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【结 构 式】

【分子编号】12263

【品名】Cyclopropylamine; Cyclopropanamine

【CA登记号】765-30-0

【 分 子 式 】C3H7N

【 分 子 量 】57.09532

【元素组成】C 63.11% H 12.36% N 24.53%
与该中间体有关的原料药合成路线共 41 条
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合成路线1

该中间体在本合成路线中的序号：(VII)

The condensation of 2,4-dichloro-5-fluorobenzoyl chloride (I) with diethyl malonate (II) by means of magnesium ethoxide in ether gives diethyl 2,4-dichloro-5-fluorobenzoylmalonate (III), which is partially hydrolyzed and decarboxylated with p-toluenesulfonic acid water yielding ethyl 2,4-dichloro-5-fluorobenzoylacetate (IV). The condensation of (IV) with triethyl orthoformate (V) in refluxing acetic anhydride affords ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-ethoxyacrylate (VI), which is treated with cyclopropylamine (VII) in ethanol to give ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-cyclopropylaminoacrylate (VIII). The cyclization of (VIII) with NaH in refluxing dioxane yields 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (IX), which is finally condensed with piperazine (X) in hot DMSO.

参考文献 中间体
合成目标
【1】 Reddy, P.G.; Baskaran, S.; Microwave assisted amination of quinolone carboxylic acids: An expeditious synthesis of fluoroquinolone antibacterials. Tetrahedron Lett 2001, 42, 38, 6775.
【2】 Grohe, K.; Zeiler, H. J.; Metzger, K.G. (Bayer AG); 1-Cyclopropyl-6-fluoro-1,4-dihidro-4-oxo-7-piperazino-quinoline-3-carboxilic acids, process for their preparation and antibacterial agents containing them. EP 0078362; JP 4253963; JP 58074667 .
【3】 Serradell, M.N.; Castaner, J.; Ciprofloxacin. Drugs Fut 1984, 9, 3, 179.
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) 22093 2,4-dichloro-5-fluorobenzoyl chloride 86393-34-2 C7H2Cl3FO 详情 详情
(II) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(III) 22095 diethyl 2-(2,4-dichloro-5-fluorobenzoyl)malonate C14H13Cl2FO5 详情 详情
(IV) 22096 ethyl 3-(2,4-dichloro-5-fluorophenyl)-3-oxopropanoate C11H9Cl2FO3 详情 详情
(V) 21304 Triethyl orthoformate; 1-(Diethoxymethoxy)ethane; Diethoxymethyl ethyl ether 122-51-0 C7H16O3 详情 详情
(VI) 22098 ethyl (Z)-2-(2,4-dichloro-5-fluorobenzoyl)-3-ethoxy-2-propenoate C14H13Cl2FO4 详情 详情
(VII) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情
(VIII) 22100 ethyl (E)-3-(cyclopropylamino)-2-(2,4-dichloro-5-fluorobenzoyl)-2-propenoate C15H14Cl2FNO3 详情 详情
(IX) 30340 ethyl 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate 86483-54-7 C15H13ClFNO3 详情 详情
(X) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情

合成路线2

该中间体在本合成路线中的序号：(VII)

1) The condensation of 2,4-dichloro-5-fluoro-benzoyl chloride (I) with diethyl malonate (II) by means of magnesium ethoxide gives diethyl 2,4-dichloro-5-fluorobenzoylmalonate (III), which is partially decarboxylated with p-toluenesulfonic acid yielding ethyl 2,4-dichloro-5-fluorobenzoylacetate (IV). The condensation of (IV) with triethyl orthoformate (V) by means of refluxing acetic anhydride affords ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-ethoxyacrylate (VI), which is treated with cyclopropylamine (VII) in ethanol giving ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-(cyclopropylamino)acrylate (VII). The cyclization of (VII) by means of NaH in refluxing dioxane yields 1-cyclopropyl-7-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (IX), which is finally condensed with N-ethylpiperazine (X) by heating at 140 C in DMSO.

参考文献 中间体
合成目标
【1】 Grohe, K.; Klimetzek, V.; Metzger, K.G.; Stunkel, K.G.; Zeiler, H.-J. (Bayer AG); Immunostimulant agent. AU 8542762; DE 3420116; EP 0165474; ES 8607020; JP 1985258163; US 4659603 .
【2】 Grohe, K.; Petersen, U.; Kuck, K.-H. (Bayer AG); Antimicrobial agent of quinolone-carboxylic acid b. DE 3248507; US 4563459 .
【3】 Castaner, J.; Prous, J.; Enrofloxacin. Drugs Fut 1988, 13, 4, 305.
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) 22093 2,4-dichloro-5-fluorobenzoyl chloride 86393-34-2 C7H2Cl3FO 详情 详情
(II) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(III) 22095 diethyl 2-(2,4-dichloro-5-fluorobenzoyl)malonate C14H13Cl2FO5 详情 详情
(IV) 22096 ethyl 3-(2,4-dichloro-5-fluorophenyl)-3-oxopropanoate C11H9Cl2FO3 详情 详情
(V) 21304 Triethyl orthoformate; 1-(Diethoxymethoxy)ethane; Diethoxymethyl ethyl ether 122-51-0 C7H16O3 详情 详情
(VI) 22098 ethyl (Z)-2-(2,4-dichloro-5-fluorobenzoyl)-3-ethoxy-2-propenoate C14H13Cl2FO4 详情 详情
(VII) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情
(VIII) 22100 ethyl (E)-3-(cyclopropylamino)-2-(2,4-dichloro-5-fluorobenzoyl)-2-propenoate C15H14Cl2FNO3 详情 详情
(IX) 22101 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid 86393-33-1 C13H9ClFNO3 详情 详情
(X) 14213 N-Ethylpiperazine; 1-Ethylpiperazine 5308-25-8 C6H14N2 详情 详情

合成路线3

该中间体在本合成路线中的序号：(II)

A cost-efficient synthesis of simvastatin has been reported: 1) The reaction of lovastatin (mevinolin) (I) with cyclopropylamine (II) gives the corresponding amide (III), which is methylated by means of BuLi, methyl iodide and pyrrolidine in THF yielding the dimethylbutyryl derivative (IV). Hydrolysis of (IV) with NaOH in refluxing methanol, followed by a treatment with NH4OH in methanol affords the ammonium salt (V), which is finally lactonized in acidic medium. 2) The cyclopropylamide (III) can also be obtained by reaction of mevinolinic acid ammonium salt (VI) with cyclopropylamine in hot toluene.

参考文献 中间体
合成目标
【1】 Thaper, R.K.; Misra, S.; Kumar, Y.; Kumar, S.M.D.; Khanna, J.M.; A cost-efficient synthesis of simvastatin via high-conversion methylation of an alkoxide ester enolate. Org Process Res Dev 1999, 3, 6, 476.
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) 64415 (1S,3R,7S,8S,8aR)-8-{2-[(2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl}-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-1-naphthalenyl (2S)-2-methylbutanoate C24H36O5 详情 详情
(II) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情
(III) 37613 (1S,3R,7S,8S,8aR)-8-[(3R,5R)-7-(cyclopropylamino)-3,5-dihydroxy-7-oxoheptyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-1-naphthalenyl (2S)-2-methylbutanoate C27H43NO5 详情 详情
(IV) 37616 ammonium (3R,5R)-7-[(1S,2S,6R,8S,8aR)-8-[(2,2-dimethylbutanoyl)oxy]-2,6-dimethyl-1,2,6,7,8,8a-hexahydro-1-naphthalenyl]-3,5-dihydroxyheptanoate C25H43NO6 详情 详情
(V) 37615 (1S,3R,7S,8S,8aR)-8-[(3R,5R)-7-(cyclopropylamino)-3,5-dihydroxy-7-oxoheptyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-1-naphthalenyl 2,2-dimethylbutanoate C28H45NO5 详情 详情
(VI) 37614 ammonium (3R,5R)-7-((1S,2S,6R,8S,8aR)-2,6-dimethyl-8-[[(2S)-2-methylbutanoyl]oxy]-1,2,6,7,8,8a-hexahydro-1-naphthalenyl)-3,5-dihydroxyheptanoate C24H41NO6 详情 详情

合成路线4

该中间体在本合成路线中的序号：

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.

参考文献 中间体
合成目标
【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5

该中间体在本合成路线中的序号：(XIII)

The reduction of 2,3,4-trichloro-5-fluoronitrobenzene (I) with Fe - HCl in hot water gives 2,3,4-trichloro-5-fluoroaniline (II), which by diazotation with NaNO2 - HCl and reaction with sodium tetrafluoroborate and cuprous cyanide is converted to 2,3,4-trichloro-5-fluorobenzonitrile (III). The reaction of (III) with KF in DMSO at 140 C affords 3-chloro-2,4,5-trifluorobenzonitrile (IV), which by hydrolysis with 30% HBr in refluxing acetic acid gives 3-chloro-2,4,5-trifluorobenzamide (V). The hydrolysis of (V) with 18N H2SO4 at 135 C yields the corresponding benzoic acid (VI), which is treated with refluxing SOCl2 to afford the acyl chloride (VII). The condensation of (VII) with diethyl malonate (VIII) by means of Mg - ethanol in hot toluene gives diethyl 3-chloro-2,4,5-trifluorobenzoylmalonate (IX), which is partially decarboxylated with p-toluenesulfonic acid in refluxing water to give ethyl 3-chloro-2,4,5-trifluorobenzoylacetate (X). The condensation of (X) with triethyl orthoformate (XI) in refluxing acetic anhydride yields ethyl 2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxyacrylate (XII), which is treated with cyclopropylamine (XIII) in ethanol to afford ethyl 2-(3-chloro-2,4,5-trifluorobenzoyl)-3-(cyclopropylamino)acrylate (XIV). The cyclization of (XIV) by means of NaF in DMF at 150 C gives ethyl 8-chloro-1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (XV), which is hydrolyzed with H2SO4 in refluxing water - acetic acid to the corresponding carboxylic acid (XVI). The condensation of (XVI) with 3-(tert-butoxycarbonylamino)pyrrolidine (XVII) by means of 1,8-diazabicyclo [5.4.0]undecane (DBU) in refluxing acetonitrile yields 7-[3-(tert-butoxycarbonylamino)-1-pyrrolidinyl]-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (XVIII), which is finally deprotected by a treatment with concentrated HCl in methanol.

参考文献 中间体
合成目标
【1】 Irikura, T.; Suzue, S.; Murayama, S.; Hirai, K.; Ishizaki, T. (Kyorin Pharmaceutical Co., Ltd.); 7-(1-Pyrrolidinyl)-3-quinolinecarboxylic acid derivs.. AU 8542829; AU 8654272; EP 0195316; EP 0195841; ES 8606330; ES 8704932; JP 1986205235; JP 1986205237; JP 1986205238; JP 1986205239; JP 1986205258; JP 1986205259 .
【2】 Serradell, M.N.; Castaner, J.; Castaner, R.M.; Saito, H.; Tomioka, H.; Sato, K.; Hirai, K.; Suzue, S.; AM-1091. Drugs Fut 1989, 14, 10, 931.
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) 21294 2,3,4-trichloro-1-fluoro-5-nitrobenzene C6HCl3FNO2 详情 详情
(II) 21295 2,3,4-trichloro-5-fluorophenylamine; 2,3,4-trichloro-5-fluoroaniline C6H3Cl3FN 详情 详情
(III) 21296 2,3,4-trichloro-5-fluorobenzonitrile C7HCl3FN 详情 详情
(IV) 21297 3-chloro-2,4,5-trifluorobenzonitrile C7HClF3N 详情 详情
(V) 21298 3-chloro-2,4,5-trifluorobenzamide C7H3ClF3NO 详情 详情
(VI) 11678 3-Chloro-2,4,5-trifluorobenzoic acid C7H2ClF3O2 详情 详情
(VII) 11679 3-Chloro-2,4,5-trifluorobenzoyl chloride C7HCl2F3O 详情 详情
(VIII) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(IX) 21302 diethyl 2-(3-chloro-2,4,5-trifluorobenzoyl)malonate C14H12ClF3O5 详情 详情
(X) 11681 ethyl 3-(3-chloro-2,4,5-trifluorophenyl)-3-oxopropanoate 101987-86-4 C11H8ClF3O3 详情 详情
(XI) 21304 Triethyl orthoformate; 1-(Diethoxymethoxy)ethane; Diethoxymethyl ethyl ether 122-51-0 C7H16O3 详情 详情
(XII) 11682 ethyl (Z)-2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxy-2-propenoate C14H12ClF3O4 详情 详情
(XIII) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情
(XIV) 11683 ethyl (E)-2-(3-chloro-2,4,5-trifluorobenzoyl)-3-(cyclopropylamino)-2-propenoate C15H13ClF3NO3 详情 详情
(XV) 21308 ethyl 8-chloro-1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate C15H12ClF2NO3 详情 详情
(XVI) 11684 8-Chloro-1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid 101987-89-7 C13H8ClF2NO3 详情 详情
(XVII) 21310 tert-butyl 3-pyrrolidinylcarbamate 99724-19-3 C9H18N2O2 详情 详情
(XVIII) 21311 7-[3-[(tert-butoxycarbonyl)amino]-1-pyrrolidinyl]-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid C22H25ClFN3O5 详情 详情

合成路线6

该中间体在本合成路线中的序号：(IX)

The reaction of 1-bromo-2,4,5-trifluoro-3-methoxybenzene (I) with CuCN and N-methyl-2-pyrrolidone at 150 C gives 2,4,5-trifluoro-3-methoxybenzonitrile (II), which by treatment with concentrated H2SO4 yields the benzamide (III). The hydrolysis of (III) with H2SO4 - water at 110 C affords 2,4,5-trifluoro-2-methoxybenzoic acid (IV), which by reaction with SOCl2 is converted into the acyl chloride (V). The condensation of (V) with diethyl malonate by means of magnesium ethoxide in toluene affords diethyl 2-(2,4,5-trifluoro-3-methoxybenzoyl)malonate (VI), which by treatment with p-toluenesulfonic acid in refluxing water gives ethyl 2-(2,4,5-trifluoro-3-methoxybenzoyl)acetate (VII). The condensation of (VII) with triethyl orthoformate in refluxing acetic anhydride yields 3-ethoxy-2-(2,4,5-trifluoro-3-methoxybenzoyl)acrylic acid ethyl ester (VIII), which is treated with cyclopropylamine (IX) to afford the corresponding cyclopropylamino derivative (X). The cyclization of (X) by means of NaF in refluxing DMF gives 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (XI), which is hydrolyzed with H2SO4 in acetic acid to yield the corresponding free acid (XII). Finally, this compound is condensed with 2-methylpiperazine (XIII) in hot DMSO.

参考文献 中间体
合成目标
【1】 Masuzawa, K.; Suzue, S.; Hirai, K.; Ishizaki, T. (Kyorin Pharmaceutical Co., Ltd.); 8-Alkyoxyquinolonecarboxylic acid and salts thereof excellent in the selective toxicity and process for preparing the same. EP 0230295; JP 1987252772; JP 1994080640; JP 1994092937; JP 1995304706; JP 1995304742; US 4980470 .
【2】 Prous, J.; Castaner, J.; AM-1155. Drugs Fut 1993, 18, 3, 203.
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) 12255 3-Bromo-2,5,6-trifluorophenyl methyl ether; 1-Bromo-2,4,5-trifluoro-3-methoxybenzene C7H4BrF3O 详情 详情
(II) 12256 2,4,5-Trifluoro-3-methoxybenzonitrile C8H4F3NO 详情 详情
(III) 12257 2,4,5-Trifluoro-3-methoxybenzamide C8H6F3NO2 详情 详情
(IV) 12258 2,4,5-Trifluoro-3-methoxybenzoic acid 112811-65-1 C8H5F3O3 详情 详情
(V) 12259 2,4,5-Trifluoro-3-methoxybenzoyl chloride C8H4ClF3O2 详情 详情
(VI) 12260 diethyl 2-(2,4,5-trifluoro-3-methoxybenzoyl)malonate C15H15F3O6 详情 详情
(VII) 12261 ethyl 3-oxo-3-(2,4,5-trifluoro-3-methoxyphenyl)propanoate C12H11F3O4 详情 详情
(VIII) 12262 ethyl (Z)-3-ethoxy-2-(2,4,5-trifluoro-3-methoxybenzoyl)-2-propenoate C15H15F3O5 详情 详情
(IX) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情
(X) 12264 ethyl (E)-3-(cyclopropylamino)-2-(2,4,5-trifluoro-3-methoxybenzoyl)-2-propenoate C16H16F3NO4 详情 详情
(XI) 12265 ethyl 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylate C16H15F2NO4 详情 详情
(XII) 12266 1-Cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid 112811-72-0 C14H11F2NO4 详情 详情
(XIII) 12267 2-Methylpiperazine 109-07-9 C5H12N2 详情 详情

合成路线7

该中间体在本合成路线中的序号：(II)

The reaction of ethyl pentafluorobenzoylacetate (I) with ethyl orthoformate in refluxing acetic anhydride and then with cyclopropylamine (II) in ether gives the aminomethylene derivative (III), which is cyclized by means of NaH in THF yielding ethyl 5,6,7,8-tetrafluoro-1-cyclopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (IV). The reaction of (IV) with benzylamine (V) by means of K2CO3 in refluxing acetonitrile affords the benzylamino derivative (VI), which is deprotected by hydrogenation with H2 over Pd/C in ethanol giving ethyl 5-amino-1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (VII). The hydrolysis of (VII) with hot H2SO4 yields the free acid (VIII), which is finally condensed with cis-2,6-dimethylpiperazine (IX) in DMF.

参考文献 中间体
合成目标
【1】 Matsumoto, J.; Miyamoto, T.; Egawa, H.; Nakamura, S. (Dainippon Pharm. Co.; Ltd.); Novel quinoline derivatives and processes for preparation thereof. AU 8664277; EP 0221463; JP 87277362 .
【2】 Prous, J.; Castaner, J.; AT-4140. Drugs Fut 1989, 14, 5, 413.
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) 20840 ethyl 3-oxo-3-(2,3,4,5,6-pentafluorophenyl)propanoate C11H7F5O3 详情 详情
(II) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情
(III) 20842 ethyl 2-[(cyclopropylamino)methyl]-3-oxo-3-(2,3,4,5,6-pentafluorophenyl)propanoate C15H14F5NO3 详情 详情
(IV) 20843 ethyl 1-cyclopropyl-5,6,7,8-tetrafluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate C15H11F4NO3 详情 详情
(V) 15147 Benzylamine; Phenylmethanamine 100-46-9 C7H9N 详情 详情
(VI) 20845 ethyl 5-(benzylamino)-1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate C22H19F3N2O3 详情 详情
(VII) 20846 ethyl 5-amino-1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate C15H13F3N2O3 详情 详情
(VIII) 19819 4-[(benzyloxy)carbonyl]-3,4-dihydro-2H-1,4-benzothiazine-7-carboxylic acid C17H15NO4S 详情 详情
(IX) 20848 (2R,6S)-2,6-dimethylpiperazine C6H14N2 详情 详情

合成路线8

该中间体在本合成路线中的序号：(X)

1) The reaction of 4,6-dihydroxypyrimidine-2,5-diamine (I) with (chloromethylene)dimethylammonium chloride (II) in refluxing chloroform gives 4,6-dichloro-2,5-bis(dimethylaminomethyleneamino)pyrimidine (III), which by reaction with aqueous HCl in hot ethanol yields monoamine (IV). The reaction of (IV) with a refluxing phosphate buffer (pH 3.2) affords N-(2-amino-4,6-dichloropyrimidin-5-yl)formamide (V). The condensation of (V) with (1S,4R)-4-amino-2-cyclopentene-1-methanol (VI) (which was obtained by optical resolution of the cis-racemate (VII) with D-dibenzoyltartaric acid, and elimination of the acid with ion exchange resin Amberlite IA-400, by means of triethylamine and NaOH in refluxing ethanol) gives N-[2-amino-4-chloro-6-[4(S)-(hydroxymethyl)-2-cyclopenten-1(R)-ylamino]pyrimidin-5-yl]formamide (VIII). The cyclization of (VIII) with refluxing diethoxymethyl acetate or triethyl orthoformate yields the corresponding purine derivative (IX), which is finally treated with cyclopropylamine (X) in refluxing n-butanol. 2) The formylation of N-(5-amino-4,6-dichloropyrimidin-2-yl)acetamide (XI) with 95% formic acid in acetic anhydride gives the expected formamide (XII), which is condensed with (1S,4R)-4-amino-2-cyclopentene-1-methanol (VI) by means of triethylamine in hot ethanol to yield the substituted pyrimidine (XIII). Finally, the cyclization of (XIII) with diethoxymethyl acetate as before affords the purine intermediate (IX).

参考文献 中间体
合成目标
【1】 Graul, A.; Castaner, J.; Leeson, P.A.; Abacavir Sulfate. Drugs Fut 1998, 23, 11, 1155-1167.
【2】 Daluge, S.M. (Glaxo Wellcome plc); Therapeutic nucleosides. EP 0434450; JP 1996092252; JP 1999158160; JP 1999343292 .
【3】 Daluge, S.M. (Glaxo Wellcome plc); Therapeutic nucleosides. AU 8937025; EP 0349242; JP 1990045486; JP 1999139976; US 5034394; US 5089500 .
【4】 Daluge, S.M.; Martin, M.T.; Fugett, M.J.F.; Chloropyrimide intermediates. WO 9521161 .
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) 17642 2,5-diamino-4,6-pyrimidinediol C4H6N4O2 详情 详情
(II) 17643 (Chloromethylene)dimethylammonium chloride; N-(chloromethylene)-N-methylmethanaminium chloride 3724-43-4 C3H7Cl2N 详情 详情
(III) 17644 N'-(4,6-dichloro-2-[[(E)-(dimethylamino)methylidene]amino]-5-pyrimidinyl)-N,N-dimethyliminoformamide C10H14Cl2N6 详情 详情
(IV) 17645 N'-(2-amino-4,6-dichloro-5-pyrimidinyl)-N,N-dimethyliminoformamide C7H9Cl2N5 详情 详情
(V) 17646 2-amino-4,6-dichloro-5-pyrimidinylformamide C5H4Cl2N4O 详情 详情
(VI) 17647 [(1S,4R)-4-amino-2-cyclopenten-1-yl]methanol C6H11NO 详情 详情
(VII) 63843 (rac)-[(1R*,4S*)-4-amino-2-cyclopenten-1-yl]methanol C6H11NO 详情 详情
(VIII) 17649 2-amino-4-chloro-6-[[(1R,4S)-4-(hydroxymethyl)-2-cyclopenten-1-yl]amino]-5-pyrimidinylformamide C11H14ClN5O2 详情 详情
(IX) 17650 [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol C11H12ClN5O 详情 详情
(X) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情
(XI) 17652 N-(5-amino-4,6-dichloro-2-pyrimidinyl)acetamide C6H6Cl2N4O 详情 详情
(XII) 17653 N-[4,6-dichloro-5-(formylamino)-2-pyrimidinyl]acetamide C7H6Cl2N4O2 详情 详情
(XIII) 17654 N-(4-chloro-5-(formylamino)-6-[[(1R,4S)-4-(hydroxymethyl)-2-cyclopenten-1-yl]amino]-2-pyrimidinyl)acetamide C13H16ClN5O3 详情 详情

合成路线9

该中间体在本合成路线中的序号：(X)

3) The condensation of (±)-cis-4-acetamido-2-cyclopentenylmethyl acetate (XIV) with 2-amino-4,6-dichloropyrimidine (XV) by means of Ba(OH)2 and triethylamine in refluxing butanol gives the expected condensation product (XVI), which is treated with 4-chlorophenyldiazonium chloride (XVII) in water/acetic acid to yield the corresponding azo-compound (XVIII). The reduction of (XVIII) with Zn/acetic acid in ethanol affords the diamine (XIX), which is cyclized with refluxing diethoxymethyl acetate (XX) to afford the corresponding purine (XXI). The reaction of (XXI) with cyclopropylamine (X) in refluxing ethanol affords racemic abacavir (XXII), which is phosphorylated with POCl3 giving the racemic 4'-O-phosphate (XXIII). Finally, this compound is submitted to stereoselective enzymatic dephosphorylation using snake venom 5'-nucleotidase (EC 3.1.3.5) from Crotalus atrox yielding the (-)-enantiomer, abacavir.

参考文献 中间体
合成目标
【1】 Graul, A.; Castaner, J.; Leeson, P.A.; Abacavir Sulfate. Drugs Fut 1998, 23, 11, 1155-1167.
【2】 Daluge, S.M. (Glaxo Wellcome plc); Therapeutic nucleosides. EP 0434450; JP 1996092252; JP 1999158160; JP 1999343292 .
【3】 Daluge, S.M. (Glaxo Wellcome plc); Therapeutic nucleosides. AU 8937025; EP 0349242; JP 1990045486; JP 1999139976; US 5034394; US 5089500 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(X) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情
(XIV) 17655 (1S,4R)-4-(acetamido)-2-cyclopenten-1-yl acetate C9H13NO3 详情 详情
(XV) 14404 4,6-dichloro-2-pyrimidinamine; 2-Amino-4,6-dichloropyrimidine; 4,6-dichloro-2-pyrimidinylamine 56-05-3 C4H3Cl2N3 详情 详情
(XVI) 17657 [(1S,4R)-4-[(2-amino-6-chloro-4-pyrimidinyl)amino]-2-cyclopenten-1-yl]methanol C10H13ClN4O 详情 详情
(XVII) 10197 4-Chlorobenzenediazonium chloride C6H4Cl2N2 详情 详情
(XVIII) 17659 [(1S,4R)-4-([2-amino-6-chloro-5-[(E)-2-(4-chlorophenyl)diazenyl]-4-pyrimidinyl]amino)-2-cyclopenten-1-yl]methanol C16H16Cl2N6O 详情 详情
(XIX) 17660 [(1S,4R)-4-[(2,5-diamino-6-chloro-4-pyrimidinyl)amino]-2-cyclopenten-1-yl]methanol C10H14ClN5O 详情 详情
(XX) 17661 Diethoxymethyl acetate 14036-06-7 C7H14O4 详情 详情
(XXI) 17650 [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol C11H12ClN5O 详情 详情
(XXII) 17663 [(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopenten-1-yl]methanol C14H18N6O 详情 详情
(XXIII) 17664 [(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopenten-1-yl]methyl dihydrogen phosphate C14H19N6O4P 详情 详情

合成路线10

该中间体在本合成路线中的序号：(XIII)

A new solid phase synthesis of abacavir has been reported: Condensation of the chiral 4(R)-benzyl-3-(4-pentenoyl)oxazolidin-2-thione (I) with acrolein (II) by means of TiCl4 and DIEA gives the adduct (III), which was transformed into the chiral cyclopentene (IV) by catalytic ring-closing metathesis. The reductive removal of the chiral auxiliary with LiBH4 affords the chiral diol (V), which is selectively silylated with TBDMSCl providing the primary silyl ether (VI). Acylation of the secondary alcohol of (VI) with benzoic anhydride gives the benzoate (VII), which is desilylated with HF in acetonitrile yielding the allylic benzoate (VIII). Benzoate (VIII) is condensed with a p-nitrophenyl Wang carbonate resin (IX) by means of DIEA and DMAP affording the solid phase resin (X) which is condensed with 2-amino-6-chloropurine (XI) by means of a Pd catalyst furnishing the adduct (XII). Thermal condensation of (XII) with cyclopropylamine (XIII) yields the diaminopurine resin (XIV) which, after cleavage from the resin by a treatment with TFA in dichloromethane, gives directly abacavir.

参考文献 中间体
合成目标
【1】 Zuercher, W.J.; Crimmins, M.T.; Solid-phase synthesis of carbocyclic nucleosides. Org Lett 2000, 2, 8, 1065.
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) 41704 1-[(4R)-4-benzyl-2-thioxo-1,3-oxazolidin-3-yl]-4-penten-1-one C15H17NO2S 详情 详情
(II) 17668 acrylaldehyde; Acrolein 107-02-8 C3H4O 详情 详情
(III) 41705 (2S,3R)-2-allyl-1-[(4R)-4-benzyl-2-thioxo-1,3-oxazolidin-3-yl]-3-hydroxy-4-penten-1-one C18H21NO3S 详情 详情
(IV) 41706 [(4R)-4-benzyl-2-thioxo-1,3-oxazolidin-3-yl][(1S,2R)-2-hydroxy-3-cyclopenten-1-yl]methanone C16H17NO3S 详情 详情
(V) 17671 (1R,5R)-5-(hydroxymethyl)-2-cyclopenten-1-ol C6H10O2 详情 详情
(VI) 41707 (1R,5R)-5-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-cyclopenten-1-ol C12H24O2Si 详情 详情
(VII) 41708 (1R,5R)-5-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-cyclopenten-1-yl benzoate C19H28O3Si 详情 详情
(VIII) 41709 (1R,5R)-5-(hydroxymethyl)-2-cyclopenten-1-yl benzoate C13H14O3 详情 详情
(XI) 11644 6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine 10310-21-1 C5H4ClN5 详情 详情
(XII) 17650 [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol C11H12ClN5O 详情 详情
(XIII) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情

合成路线11

该中间体在本合成路线中的序号：(XV)

An efficient asymmetric synthesis of abacavir has been reported: Acylation of the chiral oxazolidinone (I) with the mixed anhydride (II) by means of BuLi in THF gives the N-pentenoyloxazolidinone (III), which by condensation with acrolein (IV) catalyzed by TiCl4 and (­)-spartein in dichloromethane yields the chiral adduct (V). The ring-closing metathesis of adduct (V) by means of the ruthenium catalyst (Cy3P)Cl2Ru=CHPh in dichloromethane affords the chiral cyclopentenol (VI), which is reduced to 5(R)-(hydroxymethyl)-2-cyclopenten-1(R)-ol (VII) by means of LiBH4 in THF. Reaction of diol (VII) with a) Ac2O, TEA and DMAP, b) methyl chloroformate, TEA and DMAP or c) methyl chloroformate, pyridine and DMAP gives a) the diacetate (VIII), b) the cyclic carbonate (IX) or c) the dicarbonate (X), respectively. The condensation of diacetate (VIII), cyclic carbonate (IX) or dicarbonate (X) with 2-amino-6-chloropurine (XI) by means of Pd(PPh3)4 yields the carbocyclic purines (XII), (XIII) or (XIV), respectively. Treatment of these chloro-purines (XII), (XIII) and (XIV) with cyclopropylamine (XV) in hot DMSO provides the corresponding cyclopropylaminopurine carbonate (XVI), abacavir or cyclopropylaminopurine acetate (XVII), respectively. Finally, the protecting groups of purines (XVI) and (XVII) are hydrolyzed with aqueous NaOH.

参考文献 中间体
合成目标
【1】 Crimmins, M.T.; et al.; An efficient, general asymmetric synthesis of carbocyclic nucleosides: Application of an asymmetric aldol/ring-closing metathesis strategy. J Org Chem 2000, 65, 25, 8499.
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) 14694 (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone 90719-32-7 C10H11NO2 详情 详情
(II) 17666 1,1-dimethylpropionic 4-pentenoic anhydride C10H16O3 详情 详情
(III) 17667 (4S)-4-benzyl-3-(4-pentenoyl)-1,3-oxazolidin-2-one C15H17NO3 详情 详情
(IV) 17668 acrylaldehyde; Acrolein 107-02-8 C3H4O 详情 详情
(V) 17669 (4S)-3-[(2S,3R)-2-allyl-3-hydroxy-4-pentenoyl]-4-benzyl-1,3-oxazolidin-2-one C18H21NO4 详情 详情
(VI) 17670 (4S)-4-benzyl-3-[[(1S,2R)-2-hydroxy-3-cyclopenten-1-yl]carbonyl]-1,3-oxazolidin-2-one C16H17NO4 详情 详情
(VII) 17671 (1R,5R)-5-(hydroxymethyl)-2-cyclopenten-1-ol C6H10O2 详情 详情
(VIII) 17674 [(1R,2R)-2-(acetoxy)-3-cyclopenten-1-yl]methyl acetate C10H14O4 详情 详情
(IX) 17673 (4aR,7aR)-4,4a,5,7a-tetrahydrocyclopenta[d][1,3]dioxin-2-one C7H8O3 详情 详情
(X) 17672 [(1R,2R)-2-[(methoxycarbonyl)oxy]-3-cyclopenten-1-yl]methyl methyl carbonate C10H14O6 详情 详情
(XI) 11644 6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine 10310-21-1 C5H4ClN5 详情 详情
(XII) 45424 [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methyl acetate C13H14ClN5O2 详情 详情
(XIII) 17650 [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol C11H12ClN5O 详情 详情
(XIV) 45398 [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methyl methyl carbonate C13H14ClN5O3 详情 详情
(XV) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情
(XVI) 49433 [(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopenten-1-yl]methyl acetate C16H20N6O2 详情 详情
(XVII) 49434 [(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopenten-1-yl]methyl methyl carbonate C16H20N6O3 详情 详情

合成路线12

该中间体在本合成路线中的序号：(XV)

Alternatively, 2-amino-6-chloropurine (XI) is treated with cyclopropylamine (XV) in hot DMSO to give 2-amino-6-(cyclopropylamino)purine (XVIII), which is condensed with the chiral diacetate (VIII) by means of Pd(PPh3)4 to yield the carbocyclic purine acetate (XVI). Finally, purine (XVI) is deprotected by hydrolysis with aqueous NaOH.

参考文献 中间体
合成目标
【1】 Crimmins, M.T.; et al.; An efficient, general asymmetric synthesis of carbocyclic nucleosides: Application of an asymmetric aldol/ring-closing metathesis strategy. J Org Chem 2000, 65, 25, 8499.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIII) 17674 [(1R,2R)-2-(acetoxy)-3-cyclopenten-1-yl]methyl acetate C10H14O4 详情 详情
(XI) 11644 6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine 10310-21-1 C5H4ClN5 详情 详情
(XV) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情
(XVI) 49433 [(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopenten-1-yl]methyl acetate C16H20N6O2 详情 详情
(XVIII) 41890 N-(2-amino-9H-purin-6-yl)-N-cyclopropylamine; N(6)-cyclopropyl-9H-purine-2,6-diamine C8H10N6 详情 详情

合成路线13

该中间体在本合成路线中的序号：(IX)

The methylation of 1-bromo-2,4,5-trifluoro-3-(trimethylsilyl)benzene (I) with methyl trifluoromethylsulfonate (II) by means of diisopropylamine and butyllithium in THF gives 2-bromo-3,5,6-trifluoro-4-(trimethylsilyl)toluene (III), which is carbonated with butyllithium and CO2 in ether to yield 2,4,5-trifluoro-6-methyl-3-(trimethylsilyl)benzoic acid (IV). Elimination of the silyl group with CsF in acetonitrile affords the corresponding benzoic acid (V). The condensation of (V) with malonic acid monoethyl ester (VI) by means of oxalyl chloride and butyllithium in THF affords 3-(3,4,6-trifluoro-2-methylphenyl)-2-oxopropionic acid ethyl ester (VII), which by condensation with triethyl orthoformate in refluxing acetic anhydride is converted into the ethoxymethylene derivative (VIII). The cyclization of (VIII) with cyclopropylamine (IX) by means of sodium hydride in THF gives 1-cyclopropyl-6,7-difluoro-5-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (X), which is hydrolyzed with refluxing 6N HCl to yield the corresponding free acid (XI) (1). Finally, this compound is condensed with 2-methylpiperazine (XII) by means of triethylamine in refluxing acetonitrile.

参考文献 中间体
合成目标
【1】 Ueda, H.; Miyamoto, H.; Yamashita, H.; Tone, H. (Otsuka Pharmaceutical Co., Ltd.); Benzoheterocyclic cpds. EP 0287951; EP 0565132; JP 1989230558; JP 1995138232; JP 1995165636; US 5563138; US 5591744 .
【2】 Castaner, J.; Prous, J.; OPC-17116. Drugs Fut 1992, 17, 4, 286.
【3】 Heifetz, C.L.; Johnson, J.; Hagen, S.E.; Domagala, J.M.; Synthesis and biological activity of 5-alkyl-1,7,8-trisubstituted-6-fluoroquinoline-3-carboxylic acids. J Med Chem 1991, 34, 3, 1155.
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) 15081 (3-bromo-2,5,6-trifluorophenyl)(trimethyl)silane C9H10BrF3Si 详情 详情
(II) 15082 methyl(dioxo)(trifluoromethyl)-lambda(6)-sulfane; methyl trifluoromethyl sulfone C2H3F3O2S 详情 详情
(III) 15083 (3-bromo-2,5,6-trifluoro-4-methylphenyl)(trimethyl)silane C10H12BrF3Si 详情 详情
(IV) 15084 2,4,5-trifluoro-6-methyl-3-(trimethylsilyl)benzoic acid C11H13F3O2Si 详情 详情
(V) 15085 3,4,6-trifluoro-2-methylbenzoic acid C8H5F3O2 详情 详情
(VI) 15086 3-ethoxy-3-oxopropionic acid 1071-46-1 C5H8O4 详情 详情
(VII) 15087 ethyl 3-oxo-3-(3,4,6-trifluoro-2-methylphenyl)propanoate C12H11F3O3 详情 详情
(VIII) 15088 ethyl (Z)-3-ethoxy-2-(3,4,6-trifluoro-2-methylbenzoyl)-2-propenoate C15H15F3O4 详情 详情
(IX) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情
(X) 15090 ethyl 1-cyclopropyl-6,7-difluoro-5-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylate C16H15F2NO3 详情 详情
(XI) 15091 1-cyclopropyl-6,7-difluoro-5-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid C14H11F2NO3 详情 详情
(XII) 12267 2-Methylpiperazine 109-07-9 C5H12N2 详情 详情

合成路线14

该中间体在本合成路线中的序号：(XI)

Decarboxylation of 3,5,6-trifluoro-4-hydroxyphthalic acid (I) upon heating at 140 C in an autoclave furnished 2,4,5-trifluoro-3-hydroxybenzoic acid (II). This was converted to ethyl ester (III) by refluxing in EtOH in the presence of H2SO4. Condensation of (III) with chlorodifluoromethane and NaH in hot DMF produced the corresponding difluoromethyl ether, and subsequent basic hydrolysis of the ethyl ester yielded 3-(difluoromethoxy)-2,4,5-trifluorobenzoic acid (IV). Alternatively, acid (II) was converted to acid chloride with SOCl2 and subsequently condensed with ammonia to give amide (V). After formation of the difluoromethyl ether (VI) under similar conditions as above, acid (IV) was obtained by diazotization of the amide function of (VI) in hot sulfuric acid. The difluoromethoxy acid (IV) was also prepared by direct alkylation of hydroxy acid (II) with chlorodifluoromethane in the presence of NaOH in hot DMF. Acid (IV) was activated as the corresponding acid chloride (VII) with SOCl2. Condensation of acid chloride (VII) with the magnesium salt of diethyl malonate gave rise to the benzoylmalonate (VIII). Further decarbethoxylation of (VIII) by heating in the presence of p-toluenesulfonic acid yielded keto ester (IX). This was condensed with triethyl orthoformate in the presence of Ac2O to give the ethoxyacrylate (X), which was converted to enamine (XII) by treatment with cyclopropylamine (XI). The target quinolone system (XIII) was then obtained by intramolecular cyclization of (XII) in the presence of NaH. Then, ethyl ester (XII) cleavage using boron trifluoride etherate provided the key quinolonecarboxylic acid boron chelate (XIV)

参考文献 中间体
合成目标
【1】 Iwata, M.; Kimura, T.; Inoue, T.; Fujihara, Y.; Katsube, T. (Sankyo Co., Ltd.; Ube Industries, Ltd.); 4-Oxoquinoline-3-carboxylic acid derivs., their preparation and their use. AU 8938218; EP 0352123; EP 0610958; JP 1990124873; JP 1990231476; JP 1993255183; US 5002947; US 5073556; US 5348961 .
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) 59807 3,4,6-trifluoro-5-hydroxyphthalic acid C8H3F3O5 详情 详情
(II) 59808 2,4,5-trifluoro-3-hydroxybenzoic acid C7H3F3O3 详情 详情
(III) 59809 ethyl 2,4,5-trifluoro-3-hydroxybenzoate C9H7F3O3 详情 详情
(IV) 59812 3-(difluoromethoxy)-2,4,5-trifluorobenzoic acid C8H3F5O3 详情 详情
(V) 59810 2,4,5-trifluoro-3-hydroxybenzamide C7H4F3NO2 详情 详情
(VI) 59811 3-(difluoromethoxy)-2,4,5-trifluorobenzamide C8H4F5NO2 详情 详情
(VII) 59815 3-(difluoromethoxy)-2,4,5-trifluorobenzoyl chloride C8H2ClF5O2 详情 详情
(VIII) 59814 diethyl 2-[3-(difluoromethoxy)-2,4,5-trifluorobenzoyl]malonate C15H13F5O6 详情 详情
(IX) 59813 ethyl 3-[3-(difluoromethoxy)-2,4,5-trifluorophenyl]-3-oxopropanoate C12H9F5O4 详情 详情
(X) 59816 ethyl (Z)-2-[3-(difluoromethoxy)-2,4,5-trifluorobenzoyl]-3-ethoxy-2-propenoate C15H13F5O5 详情 详情
(XI) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情
(XII) 59819 ethyl (Z)-3-(cyclopropylamino)-2-[3-(difluoromethoxy)-2,4,5-trifluorobenzoyl]-2-propenoate C16H14F5NO4 详情 详情
(XIII) 59817 ethyl 1-cyclopropyl-8-(difluoromethoxy)-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate C16H13F4NO4 详情 详情
(XIV) 59818 1-cyclopropyl-3-{[(difluoroboryl)oxy]carbonyl}-8-(difluoromethoxy)-6,7-difluoro-4(1H)-quinolinone C14H8BF6NO4 详情 详情

合成路线15

该中间体在本合成路线中的序号：

A general synthesis of this entire class of thrombin inhibitors has been published recently. An alternative synthesis for the preparation of napsagatran is outlined in Scheme 21319301a: L-Aspartic acid is sulfonated with naphthalenesulfochloride to give the sulfonamide (I). Reaction of (I) with formaldehyde leads to the oxazolinone (II), which is reacted with N-cyclopropylglycine ethyl ester (III) to afford the aspartate (IV). Condensation of (IV) with the guanidine (IX) and saponification of the ethyl ester group provides napsagatran. For the preparation of the guanidine (IX), picolylamine is hydrogenated to give the racemic 3-aminomethyl-piperidine, from which the desired enantiomer (V) is isolated as dibenzoyltartrate by crystallization. Reaction of piperidine (V) with acetoacetate affords the protected piperidine (VI), which is amidinated with amidinotriazole (VII) to give the protected guanidine (VIII). Deprotection of (VIII) with hydrochloric acid provides the enantiomerically pure guanidine (IX) as dihydrochloride.

参考文献 中间体
合成目标
【1】 Banner, D.W.; Hilpert, K.; Ackermann, J.; et al.; Design and synthesis of potent and highly selective thrombin inhibitors. J Med Chem 1994, 37, 23, 3889-901.
【2】 Gast, A.; Kirchhofer, D.; Soukup. M.; Roux, S.; Ackermann, J.; Hilpert, K.; Tschopp, T.B.; Schmid, G.; Napsagatran. Drugs Fut 1995, 20, 5, 476.
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
13070 L-Aspartic acid; (2S)-2-Aminobutanedioic acid 56-84-8 C4H7NO4 详情 详情
16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
18731 3-pyridinylmethanamine; 3-pyridinylmethylamine 3731-52-0 C6H8N2 详情 详情
(I) 16803 (2S)-2-[(2-naphthylsulfonyl)amino]butanedioic acid C14H13NO6S 详情 详情
(II) 16804 2-[(4S)-3-(2-naphthylsulfonyl)-5-oxo-1,3-oxazolan-4-yl]acetic acid C15H13NO6S 详情 详情
(III) 16805 ethyl 2-(cyclopropylamino)acetate C7H13NO2 详情 详情
(IV) 16806 (3S)-4-[cyclopropyl(2-ethoxy-2-oxoethyl)amino]-3-[(2-naphthylsulfonyl)amino]-4-oxobutyric acid C21H24N2O7S 详情 详情
(V) 16807 (3S)hexahydro-3-pyridinylmethylamine; (3S)hexahydro-3-pyridinylmethanamine C6H14N2 详情 详情
(VI) 16808 methyl (Z)-3-[[(3R)hexahydro-3-pyridinylmethyl]amino]-2-butenoate C11H20N2O2 详情 详情
(VII) 16809 1H-1,2,4-triazole-1-carboximidamide hydrochloride C3H6ClN5 详情 详情
(VIII) 16810 methyl (Z)-3-[([(3S)-1-[amino(imino)methyl]piperidinyl]methyl)amino]-2-butenoate hydrochloride C12H23ClN4O2 详情 详情
(IX) 16811 (3S)-3-(aminomethyl)-1-piperidinecarboximidamide C7H16N4 详情 详情

合成路线16

该中间体在本合成路线中的序号：(VIII)

Nitration of 2,4,5-trifluoro-3-methylbenzoic acid (I) with H2SO4 and HNO3 provides nitrobenzoic acid derivative (II), which is then converted into the nitrobenzoyl chloride derivative (III) by reaction with oxalyl chloride in CH2Cl2 in the presence of DMF. Condensation of (III) with diethyl malonate (IV) by means of Mg in EtOH in the presence of CCl4 yields diethyl (2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)malonate (V), which is then treated with p-toluene sulfonic acid in refluxing H2O to furnish ethyl acetate derivative (VI). Reaction of (VI) with ethyl orthoformate and acetic anhydride at reflux affords ethyl acrylate derivative (VII), which is then treated with cyclopropylamine (VIII) in EtOH to give compound (IX). Cyclization of (IX) is then induced either by treatment with NaH in 1,4-dioxane or with 18-crown-6-ether and K2CO3 in THF to provide quinolone derivative (X), whose nitro group is reduced by hydrogenation over Ni Raney in HOAc to give amino derivative (XI). Hydrolysis of the ethyl ester moiety of (XI) is performed by refluxing with HCl/HOAc to furnish carboxylic acid (XII), which is then treated with boron trifluoride etherate to give boron chelate (XIII). Finally, condensation of (XIII) with (S)-7-trifluoroacetylamino-5-azaspiro[2.4]heptane hydrochloride (XIV) by means of Et3N in DMSO, followed by deprotection with KOH in H2O and treatment with MeSO3H affords the desired compound. Alternatively, the target product can also be synthesized from the Boc protected derivative (XVI) obtained either by coupling of boron chelate (XIII) with (S)-7-Boc-amino-5-azaspiro[2.4]heptane hydrochloride (XIV) by means of DIEA in DMSO (or Et3N in MeOH) or by reaction between carboxylic acid (XII) and compound (XV) by heating in DMSO. Finally, the Boc protecting group of (XVI) is removed with HCl and the corresponding methanesulfonate salt formed by treatment with MeSO3H.

参考文献 中间体
合成目标
【1】 Yoshida, T.; et al.; Studies on quinolone antibacterials.V. Synthesis and antibacterial activity of chiral 5-amino-7-(4-substituted-3-amino-1-pyrrolidinyl)-6-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acids and derivatives. Chem Pharm Bull 1996, 44, 7, 1376.
【2】 Ito, Y.; Kato, H.; Yasuda, S.; Kado, N.; Yoshida, T.; Yamamoto, Y. (Hokuriku Seiyaku Co., Ltd.); 5-Amino-8-methyl-7-pyrrolidinylquinoline-3-carboxylic acid deriv.. CA 2126118; EP 0641793; JP 1995309864; US 5547962 .
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) 51094 2,4,5-trifluoro-3-methylbenzoic acid C8H5F3O2 详情 详情
(II) 51095 2,4,5-trifluoro-3-methyl-6-nitrobenzoic acid C8H4F3NO4 详情 详情
(III) 51096 2,4,5-trifluoro-3-methyl-6-nitrobenzoyl chloride C8H3ClF3NO3 详情 详情
(IV) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(V) 51097 diethyl 2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)malonate C15H14F3NO7 详情 详情
(VI) 51098 ethyl 3-oxo-3-(2,4,5-trifluoro-3-methyl-6-nitrophenyl)propanoate C12H10F3NO5 详情 详情
(VII) 51099 ethyl (Z)-3-ethoxy-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)-2-propenoate C15H14F3NO6 详情 详情
(VIII) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情
(IX) 51100 ethyl (Z)-3-(cyclopropylamino)-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)-2-propenoate C16H15F3N2O5 详情 详情
(X) 51101 ethyl 1-cyclopropyl-6,7-difluoro-8-methyl-5-nitro-4-oxo-1,4-dihydro-3-quinolinecarboxylate C16H14F2N2O5 详情 详情
(XI) 51102 ethyl 5-amino-1-cyclopropyl-6,7-difluoro-8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylate C16H16F2N2O3 详情 详情
(XII) 51103 5-amino-1-cyclopropyl-6,7-difluoro-8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid C14H12F2N2O3 详情 详情
(XIII) 51104 　 C14H11BF4N2O3 详情 详情
(XIV) 51105 N-[(7S)-5-azaspiro[2.4]hept-7-yl]-2,2,2-trifluoroacetamide C8H11F3N2O 详情 详情
(XV) 15193 tert-butyl N-[(7S)-5-azaspiro[2.4]hept-7-yl]carbamate C11H20N2O2 详情 详情
(XVI) 51106 5-amino-7-[(7S)-7-[(tert-butoxycarbonyl)amino]-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid C25H31FN4O5 详情 详情

合成路线17

该中间体在本合成路线中的序号：(VI)

The condensation of 2,4,5-trifluoro-3-methoxybenzoyl chloride (I) with 14C-labeled diethyl malonate (II) by means of MgCl2 and TEA gives the benzoylmalonate (III), which is monodecarboxylated with TsOH in refluxing water, yielding the benzoylacetate (IV). The reaction of (IV) with triethyl orthoformate and Ac2O at 140 C affords the benzoylacrylate (V), which is treated with cyclopropylamine (VI) in cyclohexane to provide ethyl 3-(cyclopropylamino)-2-(2,4,5-trifluoro-3-methoxybenzoyl)acrylate (VII). The cyclization of (VII) by means of K2CO3 in hot N-methylpyrrolidone gives the quinolone carboxylate (VIII), which is hydrolyzed with NaOH in hot methanol, affording the carboxylic acid (IX). Finally, this compound is condensed with (S,S)-2,8-diazabicyclo[4.3.0]octane (X) by means of 1,4-diazabicyclo[2.2.2]octane (DABCO) in refluxing acetonitrile.

参考文献 中间体
合成目标
【1】 Seidel, D.; Conrad, M.; Brehmer, P.; Mohrs, K.; Petersen, U.; Synthesis of carbon-14 labelled moxifloxacin hydrochloride. J Label Compd Radiopharm 2000, 43, 8, 795.
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) 12259 2,4,5-Trifluoro-3-methoxybenzoyl chloride C8H4ClF3O2 详情 详情
(II) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(II) 45330 diethyl malonate C7H12O4 详情 详情
(III) 12260 diethyl 2-(2,4,5-trifluoro-3-methoxybenzoyl)malonate C15H15F3O6 详情 详情
(III) 45331 diethyl 2-(2,4,5-trifluoro-3-methoxybenzoyl)malonate C15H15F3O6 详情 详情
(IV) 12261 ethyl 3-oxo-3-(2,4,5-trifluoro-3-methoxyphenyl)propanoate C12H11F3O4 详情 详情
(IV) 45332 ethyl 3-oxo-3-(2,4,5-trifluoro-3-methoxyphenyl)propanoate C12H11F3O4 详情 详情
(V) 12262 ethyl (Z)-3-ethoxy-2-(2,4,5-trifluoro-3-methoxybenzoyl)-2-propenoate C15H15F3O5 详情 详情
(V) 45333 ethyl (Z)-3-ethoxy-2-(2,4,5-trifluoro-3-methoxybenzoyl)-2-propenoate C15H15F3O5 详情 详情
(VI) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情
(VII) 12264 ethyl (E)-3-(cyclopropylamino)-2-(2,4,5-trifluoro-3-methoxybenzoyl)-2-propenoate C16H16F3NO4 详情 详情
(VII) 45334 ethyl (Z)-3-(cyclopropylamino)-2-(2,4,5-trifluoro-3-methoxybenzoyl)-2-propenoate C16H16F3NO4 详情 详情
(VIII) 12265 ethyl 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylate C16H15F2NO4 详情 详情
(VIII) 45335 ethyl 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylate C16H15F2NO4 详情 详情
(IX) 12266 1-Cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid 112811-72-0 C14H11F2NO4 详情 详情
(IX) 45336 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid C14H11F2NO4 详情 详情
(X) 17253 (4aS,7aS)octahydro-1H-pyrrolo[3,4-b]pyridine C7H14N2 详情 详情

合成路线18

该中间体在本合成路线中的序号：(XIV)

The methylation of 2,6-difluorophenol (I) with methyl iodide and K2CO3 in DMF gives 2,6-difluoroanisole (II), which by treatment with butyllithium and CO2 yields 2,4-difluoro-3-methoxybenzoic acid (III). The methylation of (III) with diazomethane in ether affords the methyl ester (IV), which by reaction with BBr3 in dichloromethane results in 2,4-difluoro-3-hydroxybenzoic acid methyl ester (V). The alkylation of (V) with chlorodifluoromethane and K2CO3 in DMF gives 3-(difluoromethoxy)-2,4-difluorobenzoic acid methyl ester (VI), which is treated with sodium azide in DMSO, yielding the azido derivative (VII). The reduction of (VII) with H2 over Pd/C in ethanol affords 3-amino-2,4-difluorobenzoic acid methyl ester (VIII), which is hydrolyzed with NaOH in ethanol, giving the free acid (IX). The reaction of (IX) with NaNO2 and HBr yields 4-bromo-3-(difluoromethoxy)-2-fluorobenzoic acid (X), which is condensed with the magnesium salt of malonic acid monoethyl ester (XI) by means of CDI in THF, affording the 3-oxopropionate (XII). The reaction of (XII) with dimethylformamide dimethylacetal (XIII) and cyclopropylamine (XIV) by means of acetic anhydride in dichloromethane gives the 3-(cyclopropylamino)acrylate (XV), which is cyclized by means of K2CO3 in hot DMSO, yielding quinolone (XVI). The condensation of (XVI) with the isoindolylboronic acid derivative (XVII) - obtained by reaction of 5-bromo-1(R)-methyl-2-tritylisoindoline (XIX) with triisopropyl borate and butyllithium in THF - by means of bis(triphenylphosphine)palladium(II) chloride as catalyst in refluxing toluene affords the protected compound (XVIII), which is finally deprotected with HCl in ethanol.

参考文献 中间体
合成目标
【1】 Castañer, J.; Rabasseda, X.; Graul, A.; T-3811ME. Drugs Fut 1999, 24, 12, 1324.
【2】 Todo, Y.; Hayashi, K.; Takahata, M.; Watanabe, Y.; Narita, H. (Toyama Chemical Co., Ltd.); Quinolonecarboxylic acid derivs. or salts thereof.. EP 0882725; US 6025370; WO 9729102 .
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) 30619 2,6-difluorophenol 28177-48-2 C6H4F2O 详情 详情
(II) 30620 2,6-difluorophenyl methyl ether; 1,3-difluoro-2-methoxybenzene C7H6F2O 详情 详情
(III) 30621 2,4-difluoro-3-methoxybenzoic acid 178974-97-5 C8H6F2O3 详情 详情
(IV) 30622 methyl 2,4-difluoro-3-methoxybenzoate C9H8F2O3 详情 详情
(V) 30623 methyl 2,4-difluoro-3-hydroxybenzoate C8H6F2O3 详情 详情
(VI) 30624 methyl 3-(difluoromethoxy)-2,4-difluorobenzoate C9H6F4O3 详情 详情
(VII) 30625 methyl 4-azido-3-(difluoromethoxy)-2-fluorobenzoate C9H6F3N3O3 详情 详情
(VIII) 30626 methyl 4-amino-3-(difluoromethoxy)-2-fluorobenzoate C9H8F3NO3 详情 详情
(IX) 30627 4-amino-3-(difluoromethoxy)-2-fluorobenzoic acid C8H6F3NO3 详情 详情
(X) 30628 4-bromo-3-(difluoromethoxy)-2-fluorobenzoic acid C8H4BrF3O3 详情 详情
(XI) 14338 potassium 3-ethoxy-3-oxopropanoate 6148-64-7 C5H7KO4 详情 详情
(XII) 30629 ethyl 3-[4-bromo-3-(difluoromethoxy)-2-fluorophenyl]-3-oxopropanoate C12H10BrF3O4 详情 详情
(XIII) 11984 N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal 4637-24-5 C5H13NO2 详情 详情
(XIV) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情
(XV) 30630 ethyl (Z)-2-[4-bromo-3-(difluoromethoxy)-2-fluorobenzoyl]-3-(cyclopropylamino)-2-propenoate C16H15BrF3NO4 详情 详情
(XVI) 30631 ethyl 7-bromo-1-cyclopropyl-8-(difluoromethoxy)-4-oxo-1,4-dihydro-3-quinolinecarboxylate C16H14BrF2NO4 详情 详情
(XVII) 30632 (1R)-1-methyl-2-trityl-2,3-dihydro-1H-isoindol-5-ylboronic acid C28H26BNO2 详情 详情
(XVIII) 30633 ethyl 1-cyclopropyl-8-(difluoromethoxy)-7-[(1R)-1-methyl-2-trityl-2,3-dihydro-1H-isoindol-5-yl]-4-oxo-1,4-dihydro-3-quinolinecarboxylate C44H38F2N2O4 详情 详情
(XIX) 30634 (1R)-5-bromo-1-methyl-2-trityl-2,3-dihydro-1H-isoindole C28H24BrN 详情 详情

合成路线19

该中间体在本合成路线中的序号：(VIII)

OP C-33509 has been obtained by coupling imidazolecarboxamide (VI) with amine (IX) in refluxing CHCl3. The intermediates (VI) and (IX) have been obtained as follows: 1) Alkylation of 6-hydroxycarbostyril (I) with N-(3-bromopropyl)- phthalimide (II) in the presence of K2CO3 in DMF furnished the phthalimidopropyl ether (III). Subsequent hydrazinolysis of the phthalimide in refluxing EtOH provided the primary amine (IV). Then, the imidazolecarboxamide (VI) was obtained by treating amine (IV) with 1,1'-carbonyldiimidazole (V) and two equivalents of imidazole in DMSO. 2) Ring opening of 1,2 epoxycyclohexane (VII) with cyclopropylamine (VIII) gave the racemic trans aminoalcohol. Resolution of enantiomers (IX) and (X) was accomplished by esterification with (S)-mandelic acid (XI), followed by chromatographic separation of the diastereomeric esters. Hydrolysis of the desired ester (XII) then provided optically pure aminoalcohol (IX). Finally, the target urea derivative was obtained by coupling imidazolyl urea (VI) with amine (IX) in refluxing chloroform.

参考文献 中间体
合成目标
【1】 Koga, Y.; Kihara, Y.; Okada, M.; Inoue, Y.; Tochizawa, S.; Toga, K.; Tachibana, K.; Kimura, Y.; Nishi, T.; Hidaka, H.; 2(1H)- Quinoline derivatives as novel anti-arteriostenotic agents showing anti-thrombotic and anti-hyperplastic activities. Bioorg Med Chem Lett 1998, 8, 12, 1471.
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) 13913 6-Hydroxy-2(1H)-quinolinone C9H7NO2 详情 详情
(II) 15216 N-(3-Bromopropyl)phthalimide; 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione 5460-29-7 C11H10BrNO2 详情 详情
(III) 18912 2-[3-[(2-oxo-1,2-dihydro-6-quinolinyl)oxy]propyl]-1H-isoindole-1,3(2H)-dione C20H16N2O4 详情 详情
(IV) 18913 6-(3-aminopropoxy)-2(1H)-quinolinone C12H14N2O2 详情 详情
(V) 11353 1,1'-Carbonyldiimidazole; Di(1H-imidazol-1-yl)methanone; N,N-Carbonyldiimidazole; 1,1'-Carbonylbis(1H-imidazole) 530-62-1 C7H6N4O 详情 详情
(VI) 18915 N-[3-[(2-oxo-1,2-dihydro-6-quinolinyl)oxy]propyl]-1H-imidazole-1-carboxamide C16H16N4O3 详情 详情
(VII) 17986 7-oxabicyclo[4.1.0]heptane; cyclohexene oxide 286-20-4 C6H10O 详情 详情
(VIII) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情
(IX) 18918 (1R,2R)-2-(cyclopropylamino)cyclohexanol C9H17NO 详情 详情
(X) 18919 (1S,2S)-2-(cyclopropylamino)cyclohexanol C9H17NO 详情 详情
(XI) 12563 (2S)-2-Hydroxy-2-phenylethanoic acid; S-(+)-Mandelic acid 17199-29-0 C8H8O3 详情 详情
(XII) 18921 (1R,2R)-2-(cyclopropylamino)cyclohexyl (2S)-2-hydroxy-2-phenylethanoate C17H23NO3 详情 详情

合成路线20

该中间体在本合成路线中的序号：(IV)

Alkylation of 2-amino-6-chloropurine (I) with tosylate (II) afforded the phosphonomethoxyethyl purine (III). Subsequent displacement of the chloro atom of (III) by cyclopropylamine (IV) furnished diaminopurine (V). The isopropyl protecting groups of (IV) were finally cleaved by treatment with bromotrimethylsilane.

参考文献 中间体
合成目标
【1】 Holy, A.; De Clercq, E.D.A. (Institute of Organic Chemistry and Biochemistry; Stichting Rega Vzw); N6-Substd. nucleotide analogues and their use. US 5977061; WO 9633200 .
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) 11644 6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine 10310-21-1 C5H4ClN5 详情 详情
(II) 41887 2-[(diisopropoxyphosphoryl)methoxy]ethyl 4-methylbenzenesulfonate C16H27O7PS 详情 详情
(III) 41888 diisopropyl [2-(2-amino-6-chloro-9H-purin-9-yl)ethoxy]methylphosphonate C14H23ClN5O4P 详情 详情
(IV) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情
(V) 41889 diisopropyl [2-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]ethoxy]methylphosphonate C17H29N6O4P 详情 详情

合成路线21

该中间体在本合成路线中的序号：(IV)

In an alternative method for preparing precursor (V), 2-amino-6-chloropurine (I) was first treated with cyclopropylamine (IV) to give diaminopurine (VI), and then alkylated with tosylate (II).

参考文献 中间体
合成目标
【1】 Holy, A.; De Clercq, E.D.A. (Institute of Organic Chemistry and Biochemistry; Stichting Rega Vzw); N6-Substd. nucleotide analogues and their use. US 5977061; WO 9633200 .
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) 11644 6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine 10310-21-1 C5H4ClN5 详情 详情
(II) 41887 2-[(diisopropoxyphosphoryl)methoxy]ethyl 4-methylbenzenesulfonate C16H27O7PS 详情 详情
(IV) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情
(V) 41889 diisopropyl [2-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]ethoxy]methylphosphonate C17H29N6O4P 详情 详情
(VI) 41890 N-(2-amino-9H-purin-6-yl)-N-cyclopropylamine; N(6)-cyclopropyl-9H-purine-2,6-diamine C8H10N6 详情 详情

合成路线22

该中间体在本合成路线中的序号：(V)

The condensation of 2,2-dimethyl-7-nitro-2H-1-benzopyran-6-amine (I) with 4-methoxyphenylacetyl chloride (II) by means of triethylmaine in chloroform gives the corresponding amide (III), which is regioselectively epoxidized with ClONa and a chiral manganese catalyst yielding the epoxide (IV). Finally, this compound is treated with cyclopropylamine in refluxing ethanol.

参考文献 中间体
合成目标
【1】 Ohrai, K.; Sato, M.; Yanagihara, K.; Tanikawa, K.; Yamashita, T.; Shigeta, Y.; Structure-activity relationships and pharmacological activities of benzopyran derivatives with selective bradycardic and anti-fibrillatory effects. Symp Med Chem 1998, Abst 1-P-29.
【2】 Tanikawa, K.; Ohrai, K.; Sato, M.; Yamashita, T.; Yanagihara, K. (Nissan Chemical Industry, Ltd.); Chroman derivs.. EP 0934296; JP 1998087650; US 6066631; WO 9804542 .
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) 26757 2,2-dimethyl-7-nitro-2H-chromen-6-amine C11H12N2O3 详情 详情
(II) 26758 2-(4-methoxyphenyl)acetyl chloride 4693-91-8 C9H9ClO2 详情 详情
(III) 26759 N-(2,2-dimethyl-7-nitro-2H-chromen-6-yl)-2-(4-methoxyphenyl)acetamide C20H20N2O5 详情 详情
(IV) 26760 N-[(1aR,7bR)-2,2-dimethyl-5-nitro-1a,7b-dihydro-2H-oxireno[2,3-c]chromen-6-yl]-2-(4-methoxyphenyl)acetamide C20H20N2O6 详情 详情
(V) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情

合成路线23

该中间体在本合成路线中的序号：(IV)

The known 7,8-dihydro-8-methyl-5-(4-nitrophenyl)-9H-1,3-dioxolo-[4,5-h]-2,3-benzodiazepine (I) was condensed with 1,1'-carbonyldiimidazole (II) in refluxing THF to produce imidazolide (III). Subsequent reaction of (III) with boiling cyclopropylamine (IV) gave rise to the cyclopropylcarbamoyl derivative (V). The nitro group of (V) was then reduced to the corresponding amine by hydrogenation over Pd/C.

参考文献 中间体
合成目标
【1】 1,3-Dioxolo[4,5-h][2,3]benzodiazepine derivs. as AMPA/kainate receptor inhibitors. EP 1015457; WO 9907708 .
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) 37909 8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-[1,3]dioxolo[4,5-h][2,3]benzodiazepine C17H15N3O4 详情 详情
(II) 11353 1,1'-Carbonyldiimidazole; Di(1H-imidazol-1-yl)methanone; N,N-Carbonyldiimidazole; 1,1'-Carbonylbis(1H-imidazole) 530-62-1 C7H6N4O 详情 详情
(III) 37910 1H-imidazol-1-yl[8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-[1,3]dioxolo[4,5-h][2,3]benzodiazepin-7-yl]methanone C21H17N5O5 详情 详情
(IV) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情
(V) 37911 N-cyclopropyl-8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-[1,3]dioxolo[4,5-h][2,3]benzodiazepine-7-carboxamide C21H20N4O5 详情 详情

合成路线24

该中间体在本合成路线中的序号：(III)

Arachidonic acid (I) was converted to the mixed anhydride (II) upon treatment with isobutyl chloroformate and triethylamine. Subsequent condensation of (II) with cyclopropylamine (III) provided the target amide.

参考文献 中间体
合成目标
【1】 Murphy, V.; Greenberg, M.J.; Manna, S.; Dicamelli, R.; Ross, R.A.; Campbell, W.B.; Stevenson, L.A.; Hillard, C.J.; Pertwee, R.G.; Synthesis and characterization of potent and selective agonists of the neuronal cannabinoid receptor (CB1). J Pharmacol Exp Ther 1999, 289, 3, 1427.
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) 21406 (5Z,8Z,11Z,14Z)-5,8,11,14-icosatetraenoic acid 7771-44-0 C20H32O2 详情 详情
(II) 25848 Icosa-5(Z),8(Z),11(Z),14(Z)-tetraenoic acid isobutoxycarbonyl anhydride C25H40O4 详情 详情
(III) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情

合成路线25

该中间体在本合成路线中的序号：(VII)

Alkylation of 5-nitroindole (I) with 4-isopropylbenzyl chloride (II) in the presence of Cs2CO3 provided the N-benzylindole derivative (III). Reduction of the nitro group of (III) by hydrogenation over Pd/C gave the corresponding amine, which was isolated as the hydrochloride salt (IV). The required pyrroloquinazoline system (V) was then prepared by reaction of (IV) with trichloromethyl isocyanate, followed by treatment with POCl3. Displacement of the 1-chlorine of (V) by ammonia afforded amine (VI). The remaining 3-chlorine of (VI) was then displaced by cyclopropylamine (VII) to furnish the title compound.

参考文献 中间体
合成目标
【1】 Boykow, G.; Ahn, H.-S.; Arik, L.; et al.; Structure-activity relationships of pyrroloquinazolines as thrombin receptor antagonists. Bioorg Med Chem Lett 1999, 9, 14, 2073.
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) 26916 5-Nitroindole; 5-nitro-1H-indole 6146-52-7 C8H6N2O2 详情 详情
(II) 33769 1-(chloromethyl)-4-isopropylbenzene 2051-18-5 C10H13Cl 详情 详情
(III) 33770 1-(4-isopropylbenzyl)-5-nitro-1H-indole C18H18N2O2 详情 详情
(IV) 33771 1-(4-isopropylbenzyl)-1H-indol-5-amine; 1-(4-isopropylbenzyl)-1H-indol-5-ylamine C18H20N2 详情 详情
(V) 33772 1,3-dichloro-7-(4-isopropylbenzyl)-7H-pyrrolo[3,2-f]quinazoline C20H17Cl2N3 详情 详情
(VI) 33773 3-chloro-7-(4-isopropylbenzyl)-7H-pyrrolo[3,2-f]quinazolin-1-ylamine; 3-chloro-7-(4-isopropylbenzyl)-7H-pyrrolo[3,2-f]quinazolin-1-amine C20H19ClN4 详情 详情
(VII) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情

合成路线26

该中间体在本合成路线中的序号：(VIII)

Aromatic hydroxylation of 1-bromo-2,4-difluorobenzene (I) using tert-butyl hydroperoxide and LDA afforded phenol (II), which was methylated with iodomethane and K2CO3 to give methyl ether (III). The required benzoic acid (IV) was then obtained from (III) by lithium-bromine exchange with n-butyllithium, followed by carboxylation with CO2 gas at -70 C. Treatment of (IV) with oxalyl chloride and DMF gave acid chloride (V). This was condensed with the lithium salt of monoethyl malonate to yield, after acid decarboxylation, ketoester (VI). Subsequent condensation of (VI) with triethyl orthoformate in refluxing Ac2O provided methoxyacrylate (VII), and further treatment with cyclopropylamine (VIII) furnished aminoacrylate (IX). Cyclization of (IX) by means of NaH in THF generated the quinolone system (X). Acid hydrolysis of the ethyl ester group of (X) gave quinolinecarboxylic acid (XI), which was converted to the boron difluoride complex (XII) by treatment with BF3-Et2O in hot THF. Displacement of the aromatic fluorine of (XII) with 3R-(1S-tert-butoxycarbonylaminoethyl)pyrrolidine (XIII) in the presence of DIEA, followed by boron complex cleavage with Et3N in EtOH provided the pyrrolidinylquinoline (XIV). Finally, the Boc protecting group of (XIV) was removed by hydrolysis with ethanolic HCl.

参考文献 中间体
合成目标
【1】 Hu, X.E.; Gray, J.L.; Almstead, J.-I.K.; Ledoussal, B. (The Procter & Gamble Co.); Antimicrobial quinolones, their compsns. and uses. EP 1015445; WO 9914214 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
15086 3-ethoxy-3-oxopropionic acid 1071-46-1 C5H8O4 详情 详情
(I) 15488 1-bromo-2,4-difluorobenzene 348-57-2 C6H3BrF2 详情 详情
(II) 34648 3-bromo-2,6-difluorophenol 221220-99-1 C6H3BrF2O 详情 详情
(III) 34649 3-bromo-2,6-difluorophenyl methyl ether; 1-bromo-2,4-difluoro-3-methoxybenzene 221221-00-7 C7H5BrF2O 详情 详情
(IV) 30621 2,4-difluoro-3-methoxybenzoic acid 178974-97-5 C8H6F2O3 详情 详情
(V) 34650 2,4-difluoro-3-methoxybenzoyl chloride C8H5ClF2O2 详情 详情
(VI) 34651 ethyl 3-(2,4-difluoro-3-methoxyphenyl)-3-oxopropanoate C12H12F2O4 详情 详情
(VII) 34652 ethyl (Z)-2-(2,4-difluoro-3-methoxybenzoyl)-3-ethoxy-2-propenoate C15H16F2O5 详情 详情
(VIII) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情
(IX) 34653 ethyl (Z)-3-(cyclopropylamino)-2-(2,4-difluoro-3-methoxybenzoyl)-2-propenoate C16H17F2NO4 详情 详情
(X) 34654 ethyl 1-cyclopropyl-7-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylate C16H16FNO4 详情 详情
(XI) 34655 1-cyclopropyl-7-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid 221221-16-5 C14H12FNO4 详情 详情
(XII) 34656 　 C14H11BF3NO4 详情 详情
(XIII) 34657 tert-butyl (1S)-1-[(3R)pyrrolidinyl]ethylcarbamate C11H22N2O2 详情 详情
(XIV) 34658 7-((3R)-3-[(1S)-1-[(tert-butoxycarbonyl)amino]ethyl]pyrrolidinyl)-1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid C25H33N3O6 详情 详情

合成路线27

该中间体在本合成路线中的序号：(VI)

The acylation of 6-amino-2,2-dimethyl-7-nitro-2H-1-benzopyran (I) with p-methoxyphenylacetyl chloride (II) furnished amide (III). Subsequent bromination of the pyran ring of (III) employing N-bromosuccinimide in H2O-DMSO formed the trans bromohydrin (IV), which was further cyclized to epoxide (V) upon treatment with NaOH. Finally, oxirane ring opening in (IV) with cyclopropylamine (VI) in boiling EtOH yielded the title trans amino alcohol.

参考文献 中间体
合成目标
【1】 Tanikawa, K.; Ohrai, K.; Sato, M.; Yamashita, T.; Yanagihara, K. (Nissan Chemical Industry, Ltd.); Chroman derivs.. EP 0934296; JP 1998087650; US 6066631; WO 9804542 .
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) 26757 2,2-dimethyl-7-nitro-2H-chromen-6-amine C11H12N2O3 详情 详情
(II) 26758 2-(4-methoxyphenyl)acetyl chloride 4693-91-8 C9H9ClO2 详情 详情
(III) 26759 N-(2,2-dimethyl-7-nitro-2H-chromen-6-yl)-2-(4-methoxyphenyl)acetamide C20H20N2O5 详情 详情
(IV) 59601 N-[(3S,4R)-3-bromo-4-hydroxy-2,2-dimethyl-7-nitro-3,4-dihydro-2H-chromen-6-yl]-2-(4-methoxyphenyl)acetamide C20H21BrN2O6 详情 详情
(V) 26760 N-[(1aR,7bR)-2,2-dimethyl-5-nitro-1a,7b-dihydro-2H-oxireno[2,3-c]chromen-6-yl]-2-(4-methoxyphenyl)acetamide C20H20N2O6 详情 详情
(VI) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情

合成路线28

该中间体在本合成路线中的序号：(II)

Palladium-catalyzed displacement of 2,6-dibromotoluene (I) with cyclopropylamine (II) affords N-cyclopropyl-3-bromo-2-methylaniline (III). Subsequent condensation of aniline (III) with diethyl ethoxymethylenemalonate (IV) produces the enaminomalonate (V), which is further cyclized to the quinolinecarboxylate (VI) in hot PPA.

参考文献 中间体
合成目标
【1】 Hayashi, K.; Yamakawa, T.; Kawafuchi, H.; Kito, T.; Mitsuyama, J.; Kuroda, H. (Toyama Chemical Co., Ltd.); Quinolonecarboxylic acid derivs. or salts thereof. EP 1070713; WO 9951588 .
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) 58232 1,3-dibromo-2-methylbenzene; 2,6-Dibromotoluene 69321-60-4 C7H6Br2 详情 详情
(II) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情
(III) 58233 3-bromo-N-cyclopropyl-2-methylaniline; N-(3-bromo-2-methylphenyl)-N-cyclopropylamine C10H12BrN 详情 详情
(IV) 14088 Diethyl ethoxymethylenemalonate; Diethyl 2-(ethoxymethylene)malonate 87-13-8 C10H16O5 详情 详情
(V) 58234 diethyl 2-{[3-bromo(cyclopropyl)-2-methylanilino]methylene}malonate C18H22BrNO4 详情 详情
(VI) 58235 ethyl 7-bromo-1-cyclopropyl-8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylate C16H16BrNO3 详情 详情

合成路线29

该中间体在本合成路线中的序号：(XIII)

Condensation of 2,2-bis(hydroxymethyl)propionic acid (VIII) with morpholine (IX) in the presence of DCC and HOBt gave amide (X). The cyclic ketal (XI) was then obtained by acid-catalyzed condensation of imidazole aldehyde (VII) with diol (X) using azeotropic removal of water. Oxidation of the sulfide group of (XI) with meta-chloroperbenzoic acid furnished sulfone (XII). The methylsulfonyl group of (XII) was finally displaced with cyclopropylamine (XIII) to provide the title compound

参考文献 中间体
合成目标
【1】 Collis, A.J.; Wilsher, N.E.; Foster, M.L.; Redford, E.J.; McLay, I.M.; Page, K.M.; Maslen, C.; Halley, F.; Souness, J.E.; RPR203494 a pyrimidine analogue of the p38 inhibitor RPR200765A with an improved in vitro potency. Bioorg Med Chem Lett 2001, 11, 5, 693.
【2】 Halley, F.; Porter, B.; Bamborough, P.L.; Lewis, R.A.; Ratcliffe, A.J.; Wallace, P.A.; McLay, I.M.; McKenna, J.M.; Lythgoe, D.J.; Collis, A.J. (Rhone-Poulenc Rorer Ltd.); Imidazolyl-cyclic acetals. EP 0988301; WO 9856788 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VII) 49201 4-(4-fluorophenyl)-5-[2-(methylsulfanyl)-4-pyrimidinyl]-1H-imidazole-2-carbaldehyde C15H11FN4OS 详情 详情
(VIII) 49202 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid C5H10O4 详情 详情
(IX) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(X) 49203 3-hydroxy-2-(hydroxymethyl)-2-methyl-1-(4-morpholinyl)-1-propanone C9H17NO4 详情 详情
(XI) 49204 (2-[4-(4-fluorophenyl)-5-[2-(methylsulfanyl)-4-pyrimidinyl]-1H-imidazol-2-yl]-5-methyl-1,3-dioxan-5-yl)(4-morpholinyl)methanone C24H26FN5O4S 详情 详情
(XII) 49205 (2-[4-(4-fluorophenyl)-5-[2-(methylsulfonyl)-4-pyrimidinyl]-1H-imidazol-2-yl]-5-methyl-1,3-dioxan-5-yl)(4-morpholinyl)methanone C24H26FN5O6S 详情 详情
(XIII) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情

合成路线30

该中间体在本合成路线中的序号：(IV)

The amino groups of pseudomycin B (I) were protected by treatment with N-(benzyloxycarbonyloxy)succinimide (II). The resulting pseudomycin B tribenzyl carbamate (III) was then coupled with cyclopropylamine (IV) by using TBTU to yield amide (V).

参考文献 中间体
合成目标
【1】 Sun, X.; Chen, S.-H.; Zhang, Y.-Z.; Current, W.L.; Rodriguez, M.; Sachs, R.K.; Gidda, J.; Zeckner, D.J.; Synthesis and antifungal activities of novel 3-amido bearing pseudomycin analogues. Bioorg Med Chem Lett 2001, 11, 7, 903.
【2】 Vasudevan, V.; Rodriguez, M.J.; Hellman, S.L.; Krstenansky, J.L.; Sun, X.D.; Chen, S.H.; Usyatinsky, A.Y.; Galka, C.S.; Zweifel, M.J. (Eli Lilly and Company); Pseudomycin amide and ester analogs. WO 0105817 .
【3】 Chen, S.H.; Sun, X.D.; Rodriguez, M.J. (Eli Lilly and Company); Pseudomycin prodrugs. WO 0105813 .
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) 50469 (2S)-2-((3S,6S,12S,15S,18S,21S,24R,27S)-18-(4-aminobutyl)-15,24-bis(2-aminoethyl)-21-(carboxymethyl)-3-[(1S)-2-chloro-1-hydroxyethyl]-9-[(Z)ethylidene]-12-[(1S)-1-hydroxyethyl]-27-[[(3R)-3-hydroxytetradecanoyl]amino]-2,5,8,11,14,17,20,23,26-nonaoxo-1-oxa-4,7,10,13,16,19,22,25-octaazacyclooctacosan-6-yl)-2-hydroxyethanoic acid C51H87ClN12O19 详情 详情
(II) 30663 N-benzyloxycarbonyloxysuccinimide; 1-[[(Benzyloxy)carbonyl]oxy]-2,5-pyrrolidinedione 13139-17-8 C12H11NO5 详情 详情
(III) 51197 (2S)-2-((3S,6S,12S,15S,18S,21S,24R,27S)-18-(4-[[(benzyloxy)carbonyl]amino]butyl)-15,24-bis(2-[[(benzyloxy)carbonyl]amino]ethyl)-21-(carboxymethyl)-3-[(1S)-2-chloro-1-hydroxyethyl]-9-[(Z)ethylidene]-12-[(1S)-1-hydroxyethyl]-27-[[(3R)-3-hydroxytetradecanoyl]amino]-2,5,8,11,14,17,20,23,26-nonaoxo-1-oxa-4,7,10,13,16,19,22,25-octaazacyclooctacosan-6-yl)-2-hydroxyethanoic acid C75H105ClN12O25 详情 详情
(IV) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情
(V) 51198 (2S)-2-((3S,6S,12S,15S,18S,21S,24R,27S)-18-(4-[[(benzyloxy)carbonyl]amino]butyl)-15,24-bis(2-[[(benzyloxy)carbonyl]amino]ethyl)-3-[(1S)-2-chloro-1-hydroxyethyl]-21-[2-(cyclopropylamino)-2-oxoethyl]-9-[(Z)ethylidene]-12-[(1S)-1-hydroxyethyl]-27-[[(3R)-3-hydroxytetradecanoyl]amino]-2,5,8,11,14,17,20,23,26-nonaoxo-1-oxa-4,7,10,13,16,19,22,25-octaazacyclooctacosan-6-yl)-2-hydroxyethanoic acid C78H110ClN13O24 详情 详情

合成路线31

该中间体在本合成路线中的序号：(IV)

In a closely related method, pseudomycin B (I) was protected as the corresponding allyl carbamate (VII) by treatment with diallyl pyrocarbonate (VI). After coupling of (VII) with cyclopropylamine (IV), the allyloxycarbonyl groups were deprotected by means of tributyltin hydride and palladium chloride.

参考文献 中间体
合成目标
【1】 Sun, X.; Chen, S.-H.; Zhang, Y.-Z.; Current, W.L.; Rodriguez, M.; Sachs, R.K.; Gidda, J.; Zeckner, D.J.; Synthesis and antifungal activities of novel 3-amido bearing pseudomycin analogues. Bioorg Med Chem Lett 2001, 11, 7, 903.
【2】 Chen, S.H.; Sun, X.D.; Rodriguez, M.J. (Eli Lilly and Company); Pseudomycin prodrugs. WO 0105813 .
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) 50469 (2S)-2-((3S,6S,12S,15S,18S,21S,24R,27S)-18-(4-aminobutyl)-15,24-bis(2-aminoethyl)-21-(carboxymethyl)-3-[(1S)-2-chloro-1-hydroxyethyl]-9-[(Z)ethylidene]-12-[(1S)-1-hydroxyethyl]-27-[[(3R)-3-hydroxytetradecanoyl]amino]-2,5,8,11,14,17,20,23,26-nonaoxo-1-oxa-4,7,10,13,16,19,22,25-octaazacyclooctacosan-6-yl)-2-hydroxyethanoic acid C51H87ClN12O19 详情 详情
(IV) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情
(VI) 51199 　 C8H10O5 详情 详情
(VII) 51200 (2S)-2-((3S,6S,12S,15S,18S,21S,24R,27S)-18-(4-[[(allyloxy)carbonyl]amino]butyl)-15,24-bis(2-[[(allyloxy)carbonyl]amino]ethyl)-21-(carboxymethyl)-3-[(1S)-2-chloro-1-hydroxyethyl]-9-[(Z)ethylidene]-12-[(1S)-1-hydroxyethyl]-27-[[(3R)-3-hydroxytetradecanoyl]amino]-2,5,8,11,14,17,20,23,26-nonaoxo-1-oxa-4,7,10,13,16,19,22,25-octaazacyclooctacosan-6-yl)-2-hydroxyethanoic acid C63H99ClN12O25 详情 详情

合成路线32

该中间体在本合成路线中的序号：(V)

Acylation of pseudomycin B (I) with the succinimidyl ester (III), prepared from chloroformate (II), produced a mixture of mono-, di- and tri-N-acylated compounds, which were separated by means of HPLC. The required trisubstituted compound (IV) was then condensed with cyclopropylamine (V) in the presence of TBTU to afford the title amide.

参考文献 中间体
合成目标
【1】 Sun, X.; et al.; Prodrugs of 3-amido bearing pseudomycin analogues: Novel antifungal agents. Bioorg Med Chem Lett 2001, 11, 14, 1881.
【2】 Chen, S.H.; Sun, X.D.; Rodriguez, M.J. (Eli Lilly and Company); Pseudomycin prodrugs. WO 0105813 .
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) 50469 (2S)-2-((3S,6S,12S,15S,18S,21S,24R,27S)-18-(4-aminobutyl)-15,24-bis(2-aminoethyl)-21-(carboxymethyl)-3-[(1S)-2-chloro-1-hydroxyethyl]-9-[(Z)ethylidene]-12-[(1S)-1-hydroxyethyl]-27-[[(3R)-3-hydroxytetradecanoyl]amino]-2,5,8,11,14,17,20,23,26-nonaoxo-1-oxa-4,7,10,13,16,19,22,25-octaazacyclooctacosan-6-yl)-2-hydroxyethanoic acid C51H87ClN12O19 详情 详情
(II) 52496 [(chlorocarbonyl)oxy]methyl 2-methylpropanoate C6H9ClO4 详情 详情
(III) 52497 ({[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl}oxy)methyl 2-methylpropanoate C10H13NO7 详情 详情
(IV) 52498 　 C69H111ClN12O31 详情 详情
(V) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情

合成路线33

该中间体在本合成路线中的序号：(VIII)

Metalation of 1-bromo-2,4-difluorobenzene (I) by means of LDA, followed by treatment with tert-butyl hydroperoxide gave rise to phenol (II), which was further converted to methyl ether (III) by alkylation with iodomethane and K2CO3. Lithium halogen exchange of (III) with n-butyllithium, and subsequent quenching with CO2 produced 3-methoxy-2,4-difluorobenzoic acid (IV). After activation of (IV) as the acid chloride (V), condensation with the lithium derivative of monoethyl malonate (A) led to the benzoyl acetate ester (VI). The benzoyl ethoxyacrylate (VII), obtained by condensation of ketoester (VI) with triethyl orthoformate, was then reacted with cyclopropylamine (VIII) to afford enamine (IX). This was cyclized to the quinolone compound (X) upon treatment with NaH in THF. Acidic hydrolysis of ester (X) gave a keto acid, which was subsequently converted to the boron chelate (XI) by treatment with boron trifluoride etherate. Fluoride displacement of quinolone (XI) with the amino piperidine (XII) produced the piperidino quinolone (XIII). The boron difluoride complex of (XIII) was finally removed by means of triethylamine in boiling EtOH.

参考文献 中间体
合成目标
【1】 Hu, X.E.; Gray, J.L.; Almstead, J.-I.K.; Ledoussal, B. (The Procter & Gamble Co.); Antimicrobial quinolones, their compsns. and uses. EP 1015445; WO 9914214 .
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) 15086 3-ethoxy-3-oxopropionic acid 1071-46-1 C5H8O4 详情 详情
(I) 15488 1-bromo-2,4-difluorobenzene 348-57-2 C6H3BrF2 详情 详情
(II) 34648 3-bromo-2,6-difluorophenol 221220-99-1 C6H3BrF2O 详情 详情
(III) 34649 3-bromo-2,6-difluorophenyl methyl ether; 1-bromo-2,4-difluoro-3-methoxybenzene 221221-00-7 C7H5BrF2O 详情 详情
(IV) 30621 2,4-difluoro-3-methoxybenzoic acid 178974-97-5 C8H6F2O3 详情 详情
(V) 34650 2,4-difluoro-3-methoxybenzoyl chloride C8H5ClF2O2 详情 详情
(VI) 34651 ethyl 3-(2,4-difluoro-3-methoxyphenyl)-3-oxopropanoate C12H12F2O4 详情 详情
(VII) 34652 ethyl (Z)-2-(2,4-difluoro-3-methoxybenzoyl)-3-ethoxy-2-propenoate C15H16F2O5 详情 详情
(VIII) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情
(IX) 34653 ethyl (Z)-3-(cyclopropylamino)-2-(2,4-difluoro-3-methoxybenzoyl)-2-propenoate C16H17F2NO4 详情 详情
(X) 34654 ethyl 1-cyclopropyl-7-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylate C16H16FNO4 详情 详情
(XI) 59792 1-cyclopropyl-3-{[(difluoroboryl)oxy]carbonyl}-7-fluoro-8-methoxy-4(1H)-quinolinone C14H11BF3NO4 详情 详情
(XII) 59793 (3S,4R)-4-ethyl-3-piperidinamine; (3S,4R)-4-ethylpiperidinylamine C7H16N2 详情 详情
(XIII) 59794 7-[(3S,4R)-3-amino-4-ethylpiperidinyl]-1-cyclopropyl-3-{[(difluoroboryl)oxy]carbonyl}-8-methoxy-4(1H)-quinolinone C21H26BF2N3O4 详情 详情

合成路线34

该中间体在本合成路线中的序号：(VII)

Treatment of 2-amino-6-chloro-9-beta-D-ribofuranosylpurine (I) with acetoxyisobutyryl bromide (II) led to a mixture of acetoxy bromo derivatives (III) and (IV) which, upon reductive treatment with activated zinc, furnished the 2',3'-dehydro compound (V). Deprotection of (V) with K2CO3 in aqueous methanol provided the free nucleoside (VI). Finally, nucleophilic displacement of the chlorine of (VI) with cyclopropylamine (VII) afforded the target compound.

参考文献 中间体
合成目标
【1】 Chu, C.K.; Ray, A.S.; Anderson, K.S.; Yang, Z.; Novel use of a guanosine prodrug approach to convert 2',3'-didehydro-2',3'-dideoxyguanosine into a viable antiviral agent. Antimicrob Agents Chemother 2002, 46, 3, 887.
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) 55888 (2R,3S,4R,5R)-2-(2-amino-6-chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol C10H12ClN5O4 详情 详情
(II) 12806 2-bromo-1,1-dimethyl-2-oxoethyl acetate; alpha-Acetoxy-isobutyryl bromide 40635-67-4 C6H9BrO3 详情 详情
(III) 55889 (2R,5R)-2-(2-amino-6-chloro-9H-purin-9-yl)-4-bromo-5-{[(2,4,4-trimethyl-5-oxo-1,3-dioxolan-2-yl)oxy]methyl}tetrahydro-3-furanyl acetate C18H21BrClN5O7 详情 详情
(IV) 55890 (2R,5R)-5-(2-amino-6-chloro-9H-purin-9-yl)-4-bromo-2-{[(2,4,4-trimethyl-5-oxo-1,3-dioxolan-2-yl)oxy]methyl}tetrahydro-3-furanyl acetate C18H21BrClN5O7 详情 详情
(V) 55891 2-{[(2S,5R)-5-(2-amino-6-chloro-9H-purin-9-yl)-2,5-dihydro-2-furanyl]methoxy}-2,5,5-trimethyl-1,3-dioxolan-4-one C16H18ClN5O5 详情 详情
(VI) 55892 [(2S,5R)-5-(2-amino-6-chloro-9H-purin-9-yl)-2,5-dihydro-2-furanyl]methanol C10H10ClN5O2 详情 详情
(VII) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情

合成路线35

该中间体在本合成路线中的序号：(VI)

The title compound is prepared by solid phase synthesis employing a Rink amide resin. Acylation of the resin with chloroacetyl chloride (I) affords the chloroacetyl resin (II). Subsequent chloride displacement with s-butylamine (III) provides the aminoacid-bound resin (IV). A new acylation of (IV) with chloroacetyl chloride (I) yields the chloroacetamide (V), which is then displaced by cyclopropylamine (VI), yielding the dipeptide derivative (VII). Then, a further coupling of (VII) with acid chloride (I), followed by displacement of the resultant chloroacetamide resin (VIII) with N-(2-aminoethyl)pyrrolidine (IX) gives rise to the tripeptide resin (X). Finally, cleavage of the dipeptide amide from the solid support is accomplished by treatment with trifluoroacetic acid in CH2Cl2

参考文献 中间体
合成目标
【1】 Montoliu, C.; et al.; Prevention of in vivo excitotoxicity by a family of trialkylglycines, a novel class of neuroprotectants. J. Pharm. Exp. Ther. 2002, 301, 1, 29.
【2】 Felipo Orts, V.; Montoliu Felix, C.; Ferrer Montiel, A.; Planells Cases, R.; Merino Fernandez, J.M.; Perez Paya, E.; Sanchez Baeza, F.; Humet, M.; Messeguer Peypoch, A. (DiverDrugs SL); N-Alkylglycine trimeres capable of protecting neurons against excitotoxic aggressions and compsns. containing said trimeres. WO 0228885 .
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) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(II) 28964 2-chloroacetamide 79-07-2 C2H4ClNO 详情 详情
(III) 61462 sec-butyl amine; 2-Butanamine, (+-)-; 2-Aminobutane; 2-Butylamine; 2-Butanamine; 2-aminobutane base; butafume; deccotane; frucote; Butanamine; Methylpropylamine; SEC-BUTYLAMINE; (+/-)-sec-Butylamine; (+/-)-2-Aminobutane; Sec-Aminobutane; Sec-Butylamine; 2-Aminobutan; (+/-)-2-Butylamine; sec-Butylamine; Butylamine (sec); SBA; METHYL-n-PROPYLAMINE; (+/-)-2-Aminobutane 13952-84-6 C4H11N 详情 详情
(IV) 61463 2-(sec-butylamino)acetamide C6H14N2O 详情 详情
(V) 61464 2-[sec-butyl(2-chloroacetyl)amino]acetamide C8H15ClN2O2 详情 详情
(VI) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情
(VII) 61465 2-{sec-butyl[2-(cyclopropylamino)acetyl]amino}acetamide C11H21N3O2 详情 详情
(VIII) 61466 2-(sec-butyl{2-[(2-chloroacetyl)(cyclopropyl)amino]acetyl}amino)acetamide C13H22ClN3O3 详情 详情
(IX) 18161 2-(1-pyrrolidinyl)ethylamine; 2-(1-pyrrolidinyl)-1-ethanamine; 1-Pyrrolidineethanamine 7154-73-6 C6H14N2 详情 详情
(X) 61467 2-(sec-butyl{2-[cyclopropyl(2-{[2-(1-pyrrolidinyl)ethyl]amino}acetyl)amino]acetyl}amino)acetamide C19H35N5O3 详情 详情

合成路线36

该中间体在本合成路线中的序号：(X)

Synthesis of benzimidazole intermediate (VIII) was achieved as follows. The reaction of 2,5-difluoronitrobenzene (I) with 3-methoxypropylamine (II) by means of K2CO3 in acetonitrile gives the aniline (III), which is reduced with Fe and NH4Cl in water to yield the phenylenediamine (IV). The cyclization of (IV) with glycolic acid (V) in refluxing 4N HCl affords the benzimidazolylmethanol (VI). Finally, this compound is brominated with (bromomethylene)dimethylammonium bromide (VII) in acetonitrile to provide the target bromomethylbenzimidazole intermediate (VIII). The reaction of 4-methoxy-3-nitropyridine (IX) with cyclopropylamine (X) in refluxing ethanol gives the N-cyclopropyl-3-nitropyridine-4-amine (XI), which is reduced with H2 over Pd/C in methanol to yield the pyridinediamine (XII). The cyclization of (XII) with phosgene in acetonitrile affords 1-cyclopropyl-2,3-dihydro-1H-imidazol[4,5-c]pyridin-2-one (XIII), which is condensed with bromomethyl intermediate (VIII) by means of NaH in THF, DMF or acetonitrile to provide the adduct (XIV). Finally, this compound is demethylated by means of BBr3 in dichloromethane to furnish the target 3-hydroxypropyl compound.

参考文献 中间体
合成目标
【1】 Meanwell, N.A.; Yu, K.-L.; Combrink, K.D.; Wang, X.; Civiello, R.L.; Gulgeze, H.B.; Sin, N.; Venables, B.L. (Bristol-Myers Squibb Co.); Imidazopyridine and imidazopyrimidine antiviral agents. EP 1311268; US 2002016309; US 6489338; WO 0195910 .
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) 28544 1,4-difluoro-2-nitrobenzene 364-74-9 C6H3F2NO2 详情 详情
(II) 61531 Carbo-trap(TM) 2; 3-Methoxypropylamine; 1-Propanamine, 3-methoxy-; 3-Methoxy-1-aminopropane; 3-Methoxypropane-1-amine; 1-Amino-3-methoxypropane; 3-Methoxypropylamine; 3-Methoxypropyl-1-amine; 3-Aminopropyl Methyl Ether; 3-Methoxypropylamine with G.C.; 3-Methoxy Propylamine; 3-Methoxy-1-propanamine; 3MOPA 5332-73-0 C4H11NO 详情 详情
(III) 61532 4-fluoro-N-(3-methoxypropyl)-2-nitroaniline; N-(4-fluoro-2-nitrophenyl)-N-(3-methoxypropyl)amine C10H13FN2O3 详情 详情
(IV) 61533 N-(2-amino-4-fluorophenyl)-N-(3-methoxypropyl)amine; 4-fluoro-N~1~-(3-methoxypropyl)-1,2-benzenediamine C10H15FN2O 详情 详情
(V) 29856 2-hydroxyacetic acid;glycolic acid 79-14-1 C2H4O3 详情 详情
(VI) 61534 [1-(3-methoxypropyl)-1H-benzimidazol-2-yl]methanol C12H16N2O2 详情 详情
(VII) 61535 N-(bromomethylene)-N-methylmethanaminium bromide C3H7Br2N 详情 详情
(VIII) 61536 2-(bromomethyl)-1-(3-methoxypropyl)-1H-benzimidazole; 3-[2-(bromomethyl)-1H-benzimidazol-1-yl]propyl methyl ether C12H15BrN2O 详情 详情
(IX) 61537 4-methoxy-3-nitropyridine; methyl 3-nitro-4-pyridinyl ether C6H6N2O3 详情 详情
(X) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情
(XI) 61538 N-cyclopropyl-3-nitro-4-pyridinamine; N-cyclopropyl-N-(3-nitro-4-pyridinyl)amine C8H9N3O2 详情 详情
(XII) 61539 N-(3-amino-4-pyridinyl)-N-cyclopropylamine; N~4~-cyclopropyl-3,4-pyridinediamine C8H11N3 详情 详情
(XIII) 61540 1-cyclopropyl-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one C9H9N3O 详情 详情
(XIV) 61541 1-cyclopropyl-3-{[1-(3-methoxypropyl)-1H-benzimidazol-2-yl]methyl}-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one C21H23N5O2 详情 详情

合成路线37

该中间体在本合成路线中的序号：(X)

Hydrogenolysis of the benzyloxycarbonyl protecting group in N-Cbz-L-cyclohexylglycyl-L-tert-leucine methyl ester (I) in the presence of Pearlman’s catalyst in MeOH gives the free dipeptide ester (II), which is acylated with pyrazinecarboxylic acid (III) by means of DCC in dichloromethane/THF to yield the N-acyl dipeptide (IV) (1). Alkaline hydrolysis of the methyl ester (IV) followed by coupling of the resulting carboxylic acid (V) with ethyl cis-perhydrocyclopenta[c]pyrrole-1-carboxylate (VI) by means of DCC provides the acyl tripeptide ester (VII), which is then hydrolyzed to the corresponding carboxylic acid (VIII) upon treatment with NaOH in EtOH (1, 2). Coupling of L-norvaline (IX) with cyclopropylamine (X) in the presence of EDC and N-hydroxysuccinimide followed by catalytic hydrogenolysis of the N-Cbz group provides N-cyclopropyl-norvalinamide (XI) (3). Subsequent condensation of aminoamide (XI) with the N-acyl tripeptide (VIII) using either PyBOP or EDC/HOBt gives the tetrapeptide derivative (XII). Finally, oxidation of the secondary alcohol (XII) by means of Dess-Martin periodinane or NaOCl and a catalytic amount of TEMPO furnishes the title α-ketoamide (1-3). Scheme 1.

参考文献 中间体
合成目标
【1】 Babine, R.E., Glass, J.I., Lamar, J.E. et al. (Eli Lilly and Company). Peptidomimetic protease inhibitors. JP 2004517047, US 2005197299, WO 2002018369.
【2】 Chen, S.-H., Lamar, J., Yip, Y. et al. P1 and P1’ optimization of [3,4]-bicycloproline P2 incorporated tetrapeptidyl α-ketoamide based HCV protease inhibitors. Lett Drug Des Discov 2005, 2(2): 118-23.
【3】 Tanoury, G.J., Chen, M., Cochran, J.E. (Vertex Pharmaceuticals, Inc.). Processes and intermediates. WO 2007022459.
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) 65417 N-Cbz-L-cyclohexylglycyl-L-tert-leucine methyl ester 　 C23H34N2O5 详情 详情
(II) 65418 L-cyclohexylglycyl-L-tert-leucine methyl ester 　 C15H28N2O3 详情 详情
(III) 37256 2-pyrazinecarboxylic acid; Pyrazinoic acid 98-97-5 C5H4N2O2 详情 详情
(IV) 65419 (2S)-2-Cyclohexyl-N-(2-pyrazinylcarbonyl)glycyl-3-methyl-L-valine methyl ester 402958-95-6 C20H30N4O4 详情 详情
(V) 65420 (2S)-2-Cyclohexyl-N-(2-pyrazinylcarbonyl)glycyl-3-methyl-L-valine 402958-96-7 C19H28N4O4 详情 详情
(VI) 65421 (1S,3aR,6aS)-Octahydrocyclopenta[c]pyrrole-1-carboxylic acid ethyl ester; ethyl cis-perhydrocyclopenta[c]pyrrole-1-carboxylate 402958-25-2 C10H17NO2 详情 详情
(VII) 65422 (1S,3aR,6aS)-(2S)-2-Cyclohexyl-N-(pyrazinylcarbonyl)glycyl-3-methyl-L-valyloctahydrocyclopenta[c]pyrrole-1-carboxylic acid ethyl ester 402958-97-8 C29H43N5O5 详情 详情
(VIII) 65423 (1S,3aR,6aS)-(2S)-2-Cyclohexyl-N-(pyrazinylcarbonyl)glycyl-3-methyl-L-valyloctahydrocyclopenta[c]pyrrole-1-carboxylic acid 402958-98-9 C27H39N5O5 详情 详情
(IX) 65424 　 　 C14H19NO5 详情 详情
(X) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情
(XI) 65425 (3S)-3-Amino-N-cyclopropyl-2-hydroxyhexanamide 402960-19-4 C9H18N2O2 详情 详情
(XII) 65426 (1S,3aR,6aS)-(2S)-2-Cyclohexyl-N-(2-pyrazinylcarbonyl)glycyl-3-methyl-L-valyl-N-[(1S)-1-[2-(cyclopropylamino)-1-hydroxy-2-oxoethyl]butyl]octahydrocyclopenta[c]pyrrole-1-carboxamide 402959-36-8 C36H55N7O6 详情 详情

合成路线38

该中间体在本合成路线中的序号：(XIX)

The intermediate quinolone boron chelate (X) is prepared as follows. Ketalization of 2’,4’-difluoroacetophenone (XII) with ethylene glycol and p-TsOH provides compound (XIII), which is hydroxylated to phenol (XIV) by ortho-metalation with BuLi in THF at –65 °C, followed by treatment with trimethyl borate in AcOH and then with aqueous H2O2. Acidic hydrolysis of the ethylene ketal moiety of compound (XIV) provides the hydroxyketone (XV), which is alkylated with dimethyl sulfate and K2CO3 in toluene to give 2’,4’-difluoro-3’-methoxyacetophenone (XVI). Carboxylation of acetophenone (XVI) with diethyl carbonate and NaH gives the 2-(benzoyl)acetate (XVII), which is further condensed with dimethylformamide dimethyl acetal (DMFDMA) to produce adduct (XVIII). Subsequent displacement of the dimethylamino group of (XVIII) with cyclopropylamine (XIX) in hot toluene furnishes the N-cyclopropyl analogue (XX) (1, 2). Then, cyclization of (XX) by means of either NaH in THF or N,O-bis(trimethylsilyl)acetamide (BSA) in boiling toluene yields the quinolone carboxylate (XXI), which is hydrolyzed to the corresponding carboxylic acid (XXII) under acidic conditions. Finally, the boron chelate (X) is obtained by complexation of the keto acid (XXII) with the reagent generated from boron oxide and acetic anhydride in AcOH (1-3). Scheme 2.

参考文献 中间体
合成目标
【1】 Reilly, M. (The Procter & Gamble Co.). A coupling process for preparing quinolone intermediates. CA 2647454, EP 1999125, US 2007232804, US 7456279, WO 2007110835.
【2】 Hayes, M.P., Schunk, T.T. (The Procter & Gamble Co.). A hydride reduction process for preparing quinolone intermediates. CA 2647457, EP 1999106, US 2007232806, WO 2007110836.
【3】 Ledoussal, B., Hu, X.E., Gray, J.L., Almstead, J.-I.K. (The Procter & Gamble Co.). Antimicrobial quinolones, their compositions and uses. CA 2303389, EP 1015445, JP 2001516756, US 6329391, US 6387928, WO 1999014214.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(X) 65888 　 　 C18H17BFNO6 详情 详情
(XII) 65890 2',4'-Difluoroacetophenone; 1-(2,4-Difluorophenyl)ethanone 364-83-0 C8H6F2O 详情 详情
(XIII) 65891 2-(2,4-difluorophenyl)-2-methyl-1,3-dioxolane 　 C10H10F2O2 详情 详情
(XIV) 65892 2-(2,4-difluoro-3-hydroxyphenyl)-2-methyl-1,3-dioxolane 　 C10H10F2O3 详情 详情
(XV) 65893 2',4'-Difluoro-3'-hydroxyacetophenone; 1-(2,4-Difluoro-3-hydroxyphenyl)ethanone 951163-65-8 C8H6F2O2 详情 详情
(XVI) 65894 2',4'-Difluoro-3'-methoxyacetophenone; 1-(2,4-Difluoro-3-methoxyphenyl)ethanone 373603-19-1 C9H8F2O2 详情 详情
(XVII) 34651 ethyl 3-(2,4-difluoro-3-methoxyphenyl)-3-oxopropanoate C12H12F2O4 详情 详情
(XVIII) 65895 　 　 C15H17F2NO4 详情 详情
(XIX) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情
(XX) 34653 ethyl (Z)-3-(cyclopropylamino)-2-(2,4-difluoro-3-methoxybenzoyl)-2-propenoate C16H17F2NO4 详情 详情
(XXI) 34654 ethyl 1-cyclopropyl-7-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylate C16H16FNO4 详情 详情
(XXII) 34655 1-cyclopropyl-7-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid 221221-16-5 C14H12FNO4 详情 详情

合成路线39

该中间体在本合成路线中的序号：(XIX)

In an alternative route to the quinolone precursor (XX), deprotonation of 2,4-difluorobromobenzene (XXIII) with LDA in THF followed by addition of tert-butyl hydroperoxide gives 3-bromo-2,6-difluorophenol (XXIV), which is converted to the corresponding methyl ether (XXV) by treatment with iodomethane and K2CO3. Metalation of the aryl bromide (XXV) with butyl lithium in cold diethyl ether and subsequent addition of CO2 gas leads to 3-methoxy-2,4-difluorobenzoic acid (XXVI). After chlorination of acid (XXVI) with oxalyl chloride and catalytic DMF, the obtained acid chloride (XXVII) is condensed with monoethyl malonate (XXVIII) in the presence of butyl lithium in THF at –50 °C to yield the 2-(benzoyl)acetate (XVII). Subsequent reaction of keto ester (XVII) with triethyl orthoformate in boiling Ac2O provides the enol ether (XXIX), which is then condensed with cyclopropylamine (XIX) in EtOH to give the key enamine (XX) (3). Scheme 3.

参考文献 中间体
合成目标
【3】 Ledoussal, B., Hu, X.E., Gray, J.L., Almstead, J.-I.K. (The Procter & Gamble Co.). Antimicrobial quinolones, their compositions and uses. CA 2303389, EP 1015445, JP 2001516756, US 6329391, US 6387928, WO 1999014214.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XVII) 34651 ethyl 3-(2,4-difluoro-3-methoxyphenyl)-3-oxopropanoate C12H12F2O4 详情 详情
(XIX) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情
(XX) 34653 ethyl (Z)-3-(cyclopropylamino)-2-(2,4-difluoro-3-methoxybenzoyl)-2-propenoate C16H17F2NO4 详情 详情
(XXIII) 15488 1-bromo-2,4-difluorobenzene 348-57-2 C6H3BrF2 详情 详情
(XXIV) 34648 3-bromo-2,6-difluorophenol 221220-99-1 C6H3BrF2O 详情 详情
(XXV) 34649 3-bromo-2,6-difluorophenyl methyl ether; 1-bromo-2,4-difluoro-3-methoxybenzene 221221-00-7 C7H5BrF2O 详情 详情
(XXVI) 30621 2,4-difluoro-3-methoxybenzoic acid 178974-97-5 C8H6F2O3 详情 详情
(XXVII) 34650 2,4-difluoro-3-methoxybenzoyl chloride C8H5ClF2O2 详情 详情
(XXVIII) 15086 3-ethoxy-3-oxopropionic acid 1071-46-1 C5H8O4 详情 详情
(XXIX) 34652 ethyl (Z)-2-(2,4-difluoro-3-methoxybenzoyl)-3-ethoxy-2-propenoate C15H16F2O5 详情 详情

合成路线40

该中间体在本合成路线中的序号：(XVIII)

3,5-Dimethylfluorobenzene (VIII) is treated with chlorine in the presence of anhydrous FeCl3 in either solvent-free conditions or in 1,2-dichloroethane to yield the 2,4-dichlorobenzene derivative (IX). Photochemical chlorination of compound (IX) affords 2,4-dichloro-3-(dichloromethyl)-1-fluoro-5-(trichloromethyl)benzene (X), which is further oxidized with concentrated sulfuric acid at 70 °C to give 2,4-dichloro-5-fluoro-3-formylbenzoic acid (XI) (1, 2). Aldehyde (XI) is next condensed with hydroxylamine hydrochloride (XII) in either an ethanolic NaOH basic media at 60 °C (1, 2) or in formic acid (2) to afford aldoxime (XIII) and the 3-cyanobenzoic acid derivative (XIV), respectively. Treatment of either of the two condensation products (XIII) and (XIV) with refluxing thionyl chloride affords the 3-cyanobenzoyl chloride derivative (XV) (1, 2), which is coupled with ethyl 3-(dimethylamino)acrylate (XVI) by means of DIEA in dichloromethane at 50 °C (1, 2) or triethylamine in toluene at 60-80 °C (3) to produce the 1,3-ketoester (XVII). Tertiary dimethylenamine (XVII) is converted to the secondary cyclopropylenamine (XIX) by treatment with cyclopropylamine (XVIII) in the presence of acetic acid in dichloromethane/water (1, 2) or in a mixture of ethanol/ether (3). Without isolation, intermediate (XIX) undergoes cyclization in the presence of potassium carbonate in N-methylpyrrolidone at 60-70 °C (1, 2) or in acetonitrile (3), affording the ethyl ester (IV). Compound (IV) is hydrolyzed in the presence of sulfuric acid in refluxing AcOH/water to yield the free carboxylic acid (I) (1, 2). Scheme 2.
An alternative pathway for the synthesis of intermediate (XV) proceeds as follows. Friedel-Craft’s acylation of 2,4-dichloro-1-fluorobenzene (XX) with acetyl chloride in the presence of AlCl3 and subsequent oxidation with sodium hypochlorite in 1,4-dioxane gives 2,4-dichloro-5-fluorobenzoic acid (XXI), which is nitrated with HNO3/H2SO4 to give the nitrobenzoic acid (XXII). Esterification of compound (XXII) by means of thionyl chloride in methanol followed by hydrogenation in the presence of Raney-Ni in methanol yields amino ester (XXIII), which is subjected to a Sandmayer reaction with CuCN in the presence of 2-methyl-2-nitropropane (t-BuNO2) in DMF at 60 °C. The intermediate thus obtained is then treated with lithium hydroxide in THF/water and the resulting carboxylic acid is finally chlorinated with thionyl chloride in toluene to afford acyl chloride (XV) (3). Scheme 2.

参考文献 中间体
合成目标
【1】 Matzke, M., Petersen, U., Schenke, T. et al. (Bayer Healthcare AG). Use of 7-(2-oxa-5,8-diazabicyclo[4.3.0]non-8-yl)-quinolone carboxylic acid and naphthyridon carboxylic acid derivatives for the treatment of Helicobacter pylori infections and associated gastroduodenal diseases. CA 2274894, DE 19652239, EP 0946176, JP 200351781, JP 2000514825, US 6133260, US 6432948, WO 1998026779.
【2】 Wohlert, S.E., Jaetsch, T., Gallenkamp, B. et al. New fluoroquinolone finafloxacin HCI (FIN): Route of synthesis, physicochemical characteristics and activity under neutral and acid conditions. 48th Annu Intersci Conf Antimicrob Agents Chemother (ICAAC) Infect Dis Soc Am (IDSA) Annu Meet (Oct 25-28, Washington, D.C.) 2008, Abst F1-2036.
【3】 Hong, J., Zhang, Z., Lei, H. et al. A novel approach to finafloxacin hydrochloride (BAY35-3377). Tetrahedron Lett 2009, 50(21): 2525-8.
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) 65946 7-chloro-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid 　 C14H8ClFN2O3 详情 详情
(IV) 65949 　 　 C16H12ClFN2O3 详情 详情
(VIII) 65953 1-Fluoro-3,5-dimethylbenzene; 3,5-Dimethylfluorobenzene; 1,3-Dimethyl-5-fluorobenzene; 5-Fluoro-m-xylene 461-97-2 C8H9F 详情 详情
(IX) 65954 2,4-Dichloro-1-Fluoro-3,5-Dimethylbenzene 214774-61-5 C8H7Cl2F 详情 详情
(X) 65955 　 　 C8H2Cl7F 详情 详情
(XI) 65956 2,4-Dichloro-5-fluoro-3-formylbenzoic acid 214774-58-0 C8H3Cl2FO3 详情 详情
(XII) 65957 Hydroxylamine hydrochloride; Hydroxylammonium chloride; Oxammonium hydrochloride 5470-11-1 H3NO.HCl 详情 详情
(XIII) 65958 　 　 C8H4Cl2FNO3 详情 详情
(XIV) 65959 2,4-Dichloro-3-cyano-5-fluorobenzoic acid 117528-58-2 C8H2Cl2FNO2 详情 详情
(XV) 65960 2,4-Dichloro-3-cyano-5-fluorobenzoyl chloride 117528-59-3 C8HCl3FNO 详情 详情
(XVI) 65961 ethyl (Z)-3-(dimethylamino)-2-propenoate; Ethyl cis-3-dimethylaminoacrylate 　 C7H13NO2 详情 详情
(XVII) 65962 (Z)-ethyl 2-(2,4-dichloro-3-cyano-5-fluorobenzoyl)-3-(dimethylamino)acrylate 　 C15H13Cl2FN2O3 详情 详情
(XVIII) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情
(XIX) 65963 　 　 C16H13Cl2FN2O3 详情 详情
(XX) 65964 1,3-Dichloro-4-fluorobenzene; 2,4-Dichloro-1-fluorobenzene; 2,4-Dichlorofluorobenzene 1435-48-9 C6H3Cl2F 详情 详情
(XXI) 65965 2,4-Dichloro-5-fluorobenzoic acid 86522-89-6 C7H3Cl2FO2 详情 详情
(XXII) 65966 2,4-Dichloro-5-fluoro-3-nitrobenzoic acid; 2,4-Dichloro-3-nitro-5-fluorobenzoic acid 106809-14-7 C7H2Cl2FNO4 详情 详情
(XXIII) 65967 3-Amino-2,4-Dichloro-5-Fluorobenzoic Acid 115549-13-8 C7H4Cl2FNO2 详情 详情

合成路线41

该中间体在本合成路线中的序号：(XIV)

Uracil intermediate (I) is obtained as follows. Condensation of 2-fluoro-4-iodophenyl isocyanate (XIII) with cyclopropylamine (XIV) in Et2O , or alternatively reaction of 2-fluoro-4-iodoaniline (XV) with CDI in the presence of Et3N in DMF, followed by condensation with cyclopropylamine (XIV) affords disubstituted urea (XVI). Cyclization of urea (XVI) is treated with malonic acid (XVII) in the presence of AcCl in Ac2O at 60 °C affords the pyrimidine trione (XVIII), which is chlorinated using POCl3 in the presence of PhNMe2 and a catalytic amount of H2O at 90 °C to provide a mixture of 6-chloropyrimidine (XIX) and the corresponding regioisomer. Finally, chloropyrimidine (XIX) is treated with methylamine (XX) in EtOH at 80 °C .
In an alternative procedure, acylation of urea (XVI) with cyanoacetic acid (XXI) by means of MsCl in DMF yields the N-(cyanoacetyl)urea (XXII), which cyclizes in aqueous NaOH at 80 °C to yield the amino-pyrimidine derivative (XXIII). Condensation of amine (XXIII) with dimethylformamide dimethylacetal (XXIV) in DMF affords formamidine (XXV), which is finally reduced using NaBH4 in EtOH/t-BuOH .

参考文献 中间体
合成目标
【2】 Sakai, T., Kawasaki, H., Abe, H. et al. (Japan Tobacco, Inc.). 5-Amino-2,4,7-trioxo-3,4,7,8-tetrahydro-2H-pyrido[2,3-d]pyrimidine derivatives and related compounds for the treatment of cancer. CN 101912400, EP 1761528, EP 1894932, EP 2298768, JP 2008201788, JP 2008501631, US 2006014768, US 7378423, US 2008312228, US 201024013, WO 2005121142.
【1】 Abe, H., Kikuchi, S., Hayakawa, K. et al. Discovery of a highly potent and selective MEK inhibitor: GSK1120212 (JTP-7407 DMSO solvate). ACS Med Chem Lett 2011, 2(4): 320.
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) 68359 1-(2-fluoro-4-iodophenyl)-3-cyclopropyl-6-(methylamino)uracil;3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6-(methylamino)pyrimidine-2,4(1H,3H)-dione C14H13FIN3O2 详情 详情
(XIII) 68369 2-fluoro-4-iodophenyl isocyanate 　 C7H3FINO 详情 详情
(XIV) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情
(XV) 63342 2-fluoro-4-iodoaniline; 2-fluoro-4-iodophenylamine 29632-74-4 C6H5FIN 详情 详情
(XVI) 68370 1-cyclopropyl-3-(2-fluoro-4-iodophenyl)urea 　 C10H10FIN2O 详情 详情
(XVII) 12963 Malonic acid 141-82-2 C3H4O4 详情 详情
(XVIII) 68371 1-cyclopropyl-3-(2-fluoro-4-iodophenyl)pyrimidine-2,4,6(1H,3H,5H)-trione 　 C13H10FIN2O3 详情 详情
(XIX) 68372 6-chloro-3-cyclopropyl-1-(2-fluoro-4-iodophenyl)pyrimidine-2,4(1H,3H)-dione 　 C13H9ClFIN2O2 详情 详情
(XX) 11021 Methanamine; Methylamine 74-89-5 CH5N 详情 详情
(XXI) 12591 Cyanoacetic Acid; 2-Cyanoacetic acid 372-09-8 C3H3NO2 详情 详情
(XXII) 68373 2-cyano-N-cyclopropyl-N-((2-fluoro-4-iodophenyl)carbamoyl)acetamide 　 C13H11FIN3O2 详情 详情
(XXIII) 68374 6-amino-3-cyclopropyl-1-(2-fluoro-4-iodophenyl)pyrimidine-2,4(1H,3H)-dione 　 C13H11FIN3O2 详情 详情
(XXIV) 11984 N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal 4637-24-5 C5H13NO2 详情 详情
(XXV) 68375 (E)-N'-(1-cyclopropyl-3-(2-fluoro-4-iodophenyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)-N,N-dimethylformimidamide 　 C16H16FIN4O2 详情 详情
Extended Information