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【结 构 式】 
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【分子编号】19249 【品名】Chloromethyl chloroformate; Chloro[(chlorocarbonyl)oxy]methane 【CA登记号】22128-62-7 |
【 分 子 式 】C2H2Cl2O2 【 分 子 量 】128.94208 【元素组成】C 18.63% H 1.56% Cl 54.99% O 24.82% |
合成路线1
该中间体在本合成路线中的序号：(V)Hemifumarate salt (I) was liberated by treatment with NaHCO3 and subsequently protected with trityl chloride to afford (II). Then, the methyl ester function of (II) was hydrolyzed with NaOH to furnish acid (III). Chlorination of methyl chloroformate (IV) with sulfuryl chloride in the presence of a catalytic amount of azobis(isobutyronitrile) (AIBN) yielded chloromethyl chloroformate (V), which was condensed with 3-pentanol (VI) in pyridine to provide carbonate (VII). The O-alkylation of acid (III) with 3-pentyloxycarbonyloxymethyl chloride (VII) in the presence of K2CO3 in DMF produced the pentyloxycarbonyloxymethyl ester (VIII). Finally, the trityl protecting group of (VIII) was removed with 85% formic acid at r.t., and the resulting product was converted to the hydrochloride salt by treatment with an ethanolic solution of HCl.
| 【1】 Sekine, Y.; Kawanishi, E.; Narita, H.; Hashimoto, Y.; Mizobe, M. (Tanabe Seiyaku Co., Ltd.); Imidazopyridine derivs. and process for preparing the same. CA 2146802; EP 0682023; JP 1996003162; US 5753672 . |
| 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) | 25230 | methyl 5-acetyl-2-propyl-3-[[2'-(1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-4-carboxylate | C27H29N7O3 | 详情 | 详情 | |
| (II) | 25231 | methyl 5-acetyl-2-propyl-3-[[2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-4-carboxylate | C46H43N7O3 | 详情 | 详情 | |
| (III) | 25232 | 5-acetyl-2-propyl-3-[[2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-4-carboxylic acid | C45H41N7O3 | 详情 | 详情 | |
| (IV) | 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 |
| (V) | 19249 | Chloromethyl chloroformate; Chloro[(chlorocarbonyl)oxy]methane | 22128-62-7 | C2H2Cl2O2 | 详情 | 详情 |
| (VI) | 21970 | 3-pentanol | 584-02-1 | C5H12O | 详情 | 详情 |
| (VII) | 25234 | chloromethyl 1-ethylpropyl carbonate | C7H13ClO3 | 详情 | 详情 | |
| (VIII) | 25233 | [[(1-ethylpropoxy)carbonyl]oxy]methyl 5-acetyl-2-propyl-3-[[2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-4-carboxylate | C52H53N7O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The reaction of chloromethyl chloroformate (I) with isopropyl alcohol (II) by means of pyridine or triethylamine in ether gives the mixed carbonate (III), which is then condensed with (R)-PMPA (IV) by means of diisopropyl ethyl-amine in DMF.
| 【1】 Oliyai, R.; Dougherty, J.; Bischofberger, N.; Kim, C.U.; Mulato, A.; Shaw, J.P.; Cundy, K.C.; Arimilli, M.N.; Synthesis, in vitro biological evaluation and oral bioavailability of 9-[2-(phosphonomethoxy)propyl]adenine (PMPA) prodrugs. Antivir Chem Chemother 1997, 8, 6, 557. |
| 【2】 Sorbera, L.A.; Castañer, J.; (R)-PMPA and Bis(POC)PMPA. Drugs Fut 1998, 23, 12, 1279. |
| 【3】 Arimilli, M.N.; Cundy, K.C.; Dougherty, J.P.; Kim, C.U.; Oliyai, R.; Stella, V.J. (Gilead Sciences Inc.); Nucleotide analogs. US 5922695; WO 9804569 . |
| 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) | 19249 | Chloromethyl chloroformate; Chloro[(chlorocarbonyl)oxy]methane | 22128-62-7 | C2H2Cl2O2 | 详情 | 详情 |
| (II) | 19250 | 2-propanol | 67-63-0 | C3H8O | 详情 | 详情 |
| (III) | 19251 | chloromethyl isopropyl carbonate | C5H9ClO3 | 详情 | 详情 | |
| (IV) | 19252 | [[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethyl]oxy]methylphosphonic acid | C9H14N5O4P | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(X)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4
该中间体在本合成路线中的序号：(X)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5
该中间体在本合成路线中的序号：(V)The esterification of (rac)-6-(5-chloro-3-pyridyl)-5-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-7-one rac-(I) with chloromethyl chloroformate (V) in pyridine gives the racemic carbonate rac-(III), which is submitted to an enantioselective hydrolysis with Candida antarctica (SP 435L) lipase in dioxane/benzyl alcohol yielding a mixture of rac-(I), which is recycled, and enantiomerically pure (96% e.e.) (S)-(III). Finally, this compound is condensed with 1-methylpiperazine (IV) in acetone.
| 【1】 Culy, C.; Castañer, J.; Bayes, M.; Eszopiclone. Drugs Fut 2003, 28, 7, 640. |
| 【2】 Solares, L.F.; Diaz, M.; Brieva, R.; Sanchez, V.M.; Bayod, M.; Gotor, V.; Enzymatic resolution of new carbonate intermediates for the synthesis of (S)-(+)-zopiclone. Tetrahedron Asymmetry 2002, 13, 23, 2577. |
| 【3】 Gotor, V.; et al.; Enzymic resolution of (±)-6-(5-chloropyridin-2-yl)-7-vinyloxycarbonyloxy-6,7-dihydro[5H] pyrrolo[3,4-b]pyrazin-5-one. Synthesis of (+)-zopiclone. Tetrahedron Asymmetry 1997, 8, 7, 995. |
| 【4】 Cotrel, C.; et al. (Aventis Pharma SA); Pyrrolo-[3,4,b]pyrazine derivatives. DE 2300491; GB 1358680; JP 52048687; US 3862149 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| rac-(I) | 32796 | 6-(5-chloro-2-pyridinyl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one | C11H7ClN4O2 | 详情 | 详情 | |
| rac-(III) | 62951 | chloromethyl 6-(5-chloro-2-pyridinyl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl carbonate | C13H8Cl2N4O4 | 详情 | 详情 | |
| (S)-(III) | 62952 | chloromethyl (5S)-6-(5-chloro-2-pyridinyl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl carbonate | C13H8Cl2N4O4 | 详情 | 详情 | |
| (IV) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
| (V) | 19249 | Chloromethyl chloroformate; Chloro[(chlorocarbonyl)oxy]methane | 22128-62-7 | C2H2Cl2O2 | 详情 | 详情 |