【结 构 式】 |
【分子编号】17901 【品名】Ethyl 3,3-diethoxypropanoate 【CA登记号】10601-80-6 |
【 分 子 式 】C9H18O4 【 分 子 量 】190.23952 【元素组成】C 56.82% H 9.54% O 33.64% |
合成路线1
该中间体在本合成路线中的序号:(VI)A synthesis of the R-(+) isomer has also been reported: Reaction of phenethyl alcohol (I) and ethyl 3,3-diethoxypropionate (VI) in the presence of titanium tetrachloride affords the isochromane (VII), which is hydrolyzed to acid (VIII) with NaOH in aqueous ethanol. Resolution of the racemic acid (VIII) is effected by conversion into the diastereomeric salt with R-(+)-a-methylbenzylamine (IX) which, after recrystallization from dichloromethane and ethyl acetate, is liberated by treatment with hydrochloric acid, to yield the R-(-) acid (X). This acid is reduced to alcohol (XI) with borane-dimethyl sulfide in tetrahydrofuran. Treatment of XI with methanesulfonyl chloride, diisopropylethylamine, and a trace of dimethylaminopyridine (DMAP) in tetrahydrofuran affords mesylate (XII), which is subsequently treated with piperazine (V) in ethylene glycol to afford the R-(+) compound, isolated as the methanesulfonate salt.
【1】 TenBrink, R.E.; et al.; (S)-(-)-4-[4-[2-(Isochroman-1-yl)ethyl]-piperazin-1-yl]benzenesulfonamide, a selective dopamine D(4) antagonist. J Med Chem 1996, 39, 13, 2435. |
【2】 Ten Brink, R.E.; Ennis, M.D.; Lin, C.-H.; Lahti, R.A.; Romero, A.G.; Sih, J.C. (Pharmacia Corp.); Heterocyclic cpds. for the treatment of CNS and cardiovascular disorders. EP 0737189; JP 1997507224; US 5877317; WO 9518118 . |
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) | 17897 | Phenethyl alcohol; 2-phenyl-1-ethanol | 60-12-8 | C8H10O | 详情 | 详情 |
(V) | 12143 | 1-(4-Fluorophenyl)piperazine | 2252-63-3 | C10H13FN2 | 详情 | 详情 |
(VI) | 17901 | Ethyl 3,3-diethoxypropanoate | 10601-80-6 | C9H18O4 | 详情 | 详情 |
(VII) | 17902 | ethyl 2-(3,4-dihydro-1H-isochromen-1-yl)acetate | C13H16O3 | 详情 | 详情 | |
(VIII) | 17903 | 2-(3,4-dihydro-1H-isochromen-1-yl)acetic acid | C11H12O3 | 详情 | 详情 | |
(IX) | 20042 | (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine | C8H11N | 详情 | 详情 | |
(X) | 17905 | 2-[(1R)-3,4-dihydro-1H-isochromen-1-yl]acetic acid | C11H12O3 | 详情 | 详情 | |
(XI) | 17906 | 2-[(1R)-3,4-dihydro-1H-isochromen-1-yl]-1-ethanol | C11H14O2 | 详情 | 详情 | |
(XII) | 17907 | 2-[(1R)-3,4-dihydro-1H-isochromen-1-yl]ethyl methanesulfonate | C12H16O4S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(II)The cyclization of 2-(3-bromophenyl)ethyl alcohol (I) with ethyl 3,3-diethoxypropionate by means of TiCl4 in dichlromethane gives racemic 2-(6-bromo-3,4-dihydro-1H-2-benzopyran-1-yl)acetic acid ethyl ester (III), which is regioselectively hydrolyzed by means of Amano P-30 lipase in apH 7 buffer yielding 2-(6-bromo-3,4-dihydro-1H-2-benzopyran-1(S)-yl)acetic acid (IV). The condensation of (IV) with 1-(4-methoxyphenyl)piperazine (V) by means of diethyl cyanophosphate in dichloromethane affords the acylated piperazine (VI), which is reduced with the complex BH3.THF in THF to 6-bromo-1(S)-[2-[4-(4-methoxyphenyl)piperazin-1-yl]ethyl]-3,4-dihydro-1H-2-benzopyran (VII). The reaction of (VII) with trimethylsilyl isocyante (VIII) by means of BuLiDMF gives the crboxamide (IX), which is treated with di-tert-butyl dicarbonate and dimethylaminopyridine (DMAP) in dichloromethane to yield the N,N-bis(tert-butoxycarbonyl) derivative (X). Finally, this compound is treated with an excess of methylamine.
【1】 Ennis, M.D.; Tenbrink, R.E. (Pharmacia & Upjohn AB); 1,6-Disubstd. isochromans for treatment of migraine headaches. EP 0836599; JP 1999509532; WO 9702259 . |
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) | 19969 | 2-(3-bromophenyl)-1-ethanol; 3-Bromophenethyl alcohol | 28229-69-8 | C8H9BrO | 详情 | 详情 |
(II) | 17901 | Ethyl 3,3-diethoxypropanoate | 10601-80-6 | C9H18O4 | 详情 | 详情 |
(III) | 19971 | ethyl 2-(6-bromo-3,4-dihydro-1H-isochromen-1-yl)acetate | C13H15BrO3 | 详情 | 详情 | |
(IV) | 19972 | ethyl 2-[(1S)-6-bromo-3,4-dihydro-1H-isochromen-1-yl]acetate | C13H15BrO3 | 详情 | 详情 | |
(V) | 16312 | 1-(4-Methoxyphenyl)piperazine; Methyl 4-piperazinophenyl ether | 38212-30-5 | C11H16N2O | 详情 | 详情 |
(VI) | 19974 | 2-[(1S)-6-bromo-3,4-dihydro-1H-isochromen-1-yl]-1-[4-(4-methoxyphenyl)-1-piperazinyl]-1-ethanone | C22H25BrN2O3 | 详情 | 详情 | |
(VII) | 19975 | 1-[2-[(1S)-6-bromo-3,4-dihydro-1H-isochromen-1-yl]ethyl]-4-(4-methoxyphenyl)piperazine; 4-(4-[2-[(1S)-6-bromo-3,4-dihydro-1H-isochromen-1-yl]ethyl]-1-piperazinyl)phenyl methyl ether | C22H27BrN2O2 | 详情 | 详情 | |
(VIII) | 19976 | isocyanato(trimethyl)silane; trimethylsilyl isocyanate | C4H9NOSi | 详情 | 详情 | |
(IX) | 19977 | (1S)-1-[2-[4-(4-methoxyphenyl)-1-piperazinyl]ethyl]-3,4-dihydro-1H-isochromene-6-carboxamide | C23H29N3O3 | 详情 | 详情 | |
(X) | 19978 | 1-[2-((1S)-6-[[bis(tert-butoxycarbonyl)amino]carbonyl]-3,4-dihydro-1H-isochromen-1-yl)ethyl]-4-(4-methoxyphenyl)piperazine | C33H45N3O7 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(XXII)Cyclization of 5-aminopyrazole-4-carboxylic acid ethyl ester (XXI) with either, 3,3-diethoxypropionic acid ethyl ester (XXII) or 3-oxopropionic acid ethyl ester (XXIII) in refluxing AcOH gives 7-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester (XXIV), which is treated with POCl3 to yield the corresponding chloro derivative (XXV). Condensation of compound (XXV) with 3-(N-methylacetamido)phenylboronic acid (XXVI) by means of Pd(PPh3)4 and Na2CO3 in ethanol affords the pyrazolo-[1,5-a]pyrimidine-carboxylic acid ethyl ester (XXVII), which is finally condensed with 2-bromothiophene (XX) and Mg.
【1】 Sorbera, L.A.; Castaner, J.; Martin, L.; Indiplon. Drugs Fut 2003, 28, 8, 739. |
【2】 Wilcoxen, K.M.; Gross, R.S. (Neurocrine Biosciences Inc.); Synthesis of substd. pyrazolopyrimidines. WO 0110868 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(XX) | 13681 | 2-Bromothiophene | 1003-09-4 | C4H3BrS | 详情 | 详情 |
(XXI) | 51140 | 3-Amino-4-pyrazolecarboxylic acid ethyl ester; Ethyl 3-aminopyrazole-4-carboxylate; 3-Amino-4-carbethoxypyrazole | 6994-25-8 | C6H9N3O2 | 详情 | 详情 |
(XXII) | 17901 | Ethyl 3,3-diethoxypropanoate | 10601-80-6 | C9H18O4 | 详情 | 详情 |
(XXIII) | 62966 | ethyl 3-oxopropanoate | C5H8O3 | 详情 | 详情 | |
(XXIV) | 62967 | ethyl 7-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate | C9H9N3O3 | 详情 | 详情 | |
(XXV) | 62968 | ethyl 7-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate | C9H8ClN3O2 | 详情 | 详情 | |
(XXVI) | 62969 | 3-[acetyl(methyl)amino]phenylboronic acid | C9H12BNO3 | 详情 | 详情 | |
(XXVII) | 62970 | ethyl 7-{3-[acetyl(methyl)amino]phenyl}pyrazolo[1,5-a]pyrimidine-3-carboxylate | C18H18N4O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号:(I)
【1】 Storer R. Moussa A. Wang JY. et al. 2005. Synthesis of β-L-2-deoxy-nucleosides from furanoses and pyranoses via a chloro-sugar and anhydro-l-furanosyl-nucleobase intennediatcs as potential antiviral and antineoplastic agents. W0 2005003374 |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(X) | 12204 | 5-Methyl-2,4(1H,3H)-pyrimidinedione; Thymine | 65-71-4 | C5H6N2O2 | 详情 | 详情 |
(I) | 17901 | Ethyl 3,3-diethoxypropanoate | 10601-80-6 | C9H18O4 | 详情 | 详情 |
(II) | 66789 | 3,3-diethoxypropanal | C7H14O3 | 详情 | 详情 | |
(III) | 66790 | (E)-5,5-diethoxypent-2-en-1-ol | C9H18O3 | 详情 | 详情 | |
(IV) | 66791 | (3-(2,2-diethoxyethyl)oxiran-2-yl)methanol | C9H18O4 | 详情 | 详情 | |
(V) | 66792 | tert-butyl((3-(2,2-diethoxyethyl)oxiran-2-yl)methoxy)diphenylsilane | C25H36O4Si | 详情 | 详情 | |
(VI) | 66793 | 5-((tert-butyldiphenylsilyl)oxy)-3,4-dihydroxypentanal | C21H28O4Si | 详情 | 详情 | |
(VII) | 66794 | 2-(((tert-butyldiphenylsilyl)oxy)methyl)-5-methoxytetrahydrofuran-3-ol | C22H30O4Si | 详情 | 详情 | |
(VIII) | 62915 | {(2S,3R)-5-methoxy-3-[(4-methylbenzoyl)oxy]tetrahydro-2-furanyl}methyl 4-methylbenzoate | C22H24O6 | 详情 | 详情 | |
(IX) | 37194 | (2R,3S)-5-Chloro-2-[[(4-methylbenzoyl)oxy]methyl]tetrahydro-3-furanyl 4-methylbenzoate | 4330-21-6 | C21H21ClO5 | 详情 | 详情 |