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【结 构 式】 
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【分子编号】11306 【品名】Cyclohexanol 【CA登记号】108-93-0 |
【 分 子 式 】C6H12O 【 分 子 量 】100.16068 【元素组成】C 71.95% H 12.08% O 15.97% |
合成路线1
该中间体在本合成路线中的序号：(II)The reaction of 1-chloroethyl chloroformate (I) with cyclohexanol (II) by means of pyridine in dichloromethane gives 1-chloroethyl cyclohexyl carbonate (III), which is converted to the corresponding iodoethyl derivative (IV) with NaI in hot acetonitrile. Finaly this compound is condensed with potassium 7beta-[2-(2-aminothiazol-4-yl)acetamido]-3-[1-[2-(dimethylamino)ethyl]-1H-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylate (V) in DMF.
| 【1】 Yashiki, T.; Nishimura, T.; Numata, M.; Hirai, S.; Takanohashi, K.; Miyake, A.; Yoshimura, Y.; Hamaguchi, N.; Yamaoka, M.; Orally active 1-(cyclohexyloxycarbonyloxy)alkyl es. J Antibiot 1987, 40, 1, 81. |
| 【2】 Hirai, S.; Koyama, H.; Makino, T. (Takeda Chemical Industries, Ltd.); Antibacterial solid compsn. for oral administratio. EP 0163433; JP 1985233012; JP 1987030713 . |
| 【3】 Castaner, J.; Prous, J.; SCE-2174. Drugs Fut 1988, 13, 3, 231. |
| 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) | 22014 | 1-chloro-1-[(chlorocarbonyl)oxy]ethane | 50893-53-3 | C3H4Cl2O2 | 详情 | 详情 |
| (II) | 11306 | Cyclohexanol | 108-93-0 | C6H12O | 详情 | 详情 |
| (III) | 15573 | 1-chloroethyl cyclohexyl carbonate | C9H15ClO3 | 详情 | 详情 | |
| (IV) | 15339 | cyclohexyl 1-iodoethyl carbonate | 102672-57-1 | C9H15IO3 | 详情 | 详情 |
| (V) | 22018 | potassium (7R)-7-[[2-(2-amino-1,3-thiazol-4-yl)acetyl]amino]-3-[([1-[2-(dimethylamino)ethyl]-1H-1,2,3,4-tetraazol-5-yl]sulfanyl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C18H22KN9O4S3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XII)This compound can be prepared by two similar ways: 1) The monoacylation of ethylene glycol (I) with chloroacetyl chloride (II) and triethylamine gives 2-hydroxyethyl chloroacetate (III), which is condensed with saccharine (IV) by means of NaOH in ethylene glycol yielding 2-hydroxyethyl 3-oxo-1,2-benzisothiazoline-2-acetate 1,1-dioxide (V). Isomerization of (V) by means of potassium tert-butoxide in DMSO affords2-hydroxyethyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (VI), which is methylated with NaOH and methyl iodide in aqueous ethanol giving the corresponding N-methyl derivative (VII). Hydrolysis of (VII) with NaOH in ethanol - water yields the corresponding free acid (VIII), which is acylated with cinnamoyl chloride (IX) by means of triethylamine in dichloromethane to afford the biscinnamoyl derivative (X). Finally, this compound is treated with 2-aminopyridine (XI) in dichloromethane. 2) The preceding sequence can also be carried out with cyclohexanol (XII) instead of ethylene glycol (I), then producing compounds (XIII), (XIV), (XV) and (XVI), which by hydrolysis affords the free acid (VIII).
| 【1】 Bruzzese, T.; Dell'Acqua, E.; Ottonni, F.; Van den Heuvel, H.H. (SPA (Societa Prodotti Antibiotici)); Process for preparing benzothiazine compds. EP 0146102 . |
| 【2】 Prous, J.; Castaner, J.; CINNOXICAM. Drugs Fut 1990, 15, 2, 119. |
| 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) | 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 |
| (II) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (III) | 11297 | 2-hydroxyethyl 2-chloroacetate | C4H7ClO3 | 详情 | 详情 | |
| (IV) | 11298 | 1H-1,2-Benzisothiazole-1,1,3(2H)-trione; Saccharin | 81-07-2 | C7H5NO3S | 详情 | 详情 |
| (V) | 11299 | 2-hydroxyethyl 2-(1,1,3-trioxo-1,3-dihydro-2H-1,2-benzisothiazol-2-yl)acetate | C11H11NO6S | 详情 | 详情 | |
| (VI) | 11300 | 2-hydroxyethyl 4-hydroxy-1,1-dioxo-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate | C11H11NO6S | 详情 | 详情 | |
| (VII) | 11301 | 2-hydroxyethyl 4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate | C12H13NO6S | 详情 | 详情 | |
| (VIII) | 11302 | 4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylic acid | C10H9NO5S | 详情 | 详情 | |
| (IX) | 11303 | (E)-3-Phenyl-2-propenoyl chloride; 3-Phenyl-2-propenoyl chloride | 102-92-1 | C9H7ClO | 详情 | 详情 |
| (X) | 11304 | 2-Methyl-1,1-dioxo-4-[[(E)-3-phenyl-2-propenoyl]oxy]-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylic (E)-2-phenyl-2-propenoic anhydride | C28H21NO7S | 详情 | 详情 | |
| (XI) | 11305 | 2-Pyridinamine; 2-Pyridinylamine; 2-Aminopyridine | 504-29-0 | C5H6N2 | 详情 | 详情 |
| (XII) | 11306 | Cyclohexanol | 108-93-0 | C6H12O | 详情 | 详情 |
| (XIII) | 11307 | cyclohexyl 2-chloroacetate | C8H13ClO2 | 详情 | 详情 | |
| (XIV) | 11308 | cyclohexyl 2-(1,1,3-trioxo-1,3-dihydro-2H-1,2-benzisothiazol-2-yl)acetate | C15H17NO5S | 详情 | 详情 | |
| (XV) | 11309 | cyclohexyl 4-hydroxy-1,1-dioxo-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate | C15H17NO5S | 详情 | 详情 | |
| (XVI) | 11310 | cyclohexyl 4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate | C16H19NO5S | 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 condensation of 2-fluoronitrobenzene (I) with cyclohexanol (II) by means of NaH gives 2-(cyclohexyloxy)nitrobenzene (III), which is reduced with H2 over Pd/C in methanol yielding 2-(cyclohexyloxy)aniline (IV). The acylation of (IV) with methanesulfonyl chloride (V) in pyridine affords N-(2-cyclohexyloxy phenyl)methanesulfonamide (VI), which is finally nitrated with concentrated HNO3 in hot acetic acid.
| 【1】 Yoshikawa, K.; Ohuchi, Y.; Sekiuchi, K.; Saito, S.; Hatayama, K.; Sota, K. (Taisho Pharmaceutical Co., Ltd.); Sulfoanilide cpds. EP 0317332; JP 1990000268 . |
| 【2】 Yoshikawa, K.; Ohuchi, H.; Saito, H.; Nakajima, Y.; Hatayama, K.; Soda, H. (Taisho Pharmaceutical Co., Ltd.); Antiinflammatories, analgesics and antipyretics. JP 1990300122 . |
| 【3】 Prous, J.; Castaner, J.; Mealy, N.; NS-398. Drugs Fut 1993, 18, 7, 603. |
| 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) | 13463 | o-Fluoronitrobenzene; 1-fluoro-2-nitrobenzene | 1493-27-2 | C6H4FNO2 | 详情 | 详情 |
| (II) | 11306 | Cyclohexanol | 108-93-0 | C6H12O | 详情 | 详情 |
| (III) | 13465 | Cyclohexyl 2-nitrophenyl ether; 1-(Cyclohexyloxy)-2-nitrobenzene | C12H15NO3 | 详情 | 详情 | |
| (IV) | 13466 | 2-(Cyclohexyloxy)aniline; 2-(Cyclohexyloxy)phenylamine | C12H17NO | 详情 | 详情 | |
| (V) | 13467 | Methanesulfonyl chloride;Mesyl chloride;Methylsulfonyl chloride;Methanesulfonic acid chloride;Methanesulfonyl chloride;Methanesulphonyl chloride | 124-63-0 | CH3ClO2S | 详情 | 详情 |
| (VI) | 13468 | N-[2-(Cyclohexyloxy)phenyl]methanesulfonamide | C13H19NO3S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(III)By refluxing a solution of equimolecular quantities of 3-pentyloxyphenyl isocyanate (I) and trans-2-(1-pyrrolidinyl)cyclohexanol (II) in toluene. The obtained pentacaine base is transformed to the hydrochloride by treatment of an ether solution of anhydrous hydrogen chloride (1,2). The starting amino-alcohol (II) is prepared from cyclohexanol (III), which is first dehydrated to cyclohexene (IV). The following addition of HClO gives trans-2-chlorocyclohexanol (V), which, in turn is dehydrochlorinated to 1,2-epoxycyclohexane (VI). Final addition of pyrrolidine (A) yields the required intermediate (II).
| 【1】 Castaner, J.; Pentacaine. Drugs Fut 1976, 1, 8, 379. |
| 【2】 Subert, J.; et al.; Studies on local anesthetics. XLVIII. Preliminary analytical evaluation of the substance K-1902 (pentacaine). Cesk Farm 1975, 24, 5. |
| 【3】 Benes, L.; Borovansky, A.; Kopácová, L.; Basische trans- und cis-Cyklohexylester substituierter Alkoxycarbanilsäuren. XLI. Studien über Lokalanästhetika. Arch Pharm 1972, 305, 648. |
| 【4】 Benes, L.; Borovansky, A.; Kopácová, L.; Alkoxycarbanilic acid esters with high local anaesthetic activity. Arzneim-Forsch Drug Res 1969, 19, 1902-3. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (I) | 14636 | 3-(pentyloxy)phenyl isocyanate; 1-isocyanato-3-(pentyloxy)benzene | C12H15NO2 | 详情 | 详情 | |
| (II) | 14637 | (1R,2R)-2-(1-pyrrolidinyl)cyclohexanol | C10H19NO | 详情 | 详情 | |
| (III) | 11306 | Cyclohexanol | 108-93-0 | C6H12O | 详情 | 详情 |
| (IV) | 40446 | 1-cyclohexene | 110-83-8 | C6H10 | 详情 | 详情 |
| (V) | 40447 | (1R,2R)-2-chlorocyclohexanol | 1561-86-0 | C6H11ClO | 详情 | 详情 |
| (VI) | 40448 | (1R,6R)-7-oxabicyclo[4.1.0]heptane | C6H10O | 详情 | 详情 |