USOO5847231A United States Patent (19) 11 Patent Number: 5,847,231 Kanno et al. (45) Date of Patent: Dec. 8, 1998 54 SELECTIVE NITRATION OF PHENOL 57 ABSTRACT DERVATIVES ProceSS for preparing 4-nitrophenol derivatives of formula 75) Inventors: Hideki Kanno; Hiroyuki Chida; Yurie (IV) with high Selectivity, which comprises converting phe Otani, all of Koshigaya, Japan nols to diphenyl oxalate derivatives of formula (III) and conducting nitration reaction and hydrolysis to give Said 73 Assignee: Junsei Chemical Co., Ltd., Tokyo, 4-nitrophenol derivatives. Japan (R), 21 Appl. No.: 838,672 OH 22 Filed: Apr. 9, 1997 COO NO2 30 Foreign Application Priority Data C (R), Aug. 23, 1996 JP Japan .................................... 8-240000 COO NO2 (51) Int. Cl. .............................................. C07C 205/00 NO2 52 U.S. Cl. ............................................. 568/706; 568/709 58 Field of Search ...................................... 568/706, 709 (R), (IV) III 56) References Cited (III) U.S. PATENT DOCUMENTS In the above formulae, 5,414.148 5/1995 Metivier et al. ........................ 568/706 2 - - -2 f eWei e a f R is, the same or different from each other, an alkyl group FOREIGN PATENT DOCUMENTS having 1 to 4 carbon atoms, a halogen atom; an alkoxy group having 1 to 4 carbon atoms, a formyl group; a 743851 6/1970 Belgium ................................ 260/126 nitrile group; -COOR." (R' is an alkyl group having 1 OTHER PUBLICATIONS to 4 carbon atoms); -CONRR (R and Rare, the Same or different from each other, hydrogen atom(s) or Bischoff et al. Chem. Ber, 35: 3443-3450, 1902. alkyl group(s) having 1 to 4 carbon atoms); or -COR" Arjeh Galum et al. J. Het. Chem., 16:221-224, Mar. 1979. (R" is an alkyl group having 1 to 4 carbon atoms), and C.A. Bischoff et al., “Uber Oxalisaurearylester,” Chemische R is not Substituted at the 4-position of the phenyl ring and Berichte 35:3443-3452 (1902) (English language transla not substituted at the 2- and 6-positions of the phenyl tion). ring at the same time, and, Primary Examiner-Gary Geist n is 1, 2 or 3. ASSistant Examiner J. Parsa Attorney, Agent, or Firm Testa, Hurwitz & Thibeault, LLP 14 Claims, No Drawings 5,847,231 1 2 SELECTIVE NITRATION OF PHENOL yield by recrystallization from water after direct nitration of DERVATIVES 3-hydroxybenzaldehyde in benzene. The present inventors followed this procedure, but could not achieve the objective BACKGROUND OF THE INVENTION of obtaining the pure product in Such a high yield. 1. Field of the Invention On the other hand, Thompson et al. conducted the direct nitration of 3-cyanophenol and Separated the three nitrated The present invention relates to a process for preparing isomers from the mixture using Silica gel column chroma 4-nitrophenol derivatives which are useful intermediates to tography. The yields were 21.3% for the 2-nitro isomer produce various compounds usable as medicaments, and, (3-hydroxy-2-nitrobenzonitrile), 30.5% for the 4-nitro iso more particularly, to a proceSS for preparing 4-nitrophenol mer (5-hydroxy-2-nitrobenzonitrile), and 24.3% for the derivatives in high Selectivity, which comprises converting 6-nitro isomer (3-hydroxy-4-nitrobenzonitrile). Thus, there phenols to diphenyl oxalate derivatives and conducting has been no means other than Silica gel column chromatog nitration reaction and hydrolysis to give 4-nitrophenol raphy to Separate a single objective product in high purity derivatives. and high yield after direct nitration of phenol derivatives. 2. Description of the Prior Art 15 The procedure using Silica gel column chromatography, 4-Nitrophenol derivatives such as 5-hydroxy-2- however, is uneconomical and low in productivity, and nitrobenzaldehyde, 5-hydroxy-2-nitrobenzoic acid and therefore unsuitable for a large-scale commercial produc 5-hydroxy-2-nitrobenzonitrile are useful as intermediates tion. for preparing various physiologically active compounds. Other references disclose preparation of 5-hydroxy-2- Heretofore, 4-nitrophenol derivatives have been prepared by nitrobenzaldehyde from 3-hydroxybenzaldehyde by first direct nitration reaction of the corresponding phenols, or by esterifying the Starting compound using phosgene to prepare first converting the phenols to phenyl carbonates by reaction bis(3-formylphenyl) carbonate, then by Subjecting this car with poisonous phosgene and Subsequently conducting bonate to nitration reaction and then hydrolysis (Frederick nitration reaction. A. Mason: J. Chem. Soc., 127: 1197–1199, 1925; Martha E. Regarding the direct nitration of phenol derivatives, for 25 Smith et al.,. J. Am. Chem. Soc., 68: 1301-1303, 1946; example Lilli S. Hornig reported the two-phase nitration Arjeh Galun et al.,. J. Het. Chem., 16: 221-224, 1979). using concentrated nitric acid in benzene (J.Am. Chem. According to Mason, the yields of the products obtained Soc.,74, 4572–4577 (1952)), and Molcolm J. Thompson and in the above esterification, nitration and hydrolysis Steps Petrus J. Zeegers also reported the two-phase nitration in were 90%, 97%, and 95%, respectively. A dark brown dichloromethane as organic Solvent (Tetrahedron, 46(7), crystalline product was obtained in the hydrolysis Step, 2661-2674 (1990)). Thompson et al. reported that the two which he crystallized several times from 10% aqueous phase nitration of phenols yielded a mixture of three kinds alcohol to obtain purified 5-hydroxy-2-nitrobenzaldehyde of isomers, i.e., 2-nitro, 4-nitro and 6-nitro isomers which having a melting point of 167 C. were present in Similar ratio. They conducted the two-phase 35 In a similar Study, Smith et al. reported that they attained nitration of phenol derivatives having various Substituent 97% yield in the nitration step and also 97% yield in the groups at the 3-position, and determined the ratio of the hydrolysis Step. They Subjected the crude product in glis isomers by gas chromatography and/or "H-NMR analysis. tening tan crystals (m.p.: 164-167 C.) to recrystallization The results are shown in the following table. from ethanol-water to obtain purified 5-hydroxy-2- 40 nitrobenzaldehyde having a melting point of 163-166 C. TABLE And, Galun et al. reported a 73% total yield of crude R 2-Nitro 4-Nitro 6-Nitro Total (% o):p 5-hydroxy-2-nitrobenzaldehyde (m.p.: 132C.) through the nitration and hydrolysis StepS. 1. H 27.5 41.3 27.5 96.3 O.66 2. Me 22.5 41.O 27.9 91.4 O.62 Thus, it have been well known that converting phenols to 3. Et 20.5 41.4 29.9 91.8 O.61 45 phenyl carbonate by using phosgene and Subjecting the 4. t-But 19.3 40.7 34.8 94.5 O.66 carbonate to nitration and then hydrolysis can produce 5. OH para-nitrophenol derivatives with good Selectivity. However, 6. OMe 8.O 3O.O 49.O 87.O 0.95 7. F 17.0 31.0 37.8 85.8 O.88 phosgene is poisonous and its transfer in a gas cylinder, etc. 8. Cl 2O2 34.7 28.7 83.6 O.70 is prohibited. Therefore, the process may only be carried out 9. CN 22.0 32.5 22.9 77.4 O.69 50 in a Specifically equipped factory capable of preparing 10. CHO 22.6 38.4 25.2 86.0 O.62 phosgene. This has hindered simple and convenient nitration 11. COMe 24.9 40.3 28.7 93.9 O.66 of phenols to Selectively prepare the para-nitrophenol 12. NO, 8.5 21.0 17.4 46.9 O.62 derivatives. Instead of phosgene, Mason proposed use of ethyl chlo The above table shows that the (% o):p value, i.e., the ratio 55 rocarbonate in his Same reference mentioned above. He of the ortho nitro isomers (2-nitro and 6-nitro isomers) to the converted 3-hydroxybenzaldehyde to ethyl 3-formylphenyl para nitro isomer (4-nitro isomer) is 0.6-0.95, and therefore carbonate by reaction with ethyl chlorocarbonate, and it is Suggested that the ortho nitro isomers are predominantly nitrated the compound to obtain crude ethyl 3-formyl-4- produced by the two-phase nitration of phenol derivatives. nitrophenyl carbonate in 96% yield. He says the crude For example, in Case No. 9 of the above table, the yield 60 nitration product seems to consist of at least 50% of 4-nitro of the para nitro isomer (4-nitro isomer), i.e., 5-hydroxy-2- isomeride. Although he reports that crude 5-hydroxy-2- nitrobenzonitrile, is 32.5%, and in Case No. 10 the yield of nitrobenzaldehyde was obtained in a yellow, crystalline the para nitro isomer, i.e., 5-hydroxy-2-nitrobenzaldehyde, precipitate in 41% yield by hydrolysis of the nitrated phenyl is 38.47%. Studies have been done in order to separate a carbonate, there is no description of the melting point or the Single objective nitrated product from Such an isomeric 65 purity of this product. In view of the character of this mixture. For example, Hornig reported that 5-hydroxy-2- compound, it is impossible to attain 41% yield of a high nitrobenzaldehyde in purified form was obtained in 34% purity product separated from the crude mixture containing 5,847,231 3 4 about 50% of the 4-nitro isomer. Therefore, assuming the R is, the same or different from each other, an alkyl group content of the 4-nitro isomer to be about 50%, it is consid having 1 to 4 carbon atoms, a halogen atom; an alkoxy ered that the nitration of ethyl phenyl carbonate gives group having 1 to 4 carbon atoms, a formyl group; a para-nitrophenol derivatives in only a little higher Selectivity nitrile group; -COOR (R is an alkyl group having 1 as compared with direct nitration of phenols in View of the 5 to 4 carbon atoms); -CONRR (R and Rare, the results shown in the above table.