|
【结 构 式】 
|
【分子编号】44281 【品名】pivalic acid 【CA登记号】75-98-9 |
【 分 子 式 】C5H10O2 【 分 子 量 】102.1332 【元素组成】C 58.8% H 9.87% O 31.33% |
合成路线1
该中间体在本合成路线中的序号：(XII)Treatment of 4-oxopiperidine (IX) with chloromethyl chloroformate (X) and NaOH in H2O/Et2O provides 4-oxopiperidine-1-carboxylic acid chloromethyl ester (XI), which is then condensed with pivalic acid (XII) in DMF in the presence of K2CO3 to furnish derivative (XIII). Finally, (XIII) is reductively condensed with intermediate (VI) by means of NaBH4, HOAc and Et3N in THF/EtOAc.
| 【1】 Katano, K.; Ohuchi, S.; Miura, T.; Shitara, E.; Shimizu, M.; Yaegashi, K.; Ohkura, N.; Isomura, Y.; Iida, H.; Ishikawa, M.; Asai, K.; Hatsushiba, E. (Meiji Seika Kaisha, Ltd.); Novel cpd. having platelet aggregation inhibitor effect. EP 0721941; US 5814636; WO 9602503 . |
| 【2】 Ohuchi, S.; Suzuki, H.; Ando, T.; Katano, K.; Imai, T.; Kobayashi, K.; Ota, K.; Aizawa, K.; Miura, T. (Meiji Seika Kaisha, Ltd.); Nitrogen-containing heterocyclic cpds. having antiplatelet aggregation effect and medicinal use thereof. EP 1070712; WO 9952894 . |
| 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) | 44880 | ethyl 2-[4-[2-(2-oxo-1-piperazinyl)acetyl]phenoxy]acetate | C16H20N2O5 | 详情 | 详情 | |
| (IX) | 44883 | 1lambda(5)-piperazin-1-one | C4H10N2O | 详情 | 详情 | |
| (X) | 19249 | Chloromethyl chloroformate; Chloro[(chlorocarbonyl)oxy]methane | 22128-62-7 | C2H2Cl2O2 | 详情 | 详情 |
| (XI) | 44884 | chloromethyl 4-oxo-4lambda(5)-piperazine-1-carboxylate | C6H11ClN2O3 | 详情 | 详情 | |
| (XII) | 44281 | pivalic acid | 75-98-9 | C5H10O2 | 详情 | 详情 |
| (XIII) | 44885 | [(2,2-dimethylpropanoyl)oxy]methyl 4-oxo-4lambda(5)-piperazine-1-carboxylate | C11H20N2O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XII)Reductive condensation of 2-oxopiperazine (I) with 4-oxopiperidine-1-carboxylic acid t-butyl ester (XIV) in the presence of sodium cyanoborohydride (NaBH3CN) in MeOH/EtOH-HCl yields derivative (XV), which is then coupled to bromo derivative (IV) by means of sodium in refluxing toluene to give compound (XVI). Deprotection of (XVI) by treatment with TFA and anisole provides piperidine derivative (XVII), which is then treated with chloromethyl chloroformate (X) and proton sponge in CH2Cl2 to furnish derivative (XVIII). Finally, (XVIII) is coupled to pivalic acid (XII) by means of K2CO3 in DMF and converted into the corresponding hydrochloride salt by treatment with HCl-EtOH in EtOAc.
| 【1】 Katano, K.; Ohuchi, S.; Miura, T.; Shitara, E.; Shimizu, M.; Yaegashi, K.; Ohkura, N.; Isomura, Y.; Iida, H.; Ishikawa, M.; Asai, K.; Hatsushiba, E. (Meiji Seika Kaisha, Ltd.); Novel cpd. having platelet aggregation inhibitor effect. EP 0721941; US 5814636; WO 9602503 . |
| 【2】 Ohuchi, S.; Suzuki, H.; Ando, T.; Katano, K.; Imai, T.; Kobayashi, K.; Ota, K.; Aizawa, K.; Miura, T. (Meiji Seika Kaisha, Ltd.); Nitrogen-containing heterocyclic cpds. having antiplatelet aggregation effect and medicinal use thereof. EP 1070712; WO 9952894 . |
| 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) | 44876 | 2-piperazinone | C4H8N2O | 详情 | 详情 | |
| (IV) | 44878 | ethyl 2-[4-(1lambda(3)-dibromanylcarbonyl)phenoxy]acetate | C11H12Br2O4 | 详情 | 详情 | |
| (X) | 19249 | Chloromethyl chloroformate; Chloro[(chlorocarbonyl)oxy]methane | 22128-62-7 | C2H2Cl2O2 | 详情 | 详情 |
| (XII) | 44281 | pivalic acid | 75-98-9 | C5H10O2 | 详情 | 详情 |
| (XIV) | 44886 | tert-butyl 4-oxo-4lambda(5)-piperazine-1-carboxylate | C9H18N2O3 | 详情 | 详情 | |
| (XV) | 44887 | C13H24N4O3 | 详情 | 详情 | ||
| (XVI) | 44888 | C24H35BrN4O7 | 详情 | 详情 | ||
| (XVII) | 44889 | C20H28N4O5 | 详情 | 详情 | ||
| (XVIII) | 44890 | C22H29ClN4O7 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)Decarboxylative radical alkylation of 3,6-dichloropyridazine (I) using pivalic acid (II) and ammonium persulfate in the presence of silver nitrate catalyst furnished 3,6-dichloro-4-tert-butylpyridiazine (III). This was then condensed with 2,5-difluorobenzoyl hydrazide (IV) to produce the triazolopyridazine derivative (V). The remaining chlorine atom was finally displaced with (2-methyl-2H-1,2,4-triazol-3-yl)methanol (VI) using NaH in DMF to afford the title compound.
| 【1】 Madin, A.; Castro Pineiro, J.L.; Carling, W.R.; Street, L.J.; Russell, M.G.; Moore, K.W.; Guiblin, A.R.; Broughton, H.B. (Merck Sharp & Dohme Ltd.); Substd. triazolo-pyridazine derivs. as ligands for GABA receptors. EP 0915875; WO 9804559 . |
| 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) | 11292 | 3,6-Dichloropyridazine | 141-30-0 | C4H2Cl2N2 | 详情 | 详情 |
| (II) | 44281 | pivalic acid | 75-98-9 | C5H10O2 | 详情 | 详情 |
| (III) | 44282 | 4-(tert-butyl)-3,6-dichloropyridazine | C8H10Cl2N2 | 详情 | 详情 | |
| (IV) | 44283 | 2,5-difluorobenzohydrazide | C7H6F2N2O | 详情 | 详情 | |
| (V) | 44284 | 7-(tert-butyl)-6-chloro-3-(2,5-difluorophenyl)[1,2,4]triazolo[4,3-b]pyridazine | C15H13ClF2N4 | 详情 | 详情 | |
| (VI) | 44285 | (1-methyl-1H-1,2,4-triazol-5-yl)methanol | C4H7N3O | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XII)The esterification of 3,4-dichlorophenylacetic acid (I) with methanol and ClH gives the methyl ester (II), which is alkylated with allyl bromide and LDA in THF to yield 2-(3,4-dichlorophenyl)-4-pentenoic acid methyl ester (IV). The hydrolysis of (IV) with LiOH in MeOH/water affords the corresponding free acid (V), which is epoxidated with MCPBA in refluxing chloroform to provide epoxide (VI), which, without isolation, is treated in acid medium, giving the tetrahydrofuranone (VII). The silylation of the OH group of (VII) with Tbdms-Cl and imidazole in DMF yields the protected silyl ether (VIII), which is treated with LDA in THF to afford the lithium enolate (IX). The reaction of (IX) with phenylselenyl chloride in THF provides the phenylselenyl derivative (X), which is oxidized with MCPBA to the corresponding selenoxide. This nonisolated compound undergoes spontaneous syn elimination to give, after hydrolysis of the silyl ether with AcOH, 3-(3,4-dichlorophenyl)-5-(hydroxymethyl)furan-2(5H)-one (XI). Finally, this compound is esterified with pivaloyl chloride and pyridine in dichloromethane to afford the target ester.
| 【1】 Pour, M.; et al.; 3-Phenyl-5-acyloxymethyl-2H,5H-furan-2-ones: Synthesis and biological activity of a novel group of potential antifungal drugs. J Med Chem 2001, 44, 17, 2701. |
| 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) | 30414 | 2-(3,4-dichlorophenyl)acetic acid；2-(3,4-Dichlorophenyl)acetic acid | 5807-30-7 | C8H6Cl2O2 | 详情 | 详情 |
| (II) | 47947 | methyl 2-(3,4-dichlorophenyl)acetate | C9H8Cl2O2 | 详情 | 详情 | |
| (III) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (IV) | 50420 | methyl 2-(3,4-dichlorophenyl)-4-pentenoate | C12H12Cl2O2 | 详情 | 详情 | |
| (V) | 50421 | 2-(3,4-dichlorophenyl)-4-pentenoic acid | C11H10Cl2O2 | 详情 | 详情 | |
| (VI) | 50422 | 2-(3,4-dichlorophenyl)-3-(2-oxiranyl)propionic acid | C11H10Cl2O3 | 详情 | 详情 | |
| (VII) | 50423 | 3-(3,4-dichlorophenyl)-5-(hydroxymethyl)dihydro-2(3H)-furanone | C11H10Cl2O3 | 详情 | 详情 | |
| (VIII) | 50424 | 5-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-(3,4-dichlorophenyl)dihydro-2(3H)-furanone | C17H24Cl2O3Si | 详情 | 详情 | |
| (IX) | 50425 | C17H23Cl2LiO3Si | 详情 | 详情 | ||
| (X) | 50426 | 5-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-(3,4-dichlorophenyl)-3-(phenylselanyl)dihydro-2(3H)-furanone | C23H28Cl2O3SeSi | 详情 | 详情 | |
| (XI) | 50427 | 3-(3,4-dichlorophenyl)-5-(hydroxymethyl)-2(5H)-furanone | C11H8Cl2O3 | 详情 | 详情 | |
| (XII) | 44281 | pivalic acid | 75-98-9 | C5H10O2 | 详情 | 详情 |