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【结 构 式】 
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【分子编号】23985 【品名】Chlorodifluoromethane; Chloro(difluoro)methane 【CA登记号】75-45-6 |
【 分 子 式 】CHClF2 【 分 子 量 】86.4684464 【元素组成】C 13.89% H 1.17% Cl 41% F 43.94% |
合成路线1
该中间体在本合成路线中的序号：(II)By reaction of N2,N5-dibenzylidinolysine methly ester (I), with chlorodifluoromethane (II) in the presence of lithium diisopropylamide, followed by acid hydrolysis of the ester. Isolated as the monohydrochloride salt, monohydrate.
| 【1】 Metcalf, B.W.; et al.; Catalytic irreversible inhibition of mammalial ornithine decarboxylase (E.C.4.1.1.17) by substrate and product analogues. J Am Chem Soc 1978, 100, 2551-53. |
| 【2】 Schijvenaars, M.; Franke, B.; Mariman, E.C.M.; Steegers-Theunissen, R.; Willemen, J.; Groenen, P.; Klootwijk, R.; Hol, F.; D,L-alpha-Difluoromethyl ornithine-RMI 71782. Product data sheet, Centre de recherche Merrell, Strasbourg Cedex 2002, Abst 1027. |
| 【3】 Castaner, J.; Blancafort, P.; Serradell, M.N.; D,L-alpha-Difluoromethyl ornithine. Drugs Fut 1981, 6, 3, 142. |
合成路线2
该中间体在本合成路线中的序号：(I)This compound can be prepared by the route shown in scheme: Reaction of chlorodifluoromethane (Freon 22) with ethyl thioglycolate (II) in the presence of ethanolic sodium ethoxide gives ethyl 2-(difluoro-methylthio)acetate (III), which is hydrolyzed with aqueous potassium hydroxide to yield 2-(difluoromethylthio)acetic acid (IV). Substitution of diphenylmethyl-7alpha-benzamido-3-chloromethyl-1-oxa-3-cephem-4-carboxylate (V), an important intermediate for production of latamoxef, with 1-(2-hydroxyethyl)-1H-tetrazole-5-thiol (VI) in the presence of sodium methoxide, followed by protection of the hydroxyl group by means of p-methylbenzyl chlorocarbonate (VII) and pyridine, gives diphenylmethyl 7alpha-benzamido-3-[[1-[2-(p-methylbenzyloxycarbonyloxy)ethyl-1H-tetrazol-5-yl]thiomethyl]-1-oxa-3-cephem-4-carboxylate (VIII). Methoxylation of (VIII) with tert-butylhypochlorite and lithium methoxide, followed by the conventional side-chain cleavage with phosphorus pentachloride pyridine methanol, affords diphenylmethyl 7beta-amino-7alpha-methoxy-3-[[1-[2-(p-methylbenzyloxycarbonyloxy)ethyl]-1H-tetrazol-5-yl]thiomethyl]-1-oxa-3-cephem-4-carboxylate (X). This amine (IX) is condensed with the acid (IV) by means of phosphoryl chloride and pyridine fo yield diphenyl-methyl 7beta[2-(dfluoromelhylthio)acetamido]-7alpha-methoxy-3-[[1-[2-(p-methylbenzyloxycarbonyloxy)ethyl]-1H-tetrazol-5 yl)thiomethyl]-1-oxa-3-cephem 4-carboxylate (X), which undergoes deprotection with stannic chloride and anisole, neutralization with aqueous sodium bicarbonate and lyophilization giving the sodium salt (XI).
| 【1】 Tsuji, T.; et al.; Synthesis and antibacterial activity of 6315-S, a new member of the oxacephem antibiotic. J Antibiot 1984, 38, 4, 466. |
| 【2】 Castaner, J.; Serradell, M.N.; Flomoxef sodium. Drugs Fut 1986, 11, 6, 452. |
| 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) | 23985 | Chlorodifluoromethane; Chloro(difluoro)methane | 75-45-6 | CHClF2 | 详情 | 详情 |
| (II) | 23995 | ethyl 2-sulfanylacetate | 2713-34-0 | C4H8O2S | 详情 | 详情 |
| (III) | 23994 | ethyl 2-[(difluoromethyl)sulfanyl]acetate | C5H8F2O2S | 详情 | 详情 | |
| (IV) | 23986 | 2-[(difluoromethyl)sulfanyl]acetic acid | C3H4F2O2S | 详情 | 详情 | |
| (V) | 23987 | benzhydryl (7R)-7-(benzoylamino)-3-(chloromethyl)-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C28H23ClN2O5 | 详情 | 详情 | |
| (VI) | 23988 | 2-(5-sulfanyl-1H-1,2,3,4-tetraazol-1-yl)-1-ethanol | C3H6N4OS | 详情 | 详情 | |
| (VII) | 23989 | 1-[[(chlorocarbonyl)oxy]methyl]-4-methylbenzene | C9H9ClO2 | 详情 | 详情 | |
| (VIII) | 23990 | benzhydryl (7R)-7-(benzoylamino)-3-[([1-[2-([[(3-methylbenzyl)oxy]carbonyl]oxy)ethyl]-1H-1,2,3,4-tetraazol-5-yl]sulfanyl)methyl]-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C40H36N6O8S | 详情 | 详情 | |
| (IX) | 23991 | benzhydryl (7R)-7-amino-7-methoxy-3-[([1-[2-([[(3-methylbenzyl)oxy]carbonyl]oxy)ethyl]-1H-1,2,3,4-tetraazol-5-yl]sulfanyl)methyl]-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C34H34N6O8S | 详情 | 详情 | |
| (X) | 23992 | benzhydryl (7R)-7-([2-[(difluoromethyl)sulfanyl]acetyl]amino)-3-[[(1-[2-[(ethoxycarbonyl)oxy]ethyl]-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-7-methoxy-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C31H32F2N6O9S2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)Condensation of the benzaldehyde derivative (I) with chlorodifluoromethane (II) by means of NaOH and benzyltrimethylammonium chloride (BTMA) in dioxane/water gives 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzaldehyde (III), which is oxidized with NaClO2 and sulfamic acid in acetic acid to yield the corresponding benzoic acid derivative (IV). The reaction of (IV) with SOCl2 in refluxing toluene affords the acyl chloride (V), which is finally condensed with 3,5-dichloropyridin-4-amine (VI) by means of NaH in THF.
| 【1】 Castaner, J.; Leeson, P.A.; Sorbera, L.A.; Roflumilast. Drugs Fut 2000, 25, 12, 1261. |
| 【2】 Flockerzi, D.; Gutterer, B.; Hatzelmann, A.; Schudt, C.; Beume, R.; Kilian, U.; Wolf, H.P.O. (Byk Gulden Lomberg Chemische Fabrik GmbH); Fluoroalkoxy-substd. benzamides and their use as cyclic nucleotide phosphodiesterase inhibitors. EP 0706513; JP 1996512041; US 5712298; WO 9501338 . |
| 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) | 42496 | 3-(cyclopropylmethoxy)-4-hydroxybenzaldehyde | C11H12O3 | 详情 | 详情 | |
| (II) | 23985 | Chlorodifluoromethane; Chloro(difluoro)methane | 75-45-6 | CHClF2 | 详情 | 详情 |
| (III) | 42497 | 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzaldehyde | C12H12F2O3 | 详情 | 详情 | |
| (IV) | 42498 | 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoic acid | C12H12F2O4 | 详情 | 详情 | |
| (V) | 42499 | 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoyl chloride | C12H11ClF2O3 | 详情 | 详情 | |
| (VI) | 25135 | 3,5-dichloro-4-pyridinamine; 4-amino-3,5-dichloropyridine | 22889-78-7 | C5H4Cl2N2 | 详情 | 详情 |