【结 构 式】 |
【分子编号】36651 【品名】Ethyl (bromoacetyl)acetate;ethyl 4-bromo-3-oxobutanoate 【CA登记号】13176-46-0 |
【 分 子 式 】C6H9BrO3 【 分 子 量 】209.03966 【元素组成】C 34.47% H 4.34% Br 38.22% O 22.96% |
合成路线1
该中间体在本合成路线中的序号:(I)The reaction of ethyl 4-bromoacetoacetate (I) with 2-chloroethanol (II) by means of NaH in THF gives ethyl 4-(2-chloroethoxy)acetoacetate (III), which is treated with NaI in refluxing acetone to yield the corresponding 2-iodoethoxy derivative (IV). The condensation of (IV) with 2-chlorobenzaldehyde (V) by means of piperidine acetate in isopropanol affords ethyl 2-(2-chlorobenzylidene)-4-(2-iodoethoxy)acetoacetate (VI), which is cyclized with methyl 3-aminocrotonate (VII) in refluxing isopropanol to provide the dihydropyridine (VIII). The reaction of (VIII) with hexamethylenetetramine (IX) in hot acetonitrile gives the aminium salt (X), which is finally treated with benzenesulfonic acid in refluxing butanol (methanol)/water. Alternatively, the intermediate dihydropyridine (VIII) can be obtained as follows: The condensation of ethyl 4-(2-chloroethoxy)acetoacetate (III) with the aldehyde (V) by means of piperidine acetate in isopropanol gives ethyl 2-(2-chlorobenzylidene)-4-(2-chloroethoxy)acetoacetate (XI), which is cyclized with methyl 3-aminocrotonate (VII) in refluxing isopropanol to yield the corresponding dihydropyridine (XII). Finally, this compound is treated with NaI in refluxing isopropanol to afford the target intermediate dihydropyridine (VIII).
【1】 Németh, N.; Vereczkey, G.D.; Krasznai, G.; Koványi, G.; Német, G.; Blask, G.; Tömpe, P.; Nagy, K.; Bozsing, D.; Simig, G. (Egis Pharmaceuticals Ltd.); A process and intermediate cpds. for the preparation of amlodipine benzene sulphonate. EP 0902016 . |
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) | 36651 | Ethyl (bromoacetyl)acetate;ethyl 4-bromo-3-oxobutanoate | 13176-46-0 | C6H9BrO3 | 详情 | 详情 |
(II) | 10384 | 2-Chloro-1-ethanol; Ethylene chlorohydrin | 107-07-3 | C2H5ClO | 详情 | 详情 |
(III) | 48269 | ethyl 4-(2-chloroethoxy)-3-oxobutanoate | C8H13ClO4 | 详情 | 详情 | |
(IV) | 48270 | ethyl 4-(2-iodoethoxy)-3-oxobutanoate | C8H13IO4 | 详情 | 详情 | |
(V) | 24114 | 2-chlorobenzaldehyde | 89-98-5 | C7H5ClO | 详情 | 详情 |
(VI) | 48271 | ethyl (Z)-3-(2-chlorophenyl)-2-[2-(2-iodoethoxy)acetyl]-2-propenoate | C15H16ClIO4 | 详情 | 详情 | |
(VII) | 11372 | Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate | C5H9NO2 | 详情 | 详情 | |
(VIII) | 48272 | 3-ethyl 5-methyl 4-(2-chlorophenyl)-2-[(2-iodoethoxy)methyl]-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate | C20H23ClINO5 | 详情 | 详情 | |
(IX) | 34873 | 1,3,5,7-tetraazatricyclo[3.3.1.1(3,7)]decane | 100-97-0 | C6H12N4 | 详情 | 详情 |
(X) | 48273 | 1-(2-[[4-(2-chlorophenyl)-3-(ethoxycarbonyl)-5-(methoxycarbonyl)-6-methyl-1,4-dihydro-2-pyridinyl]methoxy]ethyl)-3,5,7-triaza-1-azoniatricyclo[3.3.1.1(3,7)]decane iodide | C26H35ClIN5O5 | 详情 | 详情 | |
(XI) | 48274 | ethyl (Z)-2-[2-(2-chloroethoxy)acetyl]-3-(2-chlorophenyl)-2-propenoate | C15H16Cl2O4 | 详情 | 详情 | |
(XII) | 48275 | 3-ethyl 5-methyl 2-[(2-chloroethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate | C20H23Cl2NO5 | 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-aminopyridine (I) with ethyl 4-bromoacetoacetate (II) by means of NaHCO3 in hot dioxane gives the imidazopyridine (III), which is hydrolyzed at the ester function with KOH in ethanol yielding the free acid (IV) . Finally, the treatment of acid (IV) with phosphorous acid and PCl3 in chlorobenzene at 115 C, followed by hydrolysis in boiling 6N HCl yielded the target bisphosphonate.
【1】 Atsumi, T.; et al.; JP 7688965 . |
【2】 Takeuchi, M.; Sakamoto, S.; Kawamuki, K.; Kurihara, H.; Nakahara, H.; Isomura, Y.; Studies on novel bone resorption inhibitors. II. Synthesis and pharmacological activities of fused aza-heteroarylbisphosphonate derivatives. Chem Pharm Bull 1998, 46, 11, 1703. |
【3】 Isomura, Y.; Takeuchi, M.; Abe, T. (Yamanouchi Pharmaceutical Co., Ltd.); Heterocyclic biphosphonic acid derivs.. EP 0354806; US 4990503; US 5039669 . |
【4】 Casagrande, C.; et al.; Synthesis and pharmacological activity of imidazo-[1,2-a]pyridine-2-acetic and -2,3-dicarboxylic acid and related compounds. Farmaco 1968, 23, 12, 1141. |
【5】 Ishii, M.; Takaoka, K. (Yamanouchi Pharmaceutical Co., Ltd.); Novel preparation method of heterocyclic bis(phosphonic acid) derivs.. JP 1999269184 . |
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) | 11305 | 2-Pyridinamine; 2-Pyridinylamine; 2-Aminopyridine | 504-29-0 | C5H6N2 | 详情 | 详情 |
(II) | 36651 | Ethyl (bromoacetyl)acetate;ethyl 4-bromo-3-oxobutanoate | 13176-46-0 | C6H9BrO3 | 详情 | 详情 |
(III) | 36652 | ethyl 2-imidazo[1,2-a]pyridin-3-ylacetate | C11H12N2O2 | 详情 | 详情 | |
(IV) | 36653 | 2-imidazo[1,2-a]pyridin-3-ylacetic acid | C9H8N2O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(II)
【1】 宫平,宫凤仙,王钝.2-(2-氨基-噻唑)-(Z)-羟基亚胺基乙酸乙酯的合成.沈阳药科大学学报,1998,15:235. |
【2】 Arita H,Ikeda K,Akamatsu H.Production of (Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetic acid ester:JP,Patent 09,194,470 1997. |
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) | 11819 | ethyl acetoacetate; ethyl 3-oxobutanoate;Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate | 141-97-9 | C6H10O3 | 详情 | 详情 |
(II) | 36651 | Ethyl (bromoacetyl)acetate;ethyl 4-bromo-3-oxobutanoate | 13176-46-0 | C6H9BrO3 | 详情 | 详情 |
(III) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
(IV) | 15889 | Ethyl 2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate;(Z)-ethyl 2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetate; ethyl 2-(2-amino-1,3-thiazol-4-yl)-2-(hydroxyimino)acetate | 60845-81-0 | C7H9N3O3S | 详情 | 详情 |