis and further decarboxylation to the arylpropionic acid (XVI) upon refluxing with HCl and HOAc. Coupling of acid (XVI) with the chiral amine (III) to give amide (XVII) was performed in refluxing toluene with azeotropic removal of water or, alternatively, by using DCC as the coupling reagent. Amide (XVII) was finally reduced to the corresponding amine by means of borane in tetrahydrofuran or with DIBAL in CH2Cl2.
| 【1】 Yamazaki, N.; et al.; Nucleophilic addition of methyllithium to chiral oxime ethers: Asymmetric preparation of 1-(aryl)ethylamines and application to a synthesis of calcimimetics (+)-NPS R-568 and its thio analogue. Tetrahedron Lett 2001, 42, 30, 5029. |
| 【2】 D'Ambra, T.E.; Vanwagenen, B.C.; Duff, S.R.; Nelson, W.A. (NPS Pharmaceuticals, Inc.); Method of making a benzylpropanamine. WO 9602492 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 56140 | (R)-1-(3-Methoxyphenyl)ethylamine; (R)-3-Methoxy-alpha-methylbenzylamine; (R)-m-Methoxy-alpha-methylbenzylamine | 88196-70-7 | C9H13NO | 详情 | 详情 |
| (XIV) | 10205 | 1-Chloro-2-(chloromethyl)benzene; 2-Chlorobenzyl chloride | 611-19-8 | C7H6Cl2 | 详情 | 详情 |
| (XV) | 56149 | diethyl 2-(2-chlorobenzyl)malonate | C14H17ClO4 | 详情 | 详情 | |
| (XVI) | 56150 | 3-(2-Chlorophenyl)propionic acid | 1643-28-3 | C9H9ClO2 | 详情 | 详情 |
| (XVII) | 56151 | 3-(2-chlorophenyl)-N-[(1R)-1-(3-methoxyphenyl)ethyl]propanamide | C18H20ClNO2 | 详情 | 详情 |
合成路线5
In a different method, the primary amine (XVIII) was prepared by reduction of nitrile (XI) with either borane-dimethyl sulfide complex or with LiAlH4. Condensation of amine (XVIII) with acetophenone (I) generated imine (XIX). The asymmetric reduction of (XIX) to furnish the title (R)-amine was accomplished by using LiAlH4 in the presence of several chiral auxiliaries, such as 1,1’-binaphthol, (-)-N-methylephedrine, or (-)-N-methylpseudoephedrine, with different degrees of enantioselectivity. Alternatively, imine (XIX) was reduced utilizing a titanium-catalyzed asymmetric hydrosilylation method.
| 【1】 Buchwald, S.L.; Hansen, M.C.; Synthesis of NPS R-568 utilizing titanium-catalyzed asymmetric hydrosilylation. Tetrahedron Lett 1999, 40, 11, 2033. |
| 【2】 Van Wagenen, B.C.; Barmore, R.M. (NPS Pharmaceuticals, Inc.); Chiral reductions of imines leading to the syntheses of optically active amines. WO 9711934 . |
| 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) | 18792 | 3-methoxyacetophenone; 1-(3-methoxyphenyl)-1-ethanone | 586-37-8 | C9H10O2 | 详情 | 详情 |
| (XI) | 56146 | 3-(2-Chlorophenyl)propionitrile; 2-Chlorohydrocinnamonitrile | C9H8ClN | 详情 | 详情 | |
| (XVIII) | 56152 | 3-(2-chlorophenyl)-1-propanamine; 3-(2-chlorophenyl)propylamine | C9H12ClN | 详情 | 详情 | |
| (XIX) | 56153 | 3-(2-chlorophenyl)-N-[(E)-1-(3-methoxyphenyl)ethylidene]-1-propanamine; N-[3-(2-chlorophenyl)propyl]-N-[(E)-1-(3-methoxyphenyl)ethylidene]amine | C18H20ClNO | 详情 | 详情 |