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【结 构 式】 
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【分子编号】14470 【品名】2-[(4R)-3,4-dihydro-2H-chromen-4-yl]-N-[(1R)-2-hydroxy-1-phenylethyl]acetamide 【CA登记号】 |
【 分 子 式 】C19H21NO3 【 分 子 量 】311.38068 【元素组成】C 73.29% H 6.8% N 4.5% O 15.41% |
合成路线1
该中间体在本合成路线中的序号：(Xa)Terikalant, the (S)-enantiomer of RP 58866, was synthesized as follows: After hydrolysis of the ethyl ester (III) with NaOH in refluxing methanol, the corresponding acid (VIII) is converted into the acid chloride by refluxing in thionyl chloride. After removal of excess thionyl chloride, the residue is distilled off under reduced pressure to yield the carboxylic acid chloride (IX). Subsequent reaction of (IX) with (R)-(-)-phenylglycinol yields a mixture of the (SR)-3,4-dihydro-N-(2-hydroxy-1-phenethyl)-2H-1-benzopyran-4-acetamide (Xa) [m.p. 143 C; alpha(D) -43 (c 1.5, EtOH)] and (RR)-3,4-dihydro-N-(2-hydroxy-1-phenethyl)-2H-1-benzopyran-4-acetamide (Xb) [m.p. 140 C; alpha(D) -6.5 (c 1.5, EtOH)] diastereoisomers, which are separated by silica gel column chromatography using methylene chloride/ethanol (95/5) as eluent and subsequently hydrolyzed to give the two pure enatiomeric carboxylic acids: (S)-(XIa) [alpha(D) -18.5 (c 1.1, EtOH)], e.e. 99.3% determined by analytical HPLC on the amide derived from (R)-(-)-phenylglycinol, and (R)-(XIb) [alpha(D) +17.4 (c 1, EtOH)]; m.p. 77-8 C. Reduction of (XIa) with lithium aluminum hydride in tetrahydrofuran gives the alcohol (XII), which is converted into the bromide (XIII) and, subsequently, to (S)-1-[2-(3,4-dihydro-2H-1-benzopyran-4-yl)ethyl]-4-(3,4-dimethoxyphenyl)piperidine (E)-2-butenedioate (1:1) , analogously with the racemic compound described in scheme 16777901a. RP 62719 is recrystallized from isopropanol and the absolute configuration is obtained through single crystal x-ray analysis of the bromhydrate. The pure (R)-isomer, RP 62718, is obtained according to the same reaction scheme as that described for (XIa), but starting with (XIb).
| 【1】 Cavero, I.; Renault, C.; Hardy, J.-C.; Barreau, M.; Bouquerel, J.; Mestre, M.; Synthesis and biological evaluation of RP 62719, the active enantiomer of RP 58866, a pure class III antiarrhythmic agent. 11th Int Symp Med Chem (Sept 2-7, Jerusalem) 1990, 37. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 14376 | (2R)-2-amino-2-phenyl-1-ethanol; (R)-(-)-2-phenylglycinol; (R)-2-amino-2-phenyl-1-ethanol | 56613-80-0 | C8H11NO | 详情 | 详情 | |
| 23808 | Fumaric acid; (E)-2-butenedioic acid | 110-17-8 | C4H4O4 | 详情 | 详情 | |
| (Xb) | 14469 | 2-[(4S)-3,4-dihydro-2H-chromen-4-yl]-N-[(1R)-2-hydroxy-1-phenylethyl]acetamide | C19H21NO3 | 详情 | 详情 | |
| (Xa) | 14470 | 2-[(4R)-3,4-dihydro-2H-chromen-4-yl]-N-[(1R)-2-hydroxy-1-phenylethyl]acetamide | C19H21NO3 | 详情 | 详情 | |
| (XIb) | 14471 | 2-[(4S)-3,4-dihydro-2H-chromen-4-yl]acetic acid | C11H12O3 | 详情 | 详情 | |
| (XIa) | 14472 | 2-[(4R)-3,4-dihydro-2H-chromen-4-yl]acetic acid | C11H12O3 | 详情 | 详情 | |
| (III) | 14463 | ethyl 2-(3,4-dihydro-2H-chromen-4-yl)acetate | C13H16O3 | 详情 | 详情 | |
| (VI) | 14466 | 4-(3,4-dimethoxyphenyl)piperidine; 2-methoxy-4-(4-piperidinyl)phenyl methyl ether | C13H19NO2 | 详情 | 详情 | |
| (VIII) | 14467 | 2-(3,4-dihydro-2H-chromen-4-yl)acetic acid | C11H12O3 | 详情 | 详情 | |
| (IX) | 14468 | 2-(3,4-dihydro-2H-chromen-4-yl)acetyl chloride | C11H11ClO2 | 详情 | 详情 | |
| (XII) | 14473 | 2-[(4S)-3,4-dihydro-2H-chromen-4-yl]-1-ethanol | C11H14O2 | 详情 | 详情 | |
| (XIII) | 14474 | (4R)-4-(2-bromoethyl)-3,4-dihydro-2H-chromene | C11H13BrO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)2) The reaction of 4-(2-formylethyl)benzoic acid ethyl ester (XIV) with paraformaldehyde (XV) by means of N-ethylbenzothiazolium bromide (XVI) and triethylamine gives the 4-hydroxy-3-oxobutyl derivative (XVII), which is condensed with ethyl cyanoacetate (I) by means of triethylamine in ethanol yielding the furancarboxylate derivative (XVIII). The cyclization of (XVIII) with guanidine (IV) by means of sodium ethoxide in ethanol affords 4-[2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl] benzoic acid ethyl ester (XIX), which is saponified with NaOH to the corresponding free acid (XX). The condensation of (XX) with L-glutamic acid diethyl ester (XXI) in the usual way affords the diethyl ester of LY-231514 (XXII), which is finally saponified with NaOH.
| 【1】 Castaner, J.; Graul, A.; Tracy, M.; Penetrexed Disodium. Drugs Fut 1998, 23, 5, 498. |
| 【2】 Taylor, E.C.; Patel, H.H. (Princeton University); Process for the preparation of pyrrolo[2,3-d]pyrimidines. CA 2084490 . |
| 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) | 11877 | Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate | 105-56-6 | C5H7NO2 | 详情 | 详情 |
| (IV) | 14470 | 2-[(4R)-3,4-dihydro-2H-chromen-4-yl]-N-[(1R)-2-hydroxy-1-phenylethyl]acetamide | C19H21NO3 | 详情 | 详情 | |
| (XIV) | 14800 | ethyl 4-(3-oxopropyl)benzoate | C12H14O3 | 详情 | 详情 | |
| (XVI) | 14801 | 3-Ethylbenzothiazolium bromide; 3-Ethyl-1,3-benzothiazol-3-ium bromide | 32446-47-2 | C9H10BrNS | 详情 | 详情 |
| (XVII) | 14802 | Ethyl 4-(4-hydroxy-3-oxobutyl)benzoate | C13H16O4 | 详情 | 详情 | |
| (XVIII) | 14803 | Ethyl 2-amino-4-[4-(ethoxycarbonyl)phenethyl]-3-furoate | C18H21NO5 | 详情 | 详情 | |
| (XIX) | 14804 | Ethyl 4-[2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoate | C17H18N4O3 | 详情 | 详情 | |
| (XX) | 14805 | 4-[2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid | C15H14N4O3 | 详情 | 详情 | |
| (XXI) | 11013 | diethyl (2S)-2-aminopentanedioate | C9H17NO4 | 详情 | 详情 | |
| (XXII) | 14807 | diethyl (2S)-2-([4-[2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]amino)pentanedioate | C24H29N5O6 | 详情 | 详情 |