|
【结 构 式】 
|
【分子编号】10792 【品名】Butanoyl chloride; Butyryl chloride 【CA登记号】141-75-3 |
【 分 子 式 】C4H7ClO 【 分 子 量 】106.55168 【元素组成】C 45.09% H 6.62% Cl 33.27% O 15.02% |
合成路线1
该中间体在本合成路线中的序号：(II)The acylation of 9-ethylamino-8-bromo-3,4-dimethoxyphenanthrene (I) with butyryl chloride (II) in CH2Cl2 gives 9-(N-ethyl-N-butyrylamino)-8-bromo-3,4-dimethoxyphenanthrene (III), which is cyclized by means of butyllithium in THF yielding 5-ethyl-4,5-dihydro-9,10-dimethoxy-4-n-propyldibenz[cd,f]indole-4-ol (IV). The reduction of (IV) with Zn-HgCl2 in refluxing ethanol water affords 5-ethyl-4,5,5a,6-tetrahydro-9,10-diethoxy-4-n-propyldibenz[cd,f]indole (V), which is finally demethylated by means of refluxing aqueous 47% HBr.
| 【1】 Giger, R.K.A. (Novartis AG); Nouveaux derives du dibenz[cd,f]indole, leur preparation et leur application comme medicaments. DE 3124086; FR 2485530; FR 2510996; WO 8200143 . |
| 【2】 Castaner, J.; Serradell, M.N.; 201678. Drugs Fut 1985, 10, 2, 99. |
| 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) | 28983 | 8-bromo-N-ethyl-3,4-dimethoxy-9-phenanthrenamine | C18H18BrNO2 | 详情 | 详情 | |
| (II) | 10792 | Butanoyl chloride; Butyryl chloride | 141-75-3 | C4H7ClO | 详情 | 详情 |
| (III) | 28984 | N-(8-bromo-3,4-dimethoxy-9-phenanthryl)-N-ethylbutanamide | C22H24BrNO3 | 详情 | 详情 | |
| (IV) | 28985 | (4R)-5-ethyl-9,10-dimethoxy-4-propyl-4,5-dihydrodibenzo[cd,f]indol-4-ol | C22H25NO3 | 详情 | 详情 | |
| (V) | 28986 | (4S,5aR)-5-ethyl-10-methoxy-4-propyl-4,5,5a,6-tetrahydrodibenzo[cd,f]indol-9-yl methyl ether | C22H27NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)The synthesis of [14C]-labeled pravastatin has been reported: The reaction of propylmagnesium bromide (I) with (14)CO2 gives [14C]-butyric acid sodium salt (II), which is converted to the corresponding acyl chloride (III) by reaction with oxalyl chloride. The condensation of (III) with 4(S)-benzyloxazolidin-2-one (IV) in THF yields the corresponding acylation product (V), which is methylated with sodium hexamethyldisilazide and methyliodide to afford a mixture of tautomeric N-[4(S)-benzyl-3-[2(R and S)-methylbutyryl]oxazolidin-2-ones, which are separated by preparative HPLC to obtain the optically pure diastereomer (VI). The oxidative cleavage of (VI) with H2O2 and LiOH, followed by acidification and treatment with NaOH, yields sodium 2(S)-methylbutyrate (VII), which is treated with oxalyl chloride to afford the corresponding acyl chloride (VIII). The condensation of (VIII) with 4(R)-(tert-butyldimethylsilyloxy)-6(R)-[2-[8(S)-hydroxy-2(S)-methyl-1,2,6,7,8,8a(R)-hexahydronaphth-1(S)-yl]ethyl]tetrahydropyran-2-one (IX) by means of 4-(dimethylamino)pyridine in CH2Cl2 gives the esterified compound (X), which is deprotected with tetrabutylammonium fluoride and acetic acid, yielding the hydroxylated pyrone (XI). Finally, this compound is submitted to an asymmetric hydroxylation with a culture broth of Mucor hiemalis MF-5021. The final product is extracted from the culture broth and purified by preparative HPLC to give a final radiochemical purity of 95%.
| 【1】 Wallace, M.A.; Dean, D.C.; White, R.F.; Ellsworth, R.L.; Melillo, D.G.; Marks, T.; The synthesis of carbon-14 labeled pravastatin. J Label Compd Radiopharm 1993, 33, 8, 697. |
| 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) | 10790 | Bromo(propyl)magnesium；bromopropylMagnesium；4-propylbutyrolactone；propylmagnesiumbromide；n-propylmagnesium bromide；Bromopropylmagnesium; | 927-77-5 | C3H7BrMg | 详情 | 详情 |
| (II) | 10791 | Butyric acid sodium salt | C4H7NaO2 | 详情 | 详情 | |
| (II) | 44674 | sodium butyrate | C4H7NaO2 | 详情 | 详情 | |
| (III) | 10792 | Butanoyl chloride; Butyryl chloride | 141-75-3 | C4H7ClO | 详情 | 详情 |
| (III) | 44675 | butanoyl chloride | C4H7ClO | 详情 | 详情 | |
| (IV) | 10793 | [(4S)-4-Benzyl-2-oxo-1,3-oxazolidin-3-yl]lithium | C10H10LiNO2 | 详情 | 详情 | |
| (V) | 10794 | (4S)-4-Benzyl-3-butyryl-1,3-oxazolan-2-one | C14H17NO3 | 详情 | 详情 | |
| (V) | 44676 | (4S)-4-benzyl-3-butyryl-1,3-oxazolidin-2-one | C14H17NO3 | 详情 | 详情 | |
| (VI) | 10795 | (4S)-4-Benzyl-3-[(2S)-2-methylbutanoyl]-1,3-oxazolan-2-one | C15H19NO3 | 详情 | 详情 | |
| (VI) | 44677 | (4S)-4-benzyl-3-[(2S)-2-methylbutanoyl]-1,3-oxazolidin-2-one | C15H19NO3 | 详情 | 详情 | |
| (VII) | 10796 | 2(S)-Methylbutyric acid sodium salt | C5H9NaO2 | 详情 | 详情 | |
| (VII) | 44678 | sodium (2S)-2-methylbutanoate | C5H9NaO2 | 详情 | 详情 | |
| (VIII) | 10797 | (2S)-2-Methylbutanoyl chloride | 57526-28-0 | C5H9ClO | 详情 | 详情 |
| (VIII) | 44679 | (2S)-2-methylbutanoyl chloride | C5H9ClO | 详情 | 详情 | |
| (IX) | 10798 | (4R,6R)-6-[2-[(1S,2S,8S,8aR)-8-Hydroxy-2-methyl-1,2,6,7,8,8a-hexahydro-1-naphthalenyl]ethyl]-4-[[tert-butyl(dimethyl)silyl]oxy]tetrahydro-2H-pyran-2-one | C24H40O4Si | 详情 | 详情 | |
| (X) | 10799 | (1S,7S,8S,8aR)-8-[2-((2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-oxotetrahydro-2H-pyran-2-yl)ethyl]-7-methyl-1,2,3,7,8,8a-hexahydro-1-naphthalenyl (2S)-2-methylbutanoate | C29H48O5Si | 详情 | 详情 | |
| (X) | 44680 | (1S,7S,8S,8aR)-8-[2-((2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-oxotetrahydro-2H-pyran-2-yl)ethyl]-7-methyl-1,2,3,7,8,8a-hexahydro-1-naphthalenyl (2S)-2-methylbutanoate | C29H48O5Si | 详情 | 详情 | |
| (XI) | 10800 | (1S,7S,8S,8aR)-8-[2-[(2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl]-7-methyl-1,2,3,7,8,8a-hexahydro-1-naphthalenyl (2S)-2-methylbutanoate; Mevastatin | 109785-28-6 | C23H34O5 | 详情 | 详情 |
| (XI) | 44681 | (1S,7S,8S,8aR)-8-[2-[(2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl]-7-methyl-1,2,3,7,8,8a-hexahydro-1-naphthalenyl (2S)-2-methylbutanoate | C23H34O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The reaction of tetrahydrofuran-2,2-dimethanol (I) with butyryl chloride (II) and Na2CO3 in dichloromethane gives the dibutyrate (III), which is asymmetrized by means of pancreas lipase type II (PPL) or microbial lipase Mucor javanicus (LMJ), yielding the (R)-monobutyrate (IV). The protection of the OH group of (IV) with Tr-Cl and pyridine in dichloromethane affords the trityl ether (V), which is treated with K2CO3 in methanol to provide the chiral carbinol (VI). The reaction of (VI) with octadecyl bromide (VII) by means of NaH and tetrabutylammonium iodide (TBAI) in refluxing THF gives the corresponding ether (VIII), which is deprotected with TFA in dichloromethane/water to yield the chiral carbinol (IX). Finally this carbinol is condensed with POCl3, choline tosylate (X), TEA and pyridine in THF to afford the target compound.
| 【1】 Prasad, K.; et al.; Asymmetrization of tetrahydrofuran-2,2-dimethanol: Synthesis of the enantiomers of SRI 62-834. J Org Chem 1995, 60, 23, 7693. |
| 【2】 Estermann, H.; Houlihan, W.J.; Kapa, P.K.; Underwood, R.L. (Novartis AG; Novartis Deutschland GmbH); Enantiomers of 2-tetrahydrofuran derivs., intermediates therefor and their preparation. EP 0462935; JP 1992270276 . |
| 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) | 47573 | [2-(hydroxymethyl)tetrahydro-2-furanyl]methanol | C6H12O3 | 详情 | 详情 | |
| (II) | 10792 | Butanoyl chloride; Butyryl chloride | 141-75-3 | C4H7ClO | 详情 | 详情 |
| (III) | 47575 | [2-[(butyryloxy)methyl]tetrahydro-2-furanyl]methyl butyrate | C14H24O5 | 详情 | 详情 | |
| (IV) | 47576 | [(2S)-2-(hydroxymethyl)tetrahydro-2-furanyl]methyl butyrate | C10H18O4 | 详情 | 详情 | |
| (V) | 47577 | [(2S)-2-[(trityloxy)methyl]tetrahydro-2-furanyl]methyl butyrate | C29H32O4 | 详情 | 详情 | |
| (VI) | 47578 | [(2R)-2-[(trityloxy)methyl]tetrahydro-2-furanyl]methanol | C25H26O3 | 详情 | 详情 | |
| (VII) | 28797 | 1-bromooctadecane | 112-89-0 | C18H37Br | 详情 | 详情 |
| (VIII) | 47582 | (2R)-2-[(octadecyloxy)methyl]-2-[(trityloxy)methyl]tetrahydrofuran; octadecyl [(2R)-2-[(trityloxy)methyl]tetrahydro-2-furanyl]methyl ether | C43H62O3 | 详情 | 详情 | |
| (IX) | 41307 | [(2S)-2-[(octadecyloxy)methyl]tetrahydro-2-furanyl]methanol | C24H48O3 | 详情 | 详情 | |
| (X) | 41265 | 2-hydroxy-N,N,N-trimethyl-1-ethanaminium 4-methylbenzenesulfonate | C12H21NO4S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)The reaction of tetrahydrofuran-2,2-dimethanol (I) with butyryl chloride (II) and Na2CO3 in dichloromethane gives the dibutyrate (III), which is asymmetrized by means of pancreas lipase type II (PPL) or microbial lipase Mucor javanicus (LMJ) yielding the (R)-monobutyrate (IV). The protection of the OH group of (IV) with Tr-Cl and pyridine in dichloromethane affords the trityl ether (V), which is treated with K2CO3 in methanol to provide the chiral carbinol (VI). The reaction of (VI) with benzyl bromide by means of NaH and tetrabutylammonium iodide (TBAI) in refluxing THF gives the corresponding benzyl ether (VII), which is deprotected with TFA in dichloromethane/water to yield the chiral carbinol (VIII). The reaction of (VIII) with octadecyl bromide (IX) by means of NaH and tetrabutylammonium iodide (TBAI) in refluxing THF gives the corresponding octadecyl ether (X), which is debenzylated by hydrogenation with H2 over Pd/C in ethanol to yield the chiral carbinol (XI). Finally, this carbinol is condensed with POCl3, choline tosylate (XII), TEA and pyridine in THF to afford the target compound.
| 【1】 Prasad, K.; et al.; Asymmetrization of tetrahydrofuran-2,2-dimethanol: Synthesis of the enantiomers of SRI 62-834. J Org Chem 1995, 60, 23, 7693. |
| 【2】 Estermann, H.; Houlihan, W.J.; Kapa, P.K.; Underwood, R.L. (Novartis AG; Novartis Deutschland GmbH); Enantiomers of 2-tetrahydrofuran derivs., intermediates therefor and their preparation. EP 0462935; JP 1992270276 . |
| 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) | 19490 | 3-chloro-1-propanol | 627-30-5 | C3H7ClO | 详情 | 详情 |
| (II) | 10792 | Butanoyl chloride; Butyryl chloride | 141-75-3 | C4H7ClO | 详情 | 详情 |
| (III) | 47575 | [2-[(butyryloxy)methyl]tetrahydro-2-furanyl]methyl butyrate | C14H24O5 | 详情 | 详情 | |
| (IV) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (V) | 47577 | [(2S)-2-[(trityloxy)methyl]tetrahydro-2-furanyl]methyl butyrate | C29H32O4 | 详情 | 详情 | |
| (VI) | 47578 | [(2R)-2-[(trityloxy)methyl]tetrahydro-2-furanyl]methanol | C25H26O3 | 详情 | 详情 | |
| (VII) | 47579 | benzyl [(2R)-2-[(trityloxy)methyl]tetrahydro-2-furanyl]methyl ether; (2R)-2-[(benzyloxy)methyl]-2-[(trityloxy)methyl]tetrahydrofuran | C32H32O3 | 详情 | 详情 | |
| (VIII) | 47580 | [(2S)-2-[(benzyloxy)methyl]tetrahydro-2-furanyl]methanol | C13H18O3 | 详情 | 详情 | |
| (IX) | 28797 | 1-bromooctadecane | 112-89-0 | C18H37Br | 详情 | 详情 |
| (X) | 47581 | (2R)-2-[(benzyloxy)methyl]-2-[(octadecyloxy)methyl]tetrahydrofuran; benzyl [(2R)-2-[(octadecyloxy)methyl]tetrahydro-2-furanyl]methyl ether | C31H54O3 | 详情 | 详情 | |
| (XI) | 41307 | [(2S)-2-[(octadecyloxy)methyl]tetrahydro-2-furanyl]methanol | C24H48O3 | 详情 | 详情 | |
| (XII) | 41265 | 2-hydroxy-N,N,N-trimethyl-1-ethanaminium 4-methylbenzenesulfonate | C12H21NO4S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)The acylation of 4-amino-3-methylbenzoic acid methyl ester (I) with butyryl chloride (II) in hot chlorobenzene gives the corresponding amide (III), which is nitrated with HNO3/H2SO4 yielding 4-butyramido-3-methyl-5-nitrobenzoic acid methyl ester (IV). The hydrogenation of (IV) with H2 over Pd/C in methanol affords the expected amino compound (V), which is cyclized in refluxing acetic acid to 2-propyl-4-methylbenzimidazole-6-carboxylic acid methyl ester (VI). The hydrolysis of (VI) with NaOH in refluxing methanol/water affords the corresponding free acid (VII), which is cyclized with N-methyl-o-phenylenediamine (VIII) by means of polyphosphoric acid (PPA) at 150 C, giving 4-methyl-6-(1-methylbenzimidazol-2-yl)-2-propylbenzimidazole (IX). The condensation of (IX) with 4'-(bromomethyl)biphenyl-4-carboxylic acid tert-butyl ester (X) by means of potassium tert-butoxide in DMSO yields the tert-butyl ester (XI), which is finally hydrolyzed with trifluoroacetic acid.
| 【1】 Merlos, M.; Casas, A.; Castaner, J.; Telmisartan. Drugs Fut 1997, 22, 10, 1112. |
| 【2】 Hauel, N.; Narr, B.; Ries, U.; Van Meel, J.; Wienen, W.; Entzeroth, M. (Dr. Karl Thomae GmbH); Benzimidazoles, medicaments containing them and process for their preparation. DE 4103492; DE 4117121; EP 0502314; EP 0543263; JP 1992346978 . |
| 【3】 Ries, U.J.; Mihm, G.; Narr, B.; Hasselbach, K.M.; Wittneben, H.; Entzeroth, M.; van Meel, J.C.A.; Wienen, W.; Hauel, N.H.; 6-Substituted benzimidazoles as new nonpeptide angiotensin II receptor antagonists: Synthesis, biological activity, and structure-activity relationships. J Med Chem 1993, 36, 25, 4040-51. |
| 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) | 16129 | methyl 4-amino-3-methylbenzoate | C9H11NO2 | 详情 | 详情 | |
| (II) | 10792 | Butanoyl chloride; Butyryl chloride | 141-75-3 | C4H7ClO | 详情 | 详情 |
| (III) | 16131 | methyl 4-(butyrylamino)-3-methylbenzoate | C13H17NO3 | 详情 | 详情 | |
| (IV) | 16132 | methyl 4-(butyrylamino)-3-methyl-5-nitrobenzoate | C13H16N2O5 | 详情 | 详情 | |
| (V) | 16133 | methyl 3-amino-4-(butyrylamino)-5-methylbenzoate | C13H18N2O3 | 详情 | 详情 | |
| (VI) | 16134 | methyl 4-methyl-2-propyl-1H-benzimidazole-6-carboxylate | C13H16N2O2 | 详情 | 详情 | |
| (VII) | 16135 | 4-methyl-2-propyl-1H-benzimidazole-6-carboxylic acid | C12H14N2O2 | 详情 | 详情 | |
| (VIII) | 16136 | N-Methyl-1,2-phenylenediamine; N(1)-methyl-1,2-benzenediamine; N-(2-aminophenyl)-N-methylamine | 4760-34-3 | C7H10N2 | 详情 | 详情 |
| (IX) | 16137 | 4-Methyl-6-(1-methylbenzaimidazol-2-yl)-2-propyl-1H-benzimidazole | C19H20N4 | 详情 | 详情 | |
| (X) | 16138 | tert-butyl 4'-(bromomethyl)[1,1'-biphenyl]-2-carboxylate | 114772-40-6 | C18H19BrO2 | 详情 | 详情 |
| (XI) | 16139 | 4'-[4-Methyl-6-(1-methylbenzaimidazol-2-yl)-2-propylbenzimidazol-1-ylmethyl]biphenyl-2-carboxylic acid tert-butyl ester | C37H38N4O2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(XIII)Reaction of 4,6-dimethylpyridin-2-amine (I) with isoamyl nitrite and HCl gives 2-chloro-4,6-dimethylpyridine (II), which is treated with hydrazine in diethylene glycol at 140 C yielding 2-hydrazino-4,6-dimethylpyridine (III). Cyclization of (III) with cyclohexanone (IV) in refluxing diethylene glycol affords the tetrahydro-alpha-carboline (V), which is dehydrogenated with Pd in refluxing diethylene glycol, giving the alpha-carboline (VI). The alkylation of (VI) with the benzyl bromide (VII) by means of potassium tert-butoxide in DMF yields the adduct (VIII), which is hydrolyzed with concentrated H2SO4 to provide the carboxylic acid (IX). Finally, this acid is condensed with (R)-2-hydroxy-1-phenylethylamine (X) by means of HOBT and EDC in CH2Cl2, giving a diastereomeric mixture of the corresponding amides that is resolved by column chromatography. The benzyl bromide intermediate (VII) has been obtained as follows: Esterification of 2-(4-methylphenyl)acetic acid (XI) with tert-butanol and DCC and DMAP in CH2Cl2 gives the corresponding tert-butyl ester (XII), which is condensed with cyclopentyl bromide (XIII) by means of t-BuOK in DMF to yield racemic 2-cyclopentyl-2-(4-methylphenyl)acetic acid tert-butyl ester (XIV). Finally, this compound is brominated with NBS and AIBN in refluxing CCl4.
| 【1】 Castañer, J.; Silvestre, J.S.; Sorbera, L.A.; Martín, L.; Implitapide. Drugs Fut 2000, 25, 11, 1138. |
| 【2】 Muller, U.; Connell, R.; Goldmann, S.; Grutzmann, R.; Beuck, M.; Bischoff, H.; Denzer, D.; Domdey-Bette, A.; Wohlfeil, S. (Bayer AG); Cycloalkano-indole- and -azaindole derivs.. CA 2159546; DE 4435477; EP 0705831; JP 1996225526; US 5684014 . |
| 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) | 41793 | 4,6-dimethyl-2-pyridinamine; 4,6-dimethyl-2-pyridinylamine | 5407-87-4 | C7H10N2 | 详情 | 详情 |
| (II) | 41794 | 2-chloro-4,6-dimethylpyridine | 30838-93-8 | C7H8ClN | 详情 | 详情 |
| (III) | 41795 | 2-hydrazino-4,6-dimethylpyridine | C7H11N3 | 详情 | 详情 | |
| (IV) | 11059 | Cyclohexanone | 108-94-1 | C6H10O | 详情 | 详情 |
| (V) | 41796 | 2,4-dimethyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole | C13H16N2 | 详情 | 详情 | |
| (VI) | 41797 | 2,4-dimethyl-9H-pyrido[2,3-b]indole | C13H12N2 | 详情 | 详情 | |
| (VII) | 41798 | tert-butyl 2-[4-(bromomethyl)phenyl]-2-cyclopentylacetate | C18H25BrO2 | 详情 | 详情 | |
| (VIII) | 41799 | tert-butyl 2-cyclopentyl-2-[4-[(2,4-dimethyl-9H-pyrido[2,3-b]indol-9-yl)methyl]phenyl]acetate | C31H36N2O2 | 详情 | 详情 | |
| (IX) | 41800 | 2-cyclopentyl-2-[4-[(2,4-dimethyl-9H-pyrido[2,3-b]indol-9-yl)methyl]phenyl]acetic acid | C27H28N2O2 | 详情 | 详情 | |
| (X) | 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 |
| (XI) | 28316 | 2-(4-methylphenyl)acetic acid | 622-47-9 | C9H10O2 | 详情 | 详情 |
| (XII) | 41801 | tert-butyl 2-(4-methylphenyl)acetate | C13H18O2 | 详情 | 详情 | |
| (XIII) | 10792 | Butanoyl chloride; Butyryl chloride | 141-75-3 | C4H7ClO | 详情 | 详情 |
| (XIV) | 41802 | tert-butyl 2-cyclopentyl-2-(4-methylphenyl)acetate | C18H26O2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(XIII)Esterification of 2-(4-methylphenyl)acetic acid (XI) with L-menthol (XV) by means of MsOH in refluxing toluene gives the ester (XVI), which is diastereoselectively condensed with cyclopentyl bromide (XIII) by means of t-BuOK in DMF, affording 2(S)-cyclopentyl-2-(4-methylphenyl)acetic acid L-menthyl ester (XVII). Bromination of (XVII) with 1,3-dibromo-5,5-dimethylhydantoin (DBMH) in hot chlorobenzene gives the chiral benzyl bromide (XVIII), which is condensed with the already described alpha-carboline (VI) by means of t-BuOK in DMF to yield the adduct (XIX). Hydrolysis of (XIX) with HBr in formic acid affords the chiral cyclopentylacetic acid (XX), which is treated with SOCl2 in refluxing CH2Cl2 to provide the corresponding acyl chloride (XXI). Finally, this compound is condensed with (R)-2-hydroxy-1-phenylethylamine (X) by means of TEA in hot toluene.
| 【1】 Castañer, J.; Silvestre, J.S.; Sorbera, L.A.; Martín, L.; Implitapide. Drugs Fut 2000, 25, 11, 1138. |
| 【2】 Fey, P.; Naab, P.; Lenfers, J.-B.; Van Laak, K. (Bayer AG); Process for the preparation of enantiomerically pure cycloalkano-indol -and azaindol -and pyrimido[1,2a]indolcarboxycyclic acids and their activated derivs.. CA 2201435; DE 19613549; EP 0799829; JP 1998045759; US 5952498 . |
| 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) | 41797 | 2,4-dimethyl-9H-pyrido[2,3-b]indole | C13H12N2 | 详情 | 详情 | |
| (X) | 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 |
| (XI) | 28316 | 2-(4-methylphenyl)acetic acid | 622-47-9 | C9H10O2 | 详情 | 详情 |
| (XIII) | 10792 | Butanoyl chloride; Butyryl chloride | 141-75-3 | C4H7ClO | 详情 | 详情 |
| (XV) | 41803 | (1R,2S,5R)-2-isopropyl-5-methylcyclohexanol; L-menthol | 2216-51-5 | C10H20O | 详情 | 详情 |
| (XVI) | 41804 | (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 2-(4-methylphenyl)acetate | C19H28O2 | 详情 | 详情 | |
| (XVII) | 41805 | (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (2S)-2-cyclopentyl-2-(4-methylphenyl)ethanoate | C24H36O2 | 详情 | 详情 | |
| (XVIII) | 41806 | (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (2S)-2-[4-(bromomethyl)phenyl]-2-cyclopentylethanoate | C24H35BrO2 | 详情 | 详情 | |
| (XIX) | 41807 | (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (2S)-2-cyclopentyl-2-[4-[(2,4-dimethyl-9H-pyrido[2,3-b]indol-9-yl)methyl]phenyl]ethanoate | C37H46N2O2 | 详情 | 详情 | |
| (XX) | 41808 | (2S)-2-cyclopentyl-2-[4-[(2,4-dimethyl-9H-pyrido[2,3-b]indol-9-yl)methyl]phenyl]ethanoic acid | C27H28N2O2 | 详情 | 详情 | |
| (XXI) | 41809 | (2S)-2-cyclopentyl-2-[4-[(2,4-dimethyl-9H-pyrido[2,3-b]indol-9-yl)methyl]phenyl]ethanoyl chloride | C27H27ClN2O | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(XI)The condensation of indolizine (I) with 4-chloro-4-oxobutyric acid ethyl ester (II) by means of AlCl3 in dichloromethane gives 4-(3-indolizinyl)-4-oxobutyric acid ethyl ester (III), which is reduced with borane in THF to yield 4-(3-indolizinyl)butyric acid ethyl ester (IV). The condensation of (IV) with 4-acetoxybenzoyl chloride (V) by means of AlCl3 in dichloromethane affords the 1-(4-acetoxybenzoyl)indolizine derivative (VI), which is demethylated with NaH in ethanol to provide the corresponding 4-hydroxybenzoyl derivative (VII). The condensation of (VII) with 1(R)-(4-isobutyl)phenyl-1-butanol under Mitsunobu conditions (DEAD, PPh3) gives the corresponding (S)-ether (XI), which is finally hydrolyzed to the target acid by means of NaOH in methanol/THF. The chiral intermediate alcohol (VIII) has been obtained as follows: The condensation of isobutylbenzene (X) with butyryl chloride (XI) by means of AlCl3 in dichloromethane gives the butyrophenone (XII), which is then enantioselectively reduced with (+)-B-chlorodiisopinocampheyl borane [(+)-DIP- chloride] in isopropanol.
| 【1】 Okada, S.; Kuroda, A.; Sawada, K.; Sawada, Y.; Watanabe, S.; Tanaka, H.; 4-(Benzoylindolizinyl)butyric acids; novel nonsteroidal inhibitors of steroid 5alpha-reductase. III. Chem Pharm Bull 2001, 49, 7, 779. |
| 【2】 Okada, S.; Sawada, K.; Kuroda, A.; Watanabe, S.; Tanaka, H. (Fujisawa Pharmaceutical Co., Ltd.); Indolizin derivs., process for their preparation and pharmaceutical compsn. containing them. EP 0519353; JP 1993178856; US 5334716 . |
| 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) | 49217 | Indolizine | C8H7N | 详情 | 详情 | |
| (II) | 40684 | ethyl 4-chloro-4-oxobutanoate; Ethyl succinyl chloride | 14794-31-1 | C6H9ClO3 | 详情 | 详情 |
| (III) | 49218 | ethyl 4-(3-indolizinyl)-4-oxobutanoate | C14H15NO3 | 详情 | 详情 | |
| (IV) | 49219 | ethyl 4-(3-indolizinyl)butanoate | C14H17NO2 | 详情 | 详情 | |
| (V) | 49220 | 4-(chlorocarbonyl)phenyl acetate | C9H7ClO3 | 详情 | 详情 | |
| (VI) | 49221 | ethyl 4-[1-[4-(acetoxy)benzoyl]-3-indolizinyl]butanoate | C23H23NO5 | 详情 | 详情 | |
| (VII) | 49222 | ethyl 4-[1-(4-hydroxybenzoyl)-3-indolizinyl]butanoate | C21H21NO4 | 详情 | 详情 | |
| (VIII) | 49223 | (1R)-1-(4-isobutylphenyl)-1-butanol | C14H22O | 详情 | 详情 | |
| (IX) | 49224 | ethyl 4-[1-(4-[[(1S)-1-(4-isobutylphenyl)butyl]oxy]benzoyl)-3-indolizinyl]butanoate | C35H41NO4 | 详情 | 详情 | |
| (X) | 49225 | 1-Phenylisobutane; Isobutylbenzene; 2-Methyl-1-phenylpropane | 538-93-2 | C10H14 | 详情 | 详情 |
| (XI) | 10792 | Butanoyl chloride; Butyryl chloride | 141-75-3 | C4H7ClO | 详情 | 详情 |
| (XII) | 49226 | 1-(4-isobutylphenyl)-1-butanone | C14H20O | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(II)Acylation of Meldrum's acid (I) with butyryl chloride (II) in the presence of pyridine gave butyryl derivative (III). Subsequent ring opening of (III) with ethanethiol (IV), followed by decarboxylation provided S-ethyl 3-oxothiocaproate (V). Ethyl 3-amino-3-phenyl-2-propenoate (VII) was prepared by reaction of benzoylacetate (VI) with ammonium acetate in refluxing ethanol. Then, Hantzsch condensation of ketothioester (V), b-enaminoester (VII), and propionaldehyde (VIII) in EtOH at 80 C in a sealed tube furnished the dihydropyridine (IX). Finally, oxidation of (IX) using chloranil (X) in boiling THF gave the target pyridine.
| 【1】 Li, A.-H.; Moro, S.; Melman, N.; Ji, X.D.; Jacobson, K.A.; Structure-activity relationships and molecular mod. J Med Chem 1998, 41, 17, 3186. |
| 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) | 14738 | Meldrum's acid; 2,2-dimethyl-1,3-dioxane-4,6-dione；Malonic acid cyclic isopropylidene ester | 2033-24-1 | C6H8O4 | 详情 | 详情 |
| (II) | 10792 | Butanoyl chloride; Butyryl chloride | 141-75-3 | C4H7ClO | 详情 | 详情 |
| (III) | 23711 | 5-butyryl-2,2-dimethyl-1,3-dioxane-4,6-dione | C10H14O5 | 详情 | 详情 | |
| (IV) | 23712 | 1-ethanethiol; ethylhydrosulfide | 75-08-1 | C2H6S | 详情 | 详情 |
| (V) | 23713 | S-ethyl 3-oxohexanethioate | C8H14O2S | 详情 | 详情 | |
| (VI) | 10004 | Ethyl 3-oxo-3-phenylpropanoate; Benzoylacetic acid, ethyl ester | 94-02-0 | C11H12O3 | 详情 | 详情 |
| (VII) | 23715 | ethyl (E)-3-amino-3-phenyl-2-propenoate | C11H13NO2 | 详情 | 详情 | |
| (VIII) | 15966 | propionaldehyde | 123-38-6 | C3H6O | 详情 | 详情 |
| (IX) | 23716 | ethyl 4-ethyl-5-[(ethylsulfanyl)carbonyl]-2-phenyl-6-propyl-1,4-dihydro-3-pyridinecarboxylate | C22H29NO3S | 详情 | 详情 | |
| (X) | 21891 | 2,3,5,6-Tetrachloro-1,4-benzoquinone; 2,3,5,6-Tetrachlorobenzo-1,4-quinone; p-Chloranil | 118-75-2 | C6Cl4O2 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(IV)The condensation of 2-bromo-N,N-bis(benzyloxycarbonylmethyl)acetamide (I) with N,N'-bis(2-hydroxyethyl)ethylene-1,2-diamine (II) by means of TEA in DMF gives the corresponding bis-adduct (III). The monoacylation of (III) with butyryl chloride (IV) and DMAP in THF yields the monobutyrate (V), which is acylated with acetyl chloride (VI) and DMAP in THF affording the mixed diester monoacetate monobutyrate (VII). The deprotection of (VII) by hydrogenation with H2 over Pd/C in ethanol provides the tetraacetic acid (VIII), which is finally treated with gadolinium trichloride and NaOH to furnish the target compound.
| 【1】 Saab-Ismail, N.H.; et al.; Synthesis and in vivo evaluation of new contrast agents for cardiac MRI. J Med Chem 1999, 42, 15, 2852. |
| 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) | 38376 | benzyl 2-[[2-(benzyloxy)-2-oxoethyl](2-bromoacetyl)amino]acetate | C20H20BrNO5 | 详情 | 详情 | |
| (II) | 38377 | 2-([2-[(2-hydroxyethyl)amino]ethyl]amino)-1-ethanol | 4439-20-7 | C6H16N2O2 | 详情 | 详情 |
| (III) | 38378 | dibenzyl 3,12-bis[2-(benzyloxy)-2-oxoethyl]-6,9-bis(2-hydroxyethyl)-4,11-dioxo-3,6,9,12-tetraazatetradecane-1,14-dioate | C46H54N4O12 | 详情 | 详情 | |
| (IV) | 10792 | Butanoyl chloride; Butyryl chloride | 141-75-3 | C4H7ClO | 详情 | 详情 |
| (V) | 38379 | dibenzyl 3,12-bis[2-(benzyloxy)-2-oxoethyl]-6-[2-(butyryloxy)ethyl]-9-(2-hydroxyethyl)-4,11-dioxo-3,6,9,12-tetraazatetradecane-1,14-dioate | C50H60N4O13 | 详情 | 详情 | |
| (VI) | 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 |
| (VII) | 38380 | dibenzyl 6-[2-(acetoxy)ethyl]-3,12-bis[2-(benzyloxy)-2-oxoethyl]-9-[2-(butyryloxy)ethyl]-4,11-dioxo-3,6,9,12-tetraazatetradecane-1,14-dioate | C52H62N4O14 | 详情 | 详情 | |
| (VIII) | 38381 | 6-[2-(acetoxy)ethyl]-9-[2-(butyryloxy)ethyl]-3,12-bis(carboxymethyl)-4,11-dioxo-3,6,9,12-tetraazatetradecane-1,14-dioic acid | C24H38N4O14 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(II)4-Chloroanthranilic acid (I) is acylated by butyryl chloride (II) in DMF to produce amide (III). This is then cyclized to the benzoxazinone (IV) upon heating with acetic anhydride. Condensation of (IV) with benzylamine (V) in refluxing chloroform, followed by treatment with NaOH in hot ethyleneglycol, gives rise to the quinazolinone (VI). Subsequent benzylic bromination of (VI) at the propyl side chain produces (VII). The bromide group of (VII) is then displaced with N,N-dimethyl-1,3-propanediamine (VIII) to furnish (IX). Finally, amine (IX) is acylated by 4-bromobenzoyl chloride (X) to afford the corresponding benzamide.
| 【1】 Chabala, J.C.; Morgans, D.J. Jr.; Feng, B.; Finer, J.T.; Bergnes, G.; Smith, W.W. (Cytokinetics, Inc.); Methods and compsns. utilizing quinazolinones. WO 0198278 . |
| 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) | 52504 | 4-Chloro-2-aminobenzoic acid; 2-Amino-4-chlorobenzoic acid; 2-Carboxy-5-chloroaniline; 3-Amino-4-carboxy-1-chlorobenzene; 4-Chloroanthranilic acid | 89-77-0 | C7H6ClNO2 | 详情 | 详情 |
| (II) | 10792 | Butanoyl chloride; Butyryl chloride | 141-75-3 | C4H7ClO | 详情 | 详情 |
| (III) | 58445 | 2-(butyrylamino)-4-chlorobenzoic acid | C11H12ClNO3 | 详情 | 详情 | |
| (IV) | 58446 | 7-chloro-2-propyl-4H-3,1-benzoxazin-4-one | C11H10ClNO2 | 详情 | 详情 | |
| (V) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (VI) | 58447 | 3-benzyl-7-chloro-2-propyl-4(3H)-quinazolinone | C18H17ClN2O | 详情 | 详情 | |
| (VII) | 58448 | 3-benzyl-2-(1-bromopropyl)-7-chloro-4(3H)-quinazolinone | C18H16BrClN2O | 详情 | 详情 | |
| (VIII) | 25248 | N-(3-aminopropyl)-N,N-dimethylamine; N(1),N(1)-dimethyl-1,3-propanediamine | 109-55-7 | C5H14N2 | 详情 | 详情 |
| (IX) | 58449 | 3-benzyl-7-chloro-2-(1-{[3-(dimethylamino)propyl]amino}propyl)-4(3H)-quinazolinone | C23H29ClN4O | 详情 | 详情 | |
| (X) | 45960 | 4-bromobenzoyl chloride | 586-75-4 | C7H4BrClO | 详情 | 详情 |