WO2004037765A1 - A process for the preparation of 3,4,5-trifluoronitrobenzene - Google Patents
A process for the preparation of 3,4,5-trifluoronitrobenzene Download PDFInfo
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- WO2004037765A1 WO2004037765A1 PCT/IB2002/004403 IB0204403W WO2004037765A1 WO 2004037765 A1 WO2004037765 A1 WO 2004037765A1 IB 0204403 W IB0204403 W IB 0204403W WO 2004037765 A1 WO2004037765 A1 WO 2004037765A1
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- 238000000034 method Methods 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- PTTUMBGORBMNBN-UHFFFAOYSA-N 1,2,3-trifluoro-5-nitrobenzene Chemical compound [O-][N+](=O)C1=CC(F)=C(F)C(F)=C1 PTTUMBGORBMNBN-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 43
- 239000002904 solvent Substances 0.000 claims description 27
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 25
- 238000006243 chemical reaction Methods 0.000 claims description 23
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 10
- 229910017604 nitric acid Inorganic materials 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 8
- 230000009615 deamination Effects 0.000 claims description 7
- 238000006481 deamination reaction Methods 0.000 claims description 7
- 230000000802 nitrating effect Effects 0.000 claims description 7
- 230000002829 reductive effect Effects 0.000 claims description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- -1 butyl nitrile Chemical group 0.000 claims description 6
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- 238000006396 nitration reaction Methods 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- 239000012345 acetylating agent Substances 0.000 claims description 3
- 230000021736 acetylation Effects 0.000 claims description 3
- 238000006640 acetylation reaction Methods 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- ZJIJYZSGABIPDP-UHFFFAOYSA-N 2-n,4-n-dimethylpyridine-2,4-diamine Chemical compound CNC1=CC=NC(NC)=C1 ZJIJYZSGABIPDP-UHFFFAOYSA-N 0.000 claims description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 2
- 239000012346 acetyl chloride Substances 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 229950005499 carbon tetrachloride Drugs 0.000 claims description 2
- 230000000850 deacetylating effect Effects 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 230000009466 transformation Effects 0.000 abstract description 2
- 238000000844 transformation Methods 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- ILENVKAVEFKZSD-UHFFFAOYSA-N 2,3,4-trifluoro-6-nitroaniline Chemical compound NC1=C(F)C(F)=C(F)C=C1[N+]([O-])=O ILENVKAVEFKZSD-UHFFFAOYSA-N 0.000 description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- JFPJVTNYCURRAB-UHFFFAOYSA-N 2-nitro-n-phenylacetamide Chemical compound [O-][N+](=O)CC(=O)NC1=CC=CC=C1 JFPJVTNYCURRAB-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- SHERLLWHOMUAER-UHFFFAOYSA-N n,n,2-trifluoroaniline Chemical compound FN(F)C1=CC=CC=C1F SHERLLWHOMUAER-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- ARCACZWMYGILNI-UHFFFAOYSA-N 1,2,3-trifluoro-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C(F)=C1F ARCACZWMYGILNI-UHFFFAOYSA-N 0.000 description 1
- SAPQIENQEZURNZ-UHFFFAOYSA-N 2,2,2-trifluoro-n-phenylacetamide Chemical compound FC(F)(F)C(=O)NC1=CC=CC=C1 SAPQIENQEZURNZ-UHFFFAOYSA-N 0.000 description 1
- 239000004128 Copper(II) sulphate Substances 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 229910006069 SO3H Inorganic materials 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- IWOUKMZUPDVPGQ-UHFFFAOYSA-N barium nitrate Inorganic materials [Ba+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O IWOUKMZUPDVPGQ-UHFFFAOYSA-N 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 230000006196 deacetylation Effects 0.000 description 1
- 238000003381 deacetylation reaction Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 238000003682 fluorination reaction Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 1
- VBEGHXKAFSLLGE-UHFFFAOYSA-N n-phenylnitramide Chemical compound [O-][N+](=O)NC1=CC=CC=C1 VBEGHXKAFSLLGE-UHFFFAOYSA-N 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 239000004323 potassium nitrate Substances 0.000 description 1
- 235000010333 potassium nitrate Nutrition 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000012414 tert-butyl nitrite Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/62—Preparation of compounds containing amino groups bound to a carbon skeleton by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
Definitions
- the present invention relates to a process for the preparation of 3,4,5- trifluoronitrobenzene of the formula (1), which is useful in the preparation of several pharmaceutically useful molecules
- the trifluoronitrobenzene of the formula (1) is useful in the preparation of several antibacterial compounds such as the compound of the formula (2a) disclosed in PCT publication no. WO02051819; (2b) and (2c) disclosed in PCT publications WO 95/07271 and WO 93/23384 respectively.
- the 3,4,5-trifluoronitrobenzene of the formula (1) is also used in the preparation of comp poouunndd ooff ffoorrmmuullaa ((22dd)) I (Ref: Poster F-1333, 42 nd ICAAC, SanDiego, California, USA; September 27-30, 2002) (2d)
- the 3,4,5-trifluoronitrobenzene of the formula (1) is also useful in the preparation of novel antibacterial compounds disclosed in our copending WTO patent application 042/MAS/2002, some of the novel analogs of 5-substituted 3-phenyl oxazolidinones described in our copending WTO patent application numbers 368/MAS/2000 and 369/MAS/2000.
- the process for preparing the novel analogs of 5- substituted 3-phenyl oxazolidinones are described in our copending patent application numbers 446/MAS/2000 and 447/MAS/2000 which uses the compound of formula (I) as a starting material.
- the compound of formula (I) is also expected to be useful as a starting material in the other areas of medicinal chemistry research.
- UK patent application number GB 2,291,871 describes a process for preparing the fluoronitroaromatic compounds which involves reaction of fluorobenzene with a nitrating agent such as HNO 3 in the presence of elemental fluorine.
- EP 773,210 describes a process which comprises fluorination of aromatic nitro compounds using complex reagent like CF 3 CFHCF 2 SO 3 H and produces a mixture of more than two compounds and it is tedious to separate these compounds.
- the objective of the present invention is to provide a process for the preparation of 3,4,5-trilfluoronitro benzene of the formula (1) which is simple, high yielding, cost effective, commercially viable and easy to scale-up.
- the process involved straightforward transformations and eventually culminated in consistent preparation of the title compound in good quantities.
- the present invention provides a process for the preparation of 3,4,5-trifluoronitrobenzene of the formula (1), which comprises: (i) acetylation of the compound of the formula (3)
- R represents acetyl group, in the presence or absence of a base and a solvent at a temperature in the range of 0 to 80 °C for a duration in the range of 1 to 10 h,
- R represents -COCH , by using conventional nitrating agents, in the presence or absence of a base and a solvent at a temperature in the range of -25 °C to ambient temperature,
- the reductive deamination may also be carried out in the presence of tertiary butyl nitrile, by using a solvent at a temperature in the range of ambient temperature to 100 °C, for duration in the range- of 30 min to 5 h.
- Acetylation of the compound of formula (1) may be carried out using acetic anhydride or acetyl chloride in the absence or presence of bases such as pyridine, triethylamine, 2,4-dimethylaminOpyridine (DMAP) and the like.
- the reaction may be carried out in the absence or presence of solvents such as THF, chloroform, CH 2 C1 2 , carbontetrachloride, benzene, toluene and the like or mixtures thereof.
- Nitration of the compound (4) may be carried out with a 1:1 mixture of nitric acid and sulfuric acid in the absence or presence of solvents such as CH 2 C1 2 , CHC1 3 , 1,2- dichloroethane and the like, to obtain a nitroacetanilide of the formula (5) where R represents -COCH 3 group.
- the nitroacetanilide of the formula (5) can also be obtained by using reagents such as KNO 3 , NaNO 3 , Ba(NO 3 ) 2 in sulfuric acid at a temperature in the range of -10 °C to ambient temperature.
- Nitration can also be carried out using HNO 3 in the absence or presence of acetic anhydride.
- the compound of formula (5) where R represents hydrogen atom may also be obtained in a single step using nitric acid in presence of excess of sulfuric acid.
- the compound of formula (5) where R represents -COCH 3 can be deacetylated to a compound of formula (5) where R represents hydrogen atom using inorganic acid such as hydrochloric acid, sulfuric acid, perchloric acid and the like.
- the reaction may be carried out in the absence or presence of solvents such as THF, methanol, ethanol and the like or mixtures thereof.
- the reaction ' may be carried out at a temperature in- the range of ambient temperature to reflux temperature of the solvent used.
- deacetylation of compound of formula (5) where R represents -COCH 3 to a compound of formula (5) where R represents hydrogen atom may also be carried out by treating with alkali hydroxides such as NaOH, KOH and the like.
- the compound of formula (5), where R represents hydrogen atom is directly prepared from compound of formula (4) by using a nitrating agent such as nitric acid, K-NO 3 or NaNO 3 in nitric acid.
- a nitrating agent such as nitric acid, K-NO 3 or NaNO 3 in nitric acid.
- the temperature of the reaction may in the range of 0 to 80 °C, for a duration in the range of 1 to 12 h.
- the reaction may be carried out in the presence or absence of a solvent such as tetrahydrofuran, alcohols such as methanol, ethanol and the like.
- the reductive deamination of the nitroaniline of the formula (5) where R represents hydrogen atom may be carried out using NaNO 2 and sulfuric acid in methanol, ethanol followed by treatment with copper powder.
- the reductive deamination may also be carried out using tertiary butylnitrite in the presence of a solvent such as dimethylformamide, dimethylsulfoxide, CH 3 CN and the like.
- Trifluoroaniline 500 g, at 0 °C was added acetic anhydride (1.5 L) over 10 min followed by DMAP (8 g). The reaction mixture was allowed to warm to ambient temperature over 6 h and then poured onto crushed ice. The resultant precipitate was filtered on a Buchner funnel, washed with cold water and air dried to yield 2,3,4- trifluoroacetanilide_(611 g, 95%). Mp 92 °C. IR (KBr) 3272, 1674, 1515, 1477 cm “1 . 1H NMR: ⁇ 8.10-7.90 (m, 1H), 7.30 (br s, 1H), 7.02-6.87 (m, 1H), 2.23 (s, 3H).
- Trifluoroaniline 500 g, was added acetic anhydride (1.5 L) over 10 min followed by DMAP (8 g). The reaction mixture was allowed to warm to ambient temperature over 6 h and then poured onto crushed ice. The resultant precipitate was filtered on a Buchner funnel, washed with cold water and air dried to yield 2,3,4- • trifluoroacetanilide_(611 g, 95%). Mp 92 °C. LR (KBr) 3272, 1674, 1515, 1477 cm “1 . 1H NMR: ⁇ 8.10-7.90 (m, 1H), 7.30 (br s, 1H), ' 7.02-6.87 (m, 1H), 2.23 (s, 3H).
- Step 3 Preparation of 3,4,5-trifluoronitrobenzene A solution of 6-nitro 2,3,4-trifluoroaniline (14.97 g), obtained in step 2, in DMF (200 ml) was added drop wise to a mixture of tert-butylnitrite (104.4 g), in dry DMF (50 ml) at 45-75 °C over 15 min. After stirring for 2 h at the same temperature, the reaction mixture was cooled in an ice bath and poured into 20%> aq. HCl (200 ml). The resultant solution was steam distilled to yield the product as yellow liquid and was separated from the distillate (8.28 g, 60%)
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a process for the preparation of 3,4,5-trifluoronitrobenzene of the formula (1). The process involved straightforward transformations and eventually culminated in consistent preparation of the title compound in good quantities.
Description
A PROCESS FOR THE PREPARATION OF 3,4,5-TRIFLUORONITROBENZENE
Field of the Invention The present invention relates to a process for the preparation of 3,4,5- trifluoronitrobenzene of the formula (1), which is useful in the preparation of several pharmaceutically useful molecules
The trifluoronitrobenzene of the formula (1) is useful in the preparation of several antibacterial compounds such as the compound of the formula (2a) disclosed in PCT publication no. WO02051819; (2b) and (2c) disclosed in PCT publications WO 95/07271 and WO 93/23384 respectively.
(2b) (2c)
The 3,4,5-trifluoronitrobenzene of the formula (1) is also used in the preparation of comp poouunndd ooff ffoorrmmuullaa ((22dd)) I (Ref: Poster F-1333, 42nd ICAAC, SanDiego, California, USA; September 27-30, 2002)
(2d)
The 3,4,5-trifluoronitrobenzene of the formula (1) is also useful in the preparation of novel antibacterial compounds disclosed in our copending WTO patent application 042/MAS/2002, some of the novel analogs of 5-substituted 3-phenyl oxazolidinones described in our copending WTO patent application numbers 368/MAS/2000 and 369/MAS/2000. The process for preparing the novel analogs of 5- substituted 3-phenyl oxazolidinones are described in our copending patent application numbers 446/MAS/2000 and 447/MAS/2000 which uses the compound of formula (I) as a starting material. The compound of formula (I) is also expected to be useful as a starting material in the other areas of medicinal chemistry research.
In continuation of a project directed towards the preparation of afore mentioned analogs, we needed good quantities of 3,4,5-trifluoronitrobenzene for introducing fluorine atoms into aromatic ring. However, none of the major suppliers of the fine chemicals had this material in their catalogs. Very few literature references report 3,4,5- trifluoronitrobenzene of the formula (I) and the method of preparing this compound.
UK patent application number GB 2,291,871 describes a process for preparing the fluoronitroaromatic compounds which involves reaction of fluorobenzene with a nitrating agent such as HNO3 in the presence of elemental fluorine.
European Patent application number EP 773,210 describes a process which comprises fluorination of aromatic nitro compounds using complex reagent like CF3CFHCF2SO3H and produces a mixture of more than two compounds and it is tedious to separate these compounds.
The procedure reported in the J. Chem. Soc. Perkin Trans. II, 41, 1978, 141-144 involves removal of fluorine atom from a tetrafluoro nitro compound using hydrazine hydrate and copper (II) sulphate. This process uses expensive starting material and yields three side-products and does not give a method to separate them.
In view of the importance of 3,4,5-trifluoronitro benzene and its usage in the preparation of several compounds of pharmaceutical application it is very much important to have simple, cost effective and commercially viable process for the preparation of 3,4,5-trifluoronitro benzene. Objective of the Invention
The objective of the present invention is to provide a process for the preparation of 3,4,5-trilfluoronitro benzene of the formula (1) which is simple, high yielding, cost effective, commercially viable and easy to scale-up. The process involved straightforward transformations and eventually culminated in consistent preparation of the title compound in good quantities.
Summary of the Invention
Accordingly, the present invention provides a process for the preparation of 3,4,5-trifluoronitrobenzene of the formula (1), which comprises: (i) acetylation of the compound of the formula (3)
by using an acetylating agent, to p Xroduce a cmompound '" of formula (4),
F
where R represents acetyl group, in the presence or absence of a base and a solvent at a temperature in the range of 0 to 80 °C for a duration in the range of 1 to 10 h,
(ii) nitration of the compound of formula (4) to produce a compound of formula (5)
(iii) deacetylating. the compound of formula (5) where R represents -COCH3 to a compound of formula (5) where R represents hydrogen atom using conventional reagents, in the presence or absence of a solvent, at a temperature in the range of ambient temperature to the reflux temperature of the solvent used for a duration in the range of 1 to 20 h. The compound of formula (4) can be directly converted to a compound of formula (5) where R represents hydrogen atom by using a nitrating agent, (iv) aromatic reductive deamination of the compound of the formula (5) where R represents hydrogen atom using NaNO2 and H2SO4 in the presence of a solvent and copper powder, to produce the compound of formula (1). The reductive deamination may also be carried out in the presence of tertiary butyl nitrile, by using a solvent at a temperature in the range of ambient temperature to 100 °C, for duration in the range- of 30 min to 5 h.
Detailed Description of the Invention
Acetylation of the compound of formula (1) may be carried out using acetic anhydride or acetyl chloride in the absence or presence of bases such as pyridine, triethylamine, 2,4-dimethylaminOpyridine (DMAP) and the like. The reaction may be carried out in the absence or presence of solvents such as THF, chloroform, CH2C12, carbontetrachloride, benzene, toluene and the like or mixtures thereof.
Nitration of the compound (4) may be carried out with a 1:1 mixture of nitric acid and sulfuric acid in the absence or presence of solvents such as CH2C12, CHC13, 1,2- dichloroethane and the like, to obtain a nitroacetanilide of the formula (5) where R represents -COCH3 group. The nitroacetanilide of the formula (5) can also be obtained by using reagents such as KNO3, NaNO3, Ba(NO3)2 in sulfuric acid at a temperature in the range of -10 °C to ambient temperature. Nitration can also be carried out using HNO3 in the absence or presence of acetic anhydride. The compound of formula (5)
where R represents hydrogen atom may also be obtained in a single step using nitric acid in presence of excess of sulfuric acid.
The compound of formula (5) where R represents -COCH3 can be deacetylated to a compound of formula (5) where R represents hydrogen atom using inorganic acid such as hydrochloric acid, sulfuric acid, perchloric acid and the like. The reaction may be carried out in the absence or presence of solvents such as THF, methanol, ethanol and the like or mixtures thereof. The reaction' may be carried out at a temperature in- the range of ambient temperature to reflux temperature of the solvent used.
The deacetylation of compound of formula (5) where R represents -COCH3 to a compound of formula (5) where R represents hydrogen atom may also be carried out by treating with alkali hydroxides such as NaOH, KOH and the like.
Alternatively the compound of formula (5), where R represents hydrogen atom is directly prepared from compound of formula (4) by using a nitrating agent such as nitric acid, K-NO3 or NaNO3 in nitric acid. The temperature of the reaction may in the range of 0 to 80 °C, for a duration in the range of 1 to 12 h. The reaction may be carried out in the presence or absence of a solvent such as tetrahydrofuran, alcohols such as methanol, ethanol and the like.
The reductive deamination of the nitroaniline of the formula (5) where R represents hydrogen atom may be carried out using NaNO2 and sulfuric acid in methanol, ethanol followed by treatment with copper powder. The reductive deamination may also be carried out using tertiary butylnitrite in the presence of a solvent such as dimethylformamide, dimethylsulfoxide, CH3CN and the like.
The present invention is described in detail with examples given below which are provided by way of illustration only and should not be considered to limit the scope of the invention.
Example 1
Step 1 : Preparation of 2,3, 4-trifluoroacetanilide
Trifluoroaniline (500 g,) at 0 °C was added acetic anhydride (1.5 L) over 10 min followed by DMAP (8 g). The reaction mixture was allowed to warm to ambient temperature over 6 h and then poured onto crushed ice. The resultant precipitate was filtered on a Buchner funnel, washed with cold water and air dried to yield 2,3,4- trifluoroacetanilide_(611 g, 95%). Mp 92 °C. IR (KBr) 3272, 1674, 1515, 1477 cm"1. 1H NMR: δ 8.10-7.90 (m, 1H), 7.30 (br s, 1H), 7.02-6.87 (m, 1H), 2.23 (s, 3H).
Mass: m/z 190 (M++l).
Step 2 : Preparation of 6-nitro-2,3, 4-trifluoroacetanilide
IR(KBr): 3266, 1684, 1533, 1504, 1367 cm"1
1H NMR: δ 8.23 (br s, 1H), 7.87-7.75 (m, 1H), 2.28 (s, 3H).
Mass: m/z 235 (M++l).
Step 3 : Preparation of 6-nitro 2,3,4-trifluoroaniline
A solution of 6-nitro-2,3, 4-trifluoroacetanilide (500 g), obtained in step (2) in cone. HC1 (1.1 L) was refluxed for 2 h. The reaction mixture was poured onto crushed ice and neutralised with solid Na2CO3 to basic pH. The solid obtained was filtered on a Buchner funnel, washed with water and air dried. The filtrate was extracted with dichloromethane and the combined extracts were washed with water followed by brine. The residue obtained upon evaporation of the solvents was combined with the solid obtained after the filtration and the total quantity was azeotropically dried with toluene to give 6-nitro 2,3,4-trifluoroaniline_(357 g, 87%). Mp 65 °C.
IR (KBr): 3491, 3381, 1541, 1519, 1272 cm"1.
!HNMR: δ 7.92-7.82 (m, 1H), 6.14 (br s, D2O exchangeable, 2H).
MS (E.I.): m/z 193 (M++l), 190.
Step 4 : Preparation of 3,4,5-trifluoronitrobenzene
A solution of t-butyl nitrite (340 mL) in DMF (150 mL) was added to a stirring solution of 6-nitro 2,3,4-trifluoroaniline (500 g), obtained in step 3, in DMF (1 L) at 45-75 °C under argon over 3 h. After stirring for 1 h at the same temperature, the reaction mixture was treated with 20%ι aq. HC1 (2 L) under cooling. The resultant solution was steam distilled to yield 3,4,5-trifluoronitrobenzene as a yellow liquid and was separated from the distillate (289 g, 62%>). The sample obtained this way was found to be ca. 90% pure by GC. 1H NMR: δ 8.13-7.92 (m, 2H).
Example 2
Step 1: Preparation of 2,3, 4-trifluoroacetanilide
NHCOCH3
Trifluoroaniline (500 g,) at 0 °C was added acetic anhydride (1.5 L) over 10 min followed by DMAP (8 g). The reaction mixture was allowed to warm to ambient temperature over 6 h and then poured onto crushed ice. The resultant precipitate was filtered on a Buchner funnel, washed with cold water and air dried to yield 2,3,4- • trifluoroacetanilide_(611 g, 95%). Mp 92 °C. LR (KBr) 3272, 1674, 1515, 1477 cm"1. 1H NMR: δ 8.10-7.90 (m, 1H), 7.30 (br s, 1H),' 7.02-6.87 (m, 1H), 2.23 (s, 3H).
Mass: m/z 190 (M++l).
Step 2: Preparation of 6-nitro 2,3,4-trifluoroaniline
MS (E.I.): m/z 192 (M+), 175, 119
Step 3 : Preparation of 3,4,5-trifluoronitrobenzene
A solution of 6-nitro 2,3,4-trifluoroaniline (14.97 g), obtained in step 2, in DMF (200 ml) was added drop wise to a mixture of tert-butylnitrite (104.4 g), in dry DMF (50 ml) at 45-75 °C over 15 min. After stirring for 2 h at the same temperature, the reaction mixture was cooled in an ice bath and poured into 20%> aq. HCl (200 ml). The resultant solution was steam distilled to yield the product as yellow liquid and was separated from the distillate (8.28 g, 60%)
IR cm'1: (Neat) 3103, 1643, 1544, 1523, 1358, 1059 1H NMR: δ 7.80 (m, 2H) MS (E.I.): m/z 178 (M+l, 100%), 160
Advantages of the Invention: • no significant impurities in any of the steps, hence purification is not necessary in all the steps except final step.
• the process is simple, high yielding and easily scalable
• all intermediates are solids and are easy to handle in large scale.
• starts from commercially available material • all reagents involved are common and less expensive
Claims
1. A process for the preparation of 3,4,5-trifluoronitrobenzene of the formula (1), which comprises:
(i) acetylation of the compound of the formula (3)
F
NHR
Ύ (5)
F'^5/'^N02 where R represents -COCH3, by using conventional nitrating agents, in the presence or absence of a base and a solvent at a temperature in the range of -25 °C to ambient temperature, (iii) deacetylating the compound of formula (5) where R represents -COCH3 to a compound of formula (5) where R represents hydrogen atom using conventional reagents, in the presence or absence of a solvent, at a temperature in the range of ambient temperature to the reflux temperature of the solvent used for a duration in the range of 1 to 20 h. The compound of formula (4) can be directly converted to a compound of formula (5) where R represents hydrogen atom by using a nitrating agent, (iv) aromatic reductive deamination of the compound of the formula (5) where R represents hydrogen atom using NaNO2 and H SO4 in the presence of a solvent selected to produce the compound of formula (1). The reductive deamination may also be carried out in the presence of tertiary butyl nitrile, by using a solvent at a temperature in the range of ambient temperature to 100 °C, for duration in the range of 30 min to 5 h.
2. The process as claimed in claim 1, where the acetylating agent used in step (i) of the reaction is selected from acetic anhydride or acetyl chloride.
3. The process as claimed in claims 1 and 2, when the reaction in step (i) is carried out in the presence of a base, the base used is selected from pyridine, triethylamine or 2,4-dimethylaminopyridine.
4. The process as claimed in claims 1-3, when the reaction in step (i) is carried out in the presence of a solvent, the solvent used is selected from THF, chloroform, CH2C1 , carbontetrachloride, benzene, toluene or mixtures thereof.
5. The process as claimed in claims 1-4, where the temperature of the reaction in step (i) is carried out at 20 to 40 °C.
6. The process as claimed in claims 1-5, where the duration of the reaction in step (i) is at 3 to 6 h.
7. The process as claimed in claims 1-6, where the nitration in step (ii) of the reaction is carried out by using a 1 : 1 mixture of nitric acid and sulfuric acid; KNO3, NaNO or Ba(NO3) in sulfuric acid (or) nitric acid in the presence" or absence of acetic anhydride.
8. The process as claimed in claims 1-7, when the reaction in step (ii) is carried out in the presence of a solvent, the solvent used is selected from CH2C12, CHC13 or 1,2- dichloroethane.
9. The process as claimed in claims 1-8, where the temperature of the reaction in step (ii) is maintained at -10 to 15 °C
10. The process as claimed in claims 1-9, when the reaction in step (iii) is carried out in the presence of a solvent, the solvent used is selected from THF, methanol, ethanol or mixtures thereof.
11. The process as claimed in claims 1-10, where the conventional agent used in the step (iii) of the reaction is selected from hydrochloric acid, sulfuric acid or perchloric acid.
12. The process as claimed in claims 1-11, where the temperature of the reaction in step (iii) is carried out at the reflux temperature of the solvent used.
13. The process as claimed in claims 1-12, where the duration of the reaction in step (iii) is carried out at in the range of 1 to 3 h.
14. The process as claimed in claims 1-13, where the reductive deamination in step (iv) of the reaction is selected from NaNO2 and sulfuric acid (or) tertiary butylnitrite.
15. The process as claimed in claims 1-14, where the solvent used in step (iv) of the reaction is selected from methanol, ethanol, dimethylformamide, dimethylsulfoxide, CH3CN and the like.
16. The process as claimed in claims 1-15, where the temperature of the reaction is in the range of 45 to 65 °C.
17. The process as claimed in claims 1-16, where the duration of the reaction is in the range of 30 min to 2 h.
18. The process as claimed in claim 1, where the nitrating agent used in direct conversion of the compound of formula (4) to a compound of formula (5), where R represents hydrogen atom, is selected from nitric acid in presence of excess sulfuric acid.
19. A process for the preparation of compounds of the formula (1), substantially as herein described with reference to the examples 1-2.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2002339579A AU2002339579A1 (en) | 2002-10-24 | 2002-10-24 | A process for the preparation of 3,4,5-trifluoronitrobenzene |
| PCT/IB2002/004403 WO2004037765A1 (en) | 2002-10-24 | 2002-10-24 | A process for the preparation of 3,4,5-trifluoronitrobenzene |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IB2002/004403 WO2004037765A1 (en) | 2002-10-24 | 2002-10-24 | A process for the preparation of 3,4,5-trifluoronitrobenzene |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2426723C1 (en) * | 2010-02-11 | 2011-08-20 | Государственное образовательное учреждение высшего профессионального образования "Мордовский государственный университет им. Н.П. Огарева" | Method of producing 2,3,5,6-tetrabromo-4-nitrophenol |
| CN107311869A (en) * | 2017-06-14 | 2017-11-03 | 浙江解氏新材料股份有限公司 | The preparation method of 3,4,5 trifluoronitrobenzenes |
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|---|---|---|---|---|
| FR2334654A1 (en) * | 1975-12-11 | 1977-07-08 | Basf Ag | PROCESS FOR PREPARING HALOGENO-NITROBENZENES |
| WO1996002493A1 (en) * | 1994-07-20 | 1996-02-01 | Rhone-Poulenc Chimie | Method for preparing meta-substituted aromatic nitrogen derivatives |
| GB2291871A (en) * | 1994-07-29 | 1996-02-07 | Bnfl Fluorchem Ltd | Preparation of nitrofluoroaromatic compounds |
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2002
- 2002-10-24 AU AU2002339579A patent/AU2002339579A1/en not_active Abandoned
- 2002-10-24 WO PCT/IB2002/004403 patent/WO2004037765A1/en not_active Application Discontinuation
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2334654A1 (en) * | 1975-12-11 | 1977-07-08 | Basf Ag | PROCESS FOR PREPARING HALOGENO-NITROBENZENES |
| WO1996002493A1 (en) * | 1994-07-20 | 1996-02-01 | Rhone-Poulenc Chimie | Method for preparing meta-substituted aromatic nitrogen derivatives |
| GB2291871A (en) * | 1994-07-29 | 1996-02-07 | Bnfl Fluorchem Ltd | Preparation of nitrofluoroaromatic compounds |
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| DATABASE CROSSFIRE BEILSTEIN BEILSTEIN INSTITUT ZUR FOERDERUNG DER CHEMISCHEN WISSENSCHAFTEN, FRANKFURT AM MAIN, DE; XP002243239 * |
| G. C. FINGER ET AL.: "Aromatic fluorine compounds. V. 1,3,5-trifluorobenzene", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY., vol. 73, no. 1, 1951, DC US, pages 153 - 155, XP002243238 * |
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| JOHN F. W. KEANA ET AL.: "Synthesis and structure-activity relationships of substituted 1,4-dihydroquinoxaline-2,3-diones...", JOURNAL OF MEDICINAL CHEMISTRY., vol. 38, no. 22, 1995, AMERICAN CHEMICAL SOCIETY. WASHINGTON., US, pages 4367 - 4379, XP002243237, ISSN: 0022-2623 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2426723C1 (en) * | 2010-02-11 | 2011-08-20 | Государственное образовательное учреждение высшего профессионального образования "Мордовский государственный университет им. Н.П. Огарева" | Method of producing 2,3,5,6-tetrabromo-4-nitrophenol |
| CN107311869A (en) * | 2017-06-14 | 2017-11-03 | 浙江解氏新材料股份有限公司 | The preparation method of 3,4,5 trifluoronitrobenzenes |
| CN107311869B (en) * | 2017-06-14 | 2019-11-08 | 浙江解氏新材料股份有限公司 | The preparation method of 3,4,5- trifluoronitrobenzene |
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