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【结 构 式】 
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【分子编号】55902 【品名】2-Fluoro-4-nitrotoluene; 4-Nitro-2-fluorotoluene 【CA登记号】1427-07-2 |
【 分 子 式 】C7H6FNO2 【 分 子 量 】155.1285832 【元素组成】C 54.2% H 3.9% F 12.25% N 9.03% O 20.63% |
合成路线1
该中间体在本合成路线中的序号：(I)Jones oxidation of 2-fluoro-4-nitrotoluene (I) afforded carboxylic acid (II). After activation of (II) as the corresponding acid chloride with SOCl2, reaction with lithium tert-butoxide furnished the tert-butyl ester (III). Reduction of the nitro group of (III) by means of iron powder in the presence of ammonium chloride gave amine (IV), which was converted to carbamate (V) upon treatment with benzyl chloroformate. The chiral oxazolidinone (VII) was prepared by condensation of the lithium salt of carbamate (V) with (R)-glycidyl butyrate (VI). After activation of the primary hydroxyl of (VII) as the corresponding mesylate, displacement with NaN3 in hot DMF provided the alkyl azide (VIII). Tert-Butyl ester cleavage in (VIII) by means of trifluoroacetic acid afforded the carboxylic acid (IX). Curtius rearrangement of acid (IX) with diphenylphosphoryl azide in the presence of tert-butanol generated the tert-butyl carbamate (X). Further N-alkylation of carbamate (X) using iodomethane and LiH gave the N-methyl analogue (XI). Then, reduction of the azido group of (XI) to the primary amine (XII) was accomplished by treatment with triphenylphosphine followed by aqueous hydrolysis.
| 【1】 Singh, U.; Gordeev, M.F.; Luehr, G.W.; Gadwood, R.C.; Jain, R.; Hackbarth, C.J.; Trias, J.; Patel, D.V.; Lopez, S.; Acyclic C-group oxazolidinones: Antimicrobial 4'-acylamino, 4'-urea and 4'-thiourea phenyloxazolidinones. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1045. |
| 【2】 Patel, D.V.; Gadwood, R.C.; Gordeev, M.F.; Luehr, G.W. (Pharmacia Corp.); Oxazolidinones and their use as antiinfectives. EP 1200416; US 6441005; WO 0109107 . |
| 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) | 55902 | 2-Fluoro-4-nitrotoluene; 4-Nitro-2-fluorotoluene | 1427-07-2 | C7H6FNO2 | 详情 | 详情 |
| (II) | 55903 | 2-Fluoro-4-nitrobenzoic acid | 403-24-7 | C7H4FNO4 | 详情 | 详情 |
| (III) | 55904 | tert-butyl 2-fluoro-4-nitrobenzoate | C11H12FNO4 | 详情 | 详情 | |
| (IV) | 55905 | tert-butyl 4-amino-2-fluorobenzoate | C11H14FNO2 | 详情 | 详情 | |
| (V) | 55906 | tert-butyl 4-{[(benzyloxy)carbonyl]amino}-2-fluorobenzoate | C19H20FNO4 | 详情 | 详情 | |
| (VI) | 18385 | (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate | 60456-26-0 | C7H12O3 | 详情 | 详情 |
| (VII) | 55907 | tert-butyl 2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]benzoate | C15H18FNO5 | 详情 | 详情 | |
| (VIII) | 55908 | tert-butyl 4-[(5R)-5-(azidomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorobenzoate | C15H17FN4O4 | 详情 | 详情 | |
| (IX) | 55909 | 4-[(5R)-5-(azidomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorobenzoic acid | C11H9FN4O4 | 详情 | 详情 | |
| (X) | 58661 | tert-butyl 4-[(5R)-5-(azidomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenylcarbamate | C15H18FN5O4 | 详情 | 详情 | |
| (XI) | 58662 | tert-butyl 4-[(5R)-5-(azidomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl(methyl)carbamate | C16H20FN5O4 | 详情 | 详情 | |
| (XII) | 58663 | tert-butyl 4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl(methyl)carbamate | C16H22FN3O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Oxidation of 2-fluoro-4-nitrotoluene (I) by means of Jones reagent afforded the benzoic acid (II). After activation of (II) as the corresponding acid chloride with SOCl2, reaction with lithium tert-butoxide furnished the tert-butyl ester (III). Reduction of the nitro group of (III) by means of iron powder gave amine (IV), which was further converted into the carbamate (V) upon treatment with benzyl chloroformate. The chiral oxazolidinone (VII) was prepared by condensation of the lithium salt of carbamate (V) with (R)-glycidyl butyrate (VI) at -78 C. After activation of the primary hydroxyl of (VII) as the corresponding mesylate, displacement with NaN3 in hot DMF provided the alkyl azide (VIII). Tert-Butyl ester cleavage in (VIII) employing trifluoroacetic acid afforded the carboxylic acid (IX), which was cyclized to the thiadiazole (XI) by condensation with thiosemicarbazide (X) in the presence of POCl3. Reduction of the azido group of (XI) to the primary amine (XII) was accomplished by treatment with triphenylphosphine followed by aqueous hydrolysis. Finally, acylation of the aliphatic amino group of (XII) with ethyl dithioacetate gave rise to the title thioacetamide.
| 【1】 Gordeev, M.F.; Trias, J.; Lopez, S.; Hackbarth, C.J.; Fan, P.; Gadwood, R.C.; Luehr, G.W.; Patel, D.V.; Antimicrobial activity of novel 1,3,4-thiadiazole, 1,3,4-oxadiazole, and benzimidazole phenyloxazolidinones. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1046. |
| 【2】 Patel, D.V.; Gadwood, R.C.; Gordeev, M.F.; Luehr, G.W. (Pharmacia Corp.); Oxazolidinones and their use as antiinfectives. EP 1200416; US 6441005; WO 0109107 . |
| 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) | 55902 | 2-Fluoro-4-nitrotoluene; 4-Nitro-2-fluorotoluene | 1427-07-2 | C7H6FNO2 | 详情 | 详情 |
| (II) | 55903 | 2-Fluoro-4-nitrobenzoic acid | 403-24-7 | C7H4FNO4 | 详情 | 详情 |
| (III) | 55904 | tert-butyl 2-fluoro-4-nitrobenzoate | C11H12FNO4 | 详情 | 详情 | |
| (IV) | 55905 | tert-butyl 4-amino-2-fluorobenzoate | C11H14FNO2 | 详情 | 详情 | |
| (V) | 55906 | tert-butyl 4-{[(benzyloxy)carbonyl]amino}-2-fluorobenzoate | C19H20FNO4 | 详情 | 详情 | |
| (VI) | 18385 | (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate | 60456-26-0 | C7H12O3 | 详情 | 详情 |
| (VII) | 55907 | tert-butyl 2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]benzoate | C15H18FNO5 | 详情 | 详情 | |
| (VIII) | 55908 | tert-butyl 4-[(5R)-5-(azidomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorobenzoate | C15H17FN4O4 | 详情 | 详情 | |
| (IX) | 55909 | 4-[(5R)-5-(azidomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorobenzoic acid | C11H9FN4O4 | 详情 | 详情 | |
| (X) | 12954 | 1-Hydrazinecarbothioamide; Thiosemicarbazide | 79-19-6 | CH5N3S | 详情 | 详情 |
| (XI) | 55910 | (5R)-3-[4-(5-amino-1,3,4-thiadiazol-2-yl)-3-fluorophenyl]-5-(azidomethyl)-1,3-oxazolidin-2-one | C12H10FN7O2S | 详情 | 详情 | |
| (XII) | 55911 | (5S)-5-(aminomethyl)-3-[4-(5-amino-1,3,4-thiadiazol-2-yl)-3-fluorophenyl]-1,3-oxazolidin-2-one | C12H12FN5O2S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Condensation of 2-fluoro-4-nitrotoluene (I) with paraformaldehyde under basic conditions affords diol (II). Nitro group reduction in (II) by hydrogenation over Pd/C yields aniline (III), which is further protected with acetylacetone (IV), to produce the pyrrole derivative (V). After conversion of diol (V) into the mono-tosylate (VI), cyclization in the presence of BuLi furnishes the oxetane derivative (VII). Removal of the pyrrole moiety of (VII) by treatment with hydroxylamine provides amine (VIII), which is converted to the carbamate (IX) by acylation with benzyl chloroformate. Finally, condensation of (IX) with (S)-N,O-diacetyl-1-amino-3-chloro-2-propanol (X) in the presence of lithium t-butoxide produces the required oxazolidinone derivative.
| 【1】 Hao, Y.; Barbachyn, M.R.; Greene, M.L.; et al.; Synthesis and antibacterial activities of oxazolidinones incorporating C-ring oxetanes and thietanes. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-1321. |
| 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) | 55902 | 2-Fluoro-4-nitrotoluene; 4-Nitro-2-fluorotoluene | 1427-07-2 | C7H6FNO2 | 详情 | 详情 |
| (II) | 62249 | 2-(2-fluoro-4-nitrophenyl)-1,3-propanediol | C9H10FNO4 | 详情 | 详情 | |
| (III) | 62250 | 2-(4-amino-2-fluorophenyl)-1,3-propanediol | C9H12FNO2 | 详情 | 详情 | |
| (IV) | 11620 | 2,4-Pentanedione;acetylacetone | 123-54-6 | C5H8O2 | 详情 | 详情 |
| (V) | 62251 | 2-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-2-fluorophenyl]-1,3-propanediol | C15H18FNO2 | 详情 | 详情 | |
| (VI) | 62252 | 2-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-2-fluorophenyl]-3-hydroxypropyl 4-methylbenzenesulfonate | C22H24FNO4S | 详情 | 详情 | |
| (VII) | 62253 | 1-[3-fluoro-4-(3-oxetanyl)phenyl]-2,5-dimethyl-1H-pyrrole | C15H16FNO | 详情 | 详情 | |
| (VIII) | 62254 | 3-fluoro-4-(3-oxetanyl)aniline; 3-fluoro-4-(3-oxetanyl)phenylamine | C9H10FNO | 详情 | 详情 | |
| (IX) | 62255 | benzyl 3-fluoro-4-(3-oxetanyl)phenylcarbamate | C17H16FNO3 | 详情 | 详情 | |
| (X) | 61915 | (1S)-2-(acetylamino)-1-(chloromethyl)ethyl acetate | C7H12ClNO3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)Oxidation of 2-fluoro-4-nitrotoluene (I) by means of periodic acid and CrO3 affords 2-fluoro-4-nitrobenzoic acid (II), which by chlorination with SOCl2 in DMF at –5 °C, followed by condensation with methylamine, yields 2-fluoro-N-methyl-4-nitrobenzamide (III). Reduction of the nitro group in compound (III) with Fe in refluxing AcOH/EtOAc gives amine (IV), which is then condensed with pure acetone cyanohydrin (V) in the presence of anhydrous MgSO4 at 80 °C to provide 4-(1-cyano-1-methylethylamino)-2-fluoro-Nmethylbenzamide (VI). Finally, compound (VI) is condensed with 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (VII) (prepared by reaction of 4-amino-2-(trifluoromethyl)benzonitrile (VIII) with thiophosgene in H2O) in DMF heated to 100 °C under microwave irradiation, and then cyclized by means of HCl in refluxing MeOH .
| 【1】 Sawyers, C.L., Jung, M.E., Chen, C.D., Ouk, S., Welsbie, D., Tran, C., Wongvipat, J., Yoo, D. (University of California, Oakland). Diarylhydantoin compounds. EP 1893196, JP 2008540523, US 2007004753, US 7709517, WO 2006124118. |
| 【2】 Jung, M., Yoo, D., Sawyers, C.L., Tran, C. (University of California, Oakland). Diarylthiohydantoin compounds. EP 2013187, JP 2009531449, US 2007254933, US 2008139634, WO 2007127010. |
| 【3】 Jung, M.E., Ouk, S., Yoo, D., Sawyers, C.L., Chen, C., Tran, C., Wongvipat, J. Structure-activity relationship for thiohydantoin androgen receptor antagonists for castration-resistant prostate cancer (CRPC). J Med Chem 2010 53(10): 2779-96. |
| 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) | 55902 | 2-Fluoro-4-nitrotoluene; 4-Nitro-2-fluorotoluene | 1427-07-2 | C7H6FNO2 | 详情 | 详情 |
| (II) | 55903 | 2-Fluoro-4-nitrobenzoic acid | 403-24-7 | C7H4FNO4 | 详情 | 详情 |
| (III) | 68796 | 2-fluoro-N-methyl-4-nitrobenzamide | C8H7FN2O3 | 详情 | 详情 | |
| (IV) | 67496 | 4-amino-2-fluoro-N-methylbenzamide | C8H9FN2O | 详情 | 详情 | |
| (V) | 18029 | Acetone cyanohydrin; 2-Hydroxy-2-methylpropanenitrile; 2-Hydroxy-2-methylpropionitrile; 2-Hydroxyisobutyronitrile; 2-Methyllactonitrile; alpha-Hydroxyisobutyronitrile | 75-86-5 | C4H7NO | 详情 | 详情 |
| (VI) | 68797 | 4-(1-cyano-1-methylethylamino)-2-fluoro-N-methylbenzamide | C12H14FN3O | 详情 | 详情 | |
| (VII) | 68798 | 4-isothiocyanato-2-(trifluoromethyl)benzonitrile；4-Cyano-3-trifluoromethylphenylisothiocyanate | 143782-23-4 | C9H3F3N2S | 详情 | 详情 |
| (VIII) | 18743 | 4-amino-2-(trifluoromethyl)benzonitrile；5-Amino-2-cyanobenzotrifluoride | 654-70-6 | C8H5F3N2 | 详情 | 详情 |