【结 构 式】 |
【分子编号】11685 【品名】tert-butyl N-[(3S)tetrahydro-1H-pyrrol-3-yl]carbamate 【CA登记号】 |
【 分 子 式 】C9H18N2O2 【 分 子 量 】186.2542 【元素组成】C 58.04% H 9.74% N 15.04% O 17.18% |
合成路线1
该中间体在本合成路线中的序号:(X)The synthesis of [14C]-labeled clinafloxacin hydrochloride has been reported: The chlorination of 2,4,5-trifluorobromobenzene (I) with lithium diisopropylamide and hexachlorocyclopentadiene gives 3-chloro-2,4,5-trifluorobromobenzene (II), which is carbonated with 14CO2 and butyllithium in ether yielding 3-chloro-2,4,5-trifluoro-3-chlorobenzoic acid (III). The reaction of (III) with SOCl2 affords the corresponding acyl chloride (IV), which is condensed with the dilithium salt of the malonic acid monoethyl ester (V) to give the benzoylacetate (VI). The reaction of (VI) with acetic anhydride and ethyl orthoformate at 120-30 C yields the ethoxymethylene derivative (VII), which by treatment with cyclopropylamine affords the aminomethylene compound (VIII). The cyclization of (VIII) by means of potassium tert-butoxide in DMSO gives 1-cyclopropyl-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carbox ylic acid (IX), which is condensed with N-[pyrrolidin-3(S)-yl]carbamic acid tert-butyl ester by means of triethylamine in hot DMSO yielding the protected final product (XI). Finally, this compound is deprotected with 12N HCl in THF.
【1】 Huang, C.C.; Ekhato, I.V.; A synthetic approach to carbon-14 labeled anti-bacterial naphthyridine and quinolone carboxylic acids. J Label Compd Radiopharm 1993, 33, 9, 869. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
12263 | Cyclopropylamine; Cyclopropanamine | 765-30-0 | C3H7N | 详情 | 详情 | |
(I) | 11676 | 1-Bromo-2,4,5-trifluorobenzene | 327-52-6 | C6H2BrF3 | 详情 | 详情 |
(II) | 11677 | 1-Bromo-3-chloro-2,4,5-trifluorobenzene | C6HBrClF3 | 详情 | 详情 | |
(III) | 11678 | 3-Chloro-2,4,5-trifluorobenzoic acid | C7H2ClF3O2 | 详情 | 详情 | |
(III) | 45062 | 3-chloro-2,4,5-trifluorobenzoic acid | C7H2ClF3O2 | 详情 | 详情 | |
(IV) | 11679 | 3-Chloro-2,4,5-trifluorobenzoyl chloride | C7HCl2F3O | 详情 | 详情 | |
(IV) | 45063 | 3-chloro-2,4,5-trifluorobenzoyl chloride | C7HCl2F3O | 详情 | 详情 | |
(V) | 11680 | Lithium (1-carboxylato-2-ethoxy-2-oxoethyl)lithium | C5H6Li2O4 | 详情 | 详情 | |
(VI) | 11681 | ethyl 3-(3-chloro-2,4,5-trifluorophenyl)-3-oxopropanoate | 101987-86-4 | C11H8ClF3O3 | 详情 | 详情 |
(VI) | 45064 | ethyl 3-(3-chloro-2,4,5-trifluorophenyl)-3-oxopropanoate | C11H8ClF3O3 | 详情 | 详情 | |
(VII) | 11682 | ethyl (Z)-2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxy-2-propenoate | C14H12ClF3O4 | 详情 | 详情 | |
(VII) | 45065 | ethyl (Z)-2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxy-2-propenoate | C14H12ClF3O4 | 详情 | 详情 | |
(VIII) | 11683 | ethyl (E)-2-(3-chloro-2,4,5-trifluorobenzoyl)-3-(cyclopropylamino)-2-propenoate | C15H13ClF3NO3 | 详情 | 详情 | |
(VIII) | 45066 | ethyl (E)-2-(3-chloro-2,4,5-trifluorobenzoyl)-3-(cyclopropylamino)-2-propenoate | C15H13ClF3NO3 | 详情 | 详情 | |
(IX) | 11684 | 8-Chloro-1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | 101987-89-7 | C13H8ClF2NO3 | 详情 | 详情 |
(IX) | 45067 | 8-chloro-1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C13H8ClF2NO3 | 详情 | 详情 | |
(X) | 11685 | tert-butyl N-[(3S)tetrahydro-1H-pyrrol-3-yl]carbamate | C9H18N2O2 | 详情 | 详情 | |
(XI) | 11686 | 7-[(3S)-3-[(tert-Butoxycarbonyl)amino]tetrahydro-1H-pyrrol-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C22H25ClFN3O5 | 详情 | 详情 | |
(XI) | 45068 | 7-[(3S)-3-[(tert-butoxycarbonyl)amino]pyrrolidinyl]-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C22H25ClFN3O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(XIV)The reaction of 3-chlorotetrafluoropyridine (I) with sodium tert-butoxide in THF gives 4-tert-butoxy-3-chloro-2,5,6-trifluoropyridine (II), which is dechlorinated with H2 over Pd/C in methanol yielding 4-tert-butoxy-2,3,6-trifluoropyridine (III). The methylation of (III) with methyl iodide and lithium diethylamide (LDA) in THF affords 4-tert-butoxy-2,3,6-trifluoro-5-methylpyridine (IV), which is selectively defluorinated with hydrazine in refluxing propanol to give 4-tert-butoxy-2,5-difluoro-3-methylpyridine (V). The condensation of (V) with cyclopropylacetonitrile (VI) by means of LDA in THF yields 2-(4-tert-butoxy-5-fluoro-3-methyl-2-pyridyl)-2-cyclopropylacetonitrile (VII), which is treated first with trifluoroacetic acid and then with POCl3 to afford 2-(4-chloro-5-fluoro-3-methyl-2-pyridyl)-2-cyclopropylacetonitrile (VIII). The alcoholysis of (VIII) with ethanol/HCl gives the corresponding ethyl ester (IX), which is partially reduced with LiAlH4 in THF to afford the corresponding aldehyde (X). The condensation of (X) with diethyl malonate (XI) by means of piperidine in refluxing ethanol yields the ethylidenemalonate (XII), which, without isolation, is cyclized by heating at 235 C in Dowtherm to afford 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester (XIII). The reaction of (XIII) with 3(S)-(tert-butoxycarbonylamino)pyrrolidine (XIV) by means of NaHCO3 in acetonitrile gives the corresponding condensation product (XV), which is hydrolyzed ith LiOH in THF/water to the corresponding free acid (XVI). Finally, this compound is deprotected with 4N HCl in dioxandichloromethane.
【1】 Fromtling, R.A.; Castañer, J.; ABT-719. Drugs Fut 1995, 20, 11, 1103. |
【2】 Chu, D.T.W.; Li, Q.; Claiborne, A.; et al.; Synthesis and antibacterial activity of A-86719.1 and related 2-pyridones: A novel series of potent DNA gyrase inhibitors. 34th Intersci Conf Antimicrob Agents Chemother (Oct 4-7, Orlando) 1994, Abst F41. |
【3】 Chu, D.T.; Li, Q.; Cooper, C.S.; Fung, A.K.L.; Lee, C.M.; Plattner, J.J. (Abbott Laboratories Inc.); Quinolizinone type cpds. JP 1997503783; WO 9510519 . |
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) | 16819 | 3-chloro-2,4,5,6-tetrafluoropyridine; Pyridine, 3-chloro-2,4,5,6-tetrafluoro- | 1735-84-8 | C5ClF4N | 详情 | 详情 |
(II) | 16820 | 4-(tert-butoxy)-3-chloro-2,5,6-trifluoropyridine; tert-butyl 3-chloro-2,5,6-trifluoro-4-pyridinyl ether | C9H9ClF3NO | 详情 | 详情 | |
(III) | 16821 | 4-(tert-butoxy)-2,3,6-trifluoropyridine; tert-butyl 2,3,6-trifluoro-4-pyridinyl ether | C9H10F3NO | 详情 | 详情 | |
(IV) | 16822 | tert-butyl 2,3,6-trifluoro-5-methyl-4-pyridinyl ether; 4-(tert-butoxy)-2,3,6-trifluoro-5-methylpyridine | C10H12F3NO | 详情 | 详情 | |
(V) | 16823 | tert-butyl 2,5-difluoro-3-methyl-4-pyridinyl ether; 4-(tert-butoxy)-2,5-difluoro-3-methylpyridine | C10H13F2NO | 详情 | 详情 | |
(VI) | 16824 | 2-cyclopropylacetonitrile; Cyclopropylacetonitrile | 6542-60-5 | C5H7N | 详情 | 详情 |
(VII) | 16825 | 2-[4-(tert-butoxy)-5-fluoro-3-methyl-2-pyridinyl]-2-cyclopropylacetonitrile | C15H19FN2O | 详情 | 详情 | |
(VIII) | 16826 | 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylacetonitrile | C11H10ClFN2 | 详情 | 详情 | |
(IX) | 16827 | ethyl 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylacetate | C13H15ClFNO2 | 详情 | 详情 | |
(X) | 16828 | 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylacetaldehyde | C11H11ClFNO | 详情 | 详情 | |
(XI) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
(XII) | 16830 | diethyl 2-[2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylethylidene]malonate | C18H21ClFNO4 | 详情 | 详情 | |
(XIII) | 16831 | ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate | C16H15ClFNO3 | 详情 | 详情 | |
(XIV) | 11685 | tert-butyl N-[(3S)tetrahydro-1H-pyrrol-3-yl]carbamate | C9H18N2O2 | 详情 | 详情 | |
(XV) | 16833 | ethyl 8-[(3S)-3-[(tert-butoxycarbonyl)amino]tetrahydro-1H-pyrrol-1-yl]-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate | C25H32FN3O5 | 详情 | 详情 | |
(XVI) | 16834 | 8-[(3S)-3-[(tert-butoxycarbonyl)amino]tetrahydro-1H-pyrrol-1-yl]-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid | C23H28FN3O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(VII)Diazotation of 3-amino-6-nitro-1,8-naphthalic anhydride (I) in the presence of pyridine hydrofluoride afforded the fluoro derivative (II). This was brominated to (III) using Br2 and Ag2SO4 and its nitro group was subsequently reduced to amine (IV) with SnCl2. Sandmeyer reaction of amine (IV) in the presence of CuBr furnished the dibromo anhydride (V), which was treated with O-tert-butylhydroxylamine, yielding the N-tert-butoxy imide (VI). Regioselective displacement of one bromide group of (VI) with (S)-3-(Boc-amino)pyrrolidine (VII) gave rise to the protected pyrrolidinyl derivative (VIII). Finally, the tert-butyl protecting groups of (VIII) were removed by acidic treatment to produce the title compound.
【1】 Stier, M.A.; et al.; The synthesis and SAR of a series of 2-hydroxyisoquinolones: New antibacterial gyrase inhibitors. 40th Intersci Conf Antimicrob Agents Chemother (Sept 17 2000, Toronto) 2000, Abst F-1503. |
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) | 46342 | 5-amino-8-nitro-1H,3H-benzo[de]isochromene-1,3-dione | C12H6N2O5 | 详情 | 详情 | |
(II) | 46343 | 5-fluoro-8-nitro-1H,3H-benzo[de]isochromene-1,3-dione | C12H4FNO5 | 详情 | 详情 | |
(III) | 46344 | 6-bromo-5-fluoro-8-nitro-1H,3H-benzo[de]isochromene-1,3-dione | C12H3BrFNO5 | 详情 | 详情 | |
(IV) | 46345 | 8-amino-6-bromo-5-fluoro-1H,3H-benzo[de]isochromene-1,3-dione | C12H5BrFNO3 | 详情 | 详情 | |
(V) | 46346 | 6,8-dibromo-5-fluoro-1H,3H-benzo[de]isochromene-1,3-dione | C12H3Br2FO3 | 详情 | 详情 | |
(VI) | 46347 | 6,8-dibromo-2-(tert-butoxy)-5-fluoro-1H-benzo[de]isoquinoline-1,3(2H)-dione | C16H12Br2FNO3 | 详情 | 详情 | |
(VII) | 11685 | tert-butyl N-[(3S)tetrahydro-1H-pyrrol-3-yl]carbamate | C9H18N2O2 | 详情 | 详情 | |
(VIII) | 46348 | tert-butyl (3S)-1-[8-bromo-2-(tert-butoxy)-5-fluoro-1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinolin-6-yl]pyrrolidinylcarbamate | C25H29BrFN3O5 | 详情 | 详情 |