GB2087886A - Preparing biphenyl compounds by coupling - Google Patents
Preparing biphenyl compounds by coupling Download PDFInfo
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- GB2087886A GB2087886A GB8134869A GB8134869A GB2087886A GB 2087886 A GB2087886 A GB 2087886A GB 8134869 A GB8134869 A GB 8134869A GB 8134869 A GB8134869 A GB 8134869A GB 2087886 A GB2087886 A GB 2087886A
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- United Kingdom
- Prior art keywords
- process according
- alkyl
- benzene
- compound
- hydrogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical class C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 title claims abstract description 12
- 238000005859 coupling reaction Methods 0.000 title abstract description 5
- 230000008878 coupling Effects 0.000 title abstract description 3
- 238000010168 coupling process Methods 0.000 title abstract description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims abstract description 48
- -1 C1-6 alkyl nitrite Chemical compound 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 19
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims abstract description 8
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000010949 copper Substances 0.000 claims abstract description 4
- 229910052802 copper Inorganic materials 0.000 claims abstract description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- HTRNHWBOBYFTQF-UHFFFAOYSA-N 4-bromo-2-fluoro-1-phenylbenzene Chemical group FC1=CC(Br)=CC=C1C1=CC=CC=C1 HTRNHWBOBYFTQF-UHFFFAOYSA-N 0.000 claims description 6
- GZRMNMGWNKSANY-UHFFFAOYSA-N 4-bromo-2-fluoroaniline Chemical compound NC1=CC=C(Br)C=C1F GZRMNMGWNKSANY-UHFFFAOYSA-N 0.000 claims description 6
- 239000004305 biphenyl Substances 0.000 claims description 6
- 235000010290 biphenyl Nutrition 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical group CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 claims description 3
- CEPCPXLLFXPZGW-UHFFFAOYSA-N 2,4-difluoroaniline Chemical compound NC1=CC=C(F)C=C1F CEPCPXLLFXPZGW-UHFFFAOYSA-N 0.000 claims description 2
- FTZQXOJYPFINKJ-UHFFFAOYSA-N 2-fluoroaniline Chemical compound NC1=CC=CC=C1F FTZQXOJYPFINKJ-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 claims description 2
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- JVHAJKHGPDDEEU-UHFFFAOYSA-N 2,4-difluoro-1-phenylbenzene Chemical group FC1=CC(F)=CC=C1C1=CC=CC=C1 JVHAJKHGPDDEEU-UHFFFAOYSA-N 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 4
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 abstract description 3
- 229960002390 flurbiprofen Drugs 0.000 abstract description 3
- 229940121363 anti-inflammatory agent Drugs 0.000 abstract 1
- 239000002260 anti-inflammatory agent Substances 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 7
- 239000000047 product Substances 0.000 description 5
- 239000002002 slurry Substances 0.000 description 5
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 239000012954 diazonium Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- NTHGIYFSMNNHSC-UHFFFAOYSA-N 3-methylbutyl nitrate Chemical compound CC(C)CCO[N+]([O-])=O NTHGIYFSMNNHSC-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 150000001879 copper Chemical class 0.000 description 2
- 150000001989 diazonium salts Chemical class 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- CSDTZUBPSYWZDX-UHFFFAOYSA-N n-pentyl nitrite Chemical compound CCCCCON=O CSDTZUBPSYWZDX-UHFFFAOYSA-N 0.000 description 2
- 150000002828 nitro derivatives Chemical class 0.000 description 2
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 238000005986 Gomberg-Bachman reaction Methods 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229960003116 amyl nitrite Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 150000005347 biaryls Chemical class 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical compound [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000001030 gas--liquid chromatography Methods 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- GXHFUVWIGNLZSC-UHFFFAOYSA-N meldrum's acid Chemical compound CC1(C)OC(=O)CC(=O)O1 GXHFUVWIGNLZSC-UHFFFAOYSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- YCWSUKQGVSGXJO-NTUHNPAUSA-N nifuroxazide Chemical group C1=CC(O)=CC=C1C(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 YCWSUKQGVSGXJO-NTUHNPAUSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/26—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton
- C07C17/263—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Biphenyl compounds are prepared by coupling an aniline and a benzene in the presence of a C1-6 alkyl nitrite, preferably in the additional presence of copper. The process can be used to prepare 2-fluoro- 4-halobiphenyls which are useful in the preparation of the anti-inflammatory agent flurbiprofen.
Description
1
GB2087 886A 1
SPECIFICATION
Preparing biphenyl compounds by coupling
5 British Patent Application No. 8040295 (Serial No. 2065656) describes and claims a method for converting aromatic, including biphenyl, compounds to 2-arylpropionic acids. Such acids, and in particular 2-(2-fluoro-4-10 biphenylyl)propionic acid which is also known as flurbiprofen, have valuable therapeutic properties.
It is known to form diaryl compounds by the Gomberg or Gomberg-Bachmann reaction 1 5 discussed by March, Advanced Organic Chemistry (McGraw-Hill, 1968) 550-551. However, March noted that "yields are not high (usually under 40%) because of the many side-reations undergone by diazonium 20 salts" which are described as intermediates therein. Cadogan, J. Chem. Soc. (1962) 4257, discloses the use of pentyl nitrite as a diazotising agent, with increasing yields of the named biaryls. More recent references, such 25 as British Patent Specification No.
1,091,403; C.A. 64 (1 966) 5005e; and U.S. Patent Specification No. 3,992,459 disclose various coupling reactions, based on the Gomberg or Gomberg-Bachmann reaction. 30 According to the present invention, a process for preparing a biphenyl compound of the formula
„ 45 wherein R, and R2 are independently selected from hydrogen, halogen, C,^ alkoxy, (C,_4 alkoxy)carbonyl, nitro, C^,, alkyl, C4_7 cyclo-alkyl, phenyl, cyano and (T'OOC)xC(T)3_x wherein x is one or two, T is hydrogen or 50 C, _4 alkyl, the T's being the same or different when x is one, and either each T' is C,_4 alkyl or (COOT')2 forms a cyclic diester; and R3 and R4 are independently selected from hydrogen, hydroxyl, halogen, nitro, Ct_4 alkyl, C,_4 al-55 koxy, (C,^6 alkoxy)carbonyl, aryloxycarbonyl, phenyl, cyano and C4_7 cycloalkyl, which comprises simultaneously adding aC^j alkyl nitrite and an aniline compound of the formula
75 wherein R, and R2 are as defined above, to an excess of a benzene compound of the formula wherein R3 and R4 are as defined above.
85 Preferably, the products of the present invention have the formula
95 in which R1# R2, R3 and R4 are independently selected from hydrogen, chlorine, bromine and fluorine but are not all hydrogen.
The invention is of particular utility in preparing 4-bromo-2-fluorobiphenyl and 2,4-difl-100 uorobiphenyl for which the reactants are benzene and, respectively, 4-bromo-2-fluoroanil-ine and 2,4-difluoroaniline. The products can be used as starting materials for the preparation of flurbiprofen by the process of British 105 Patent Application No. 8040295 (Serial No. 2065656). 4-Bromo-2-fluoroaniline can be prepared by reacting 2-fluoroaniline with a brominating agent in a solvent comprising dimethylformamide or dimethylacetamide, by 110 the process described and claimed in British Patent Application No. 8040291 (Serial No. 2065654). If desired, however, such starting materials may also be prepared by a corresponding reaction in which the solvent is 115 formamide, N-methylformamide, dioxane, di-glyme in ethylene chloride or benzene. The use of benzene has the advantage that the reaction mixture may be used in the coupling reaction of this invention without further puri-120 fication.
The process of this invention may also be used to prepare other precursors of 2-arylpro-pionic acids, e.g. 2-(2-fluoro-4-biphenylyl)-2-methylmalonic acid alkyl esters, including cy-125 clic alkyl esters thereof. Cyclic diesters are 2, 2-di(C! _4 alkyl)-1,3-dioxane-4,6-diones; 2, 2-dimethyl-1,3-dioxane-4,6-dione is preferred.
The alkyl group in the alkyl nitrite may be methyl, ethyl, propyl, butyl, pentyl or hexyl, 1 30 or an isomer thereof. The preferred alkyl m-
2
GB2 087 886A
2
trite is isoamyl nitrite. The process may be conducted by reacting a solution of the aniline compound in excess benzene with the alkyl nitrite, e.g. isoamyl nitrite, in the presence of 5 the benzene compound. The reaction may be conducted at 20 to SOX over a period of 5 to 20 hours. Preferably, isoamyl nitrate and a solution of the aniline compound in benzene are each added dropwise separately but sub-1 0 stantially simultaneously over a period of about 20 hours to an excess amount of the benzene compound while maintaining the temperature at from 25°C to the boiling point of the solvent, preferably about 65°C. 1 5 The reaction may be modified by conducting it in the presence of copper, e.g. in the form of copper powder or a copper salt. If copper powder is chosen, reaction conditions are used which ensure a timely preparation of 20 copper salt in situ.
The biphenyl product is isolated by cooling the reaction mixture, washing, evaporating, distilling or other conventional procedures. A particularly simple and preferred work-up is 25 evaporation and extraction with hexane and washing with 85% sulfuric acid. Crude product is obtained and further purification may not be necessary for the use of the product in making the arylmagnesium bromides to be 30 reacted in the process of British Patent Application No. 8040295 (Serial No. 2065656). However, nitro compounds may be by-prod-ucts in this reaction, so it is advantageous to reduce the reaction mixture by adding iron/ 35 acetic acid mixtures or sodium dithionite, which converts these by-products to amines, such that these can be removed from the product simply by washing with acid. Conditions for the reduction of nitro compounds are 40 similar to those outlined by Faudler et a!.. Organic Functional Group Preparations, Vol. 1, (Academic Press, New York, 1968) 339.
Without wishing to be tied to any theory, it Is believed that the good results which can be 45 achieved by the process of the invention,
relative to conventional Gomberg-Bachman reactions, are the result of the restriction of the "ormation of intermediate diazonium salts and resultant side-reactions. This theory is sup-50 ported by the discovery that the processes of this invention provide an additional advantage in that no precautions are required to avoid explosive decompositions of diazonium salts while preparing and handling large amounts 55 of reaction mixtures.
The following Examples illustrate the invention. The starting material 4-bromo-2-fluoroan-iline can be prepared by the Example of British Patent Application No. 8040291 (Ser-60 .at No. 2065654).
Example 1 4-Bromo-2-fluorobiphenyl
Solutions of 375 ml (325 g, 2.8 moles) of .soamyl nitrite, and of 378 grams (2.0 moles) 65 of crude 4-bromo-2-fluoroaniline in 250 ml benzene are added separately and simultaneously dropwise over about 20 hours to 3500 ml of benzene vigorously stirred under a nitrogen atmosphere, and kept in a water bath at 70 65°C. The mixture is kept overnight at 65°C, and then cooled, washed twice with 250 ml of water and evaporated. The dark oily residue is dissolved in 750 ml methanol and 450 ml concentrated hydrochloric acid, and treated 75 with 138 grams (2.1 moles) of granular zinc, added in small portions over about 6 hours. In order to complete this "reductive upgrading", the solution is treated with 54 grams (1.0 mole) of fine iron filings over 0.5 hours. 80 Within one hour, the colour the mixture is visibly lighter. The solution is diluted with one litre of water and one litre of Skellysolve B (mixed isomeric hexanes), and the liquids are decanted from the remaining metals. The 85 aqueous phase is extracted twice with one litre of Skellysolve B and then one litre of water, one litre of 1N NaOH, and one litre of water. The solution is then passed through anhydrous sodium sulfate and evaporated to 90 provide 389 grams of 4-bromo-2-fluorobiphe-nyl.
This is distilled under vacuum to obtain a fraction of 282 grams (56%) of 2-fluoro-4-bromobiphenyl, b.p. 1 37-155°C./1 1 mm 95 Hg, which crystallises on standing.
Examples 2 and 3
Example 1 is repeated using 50 mmole of 4-bromo-2-fluoroaniline and 79 mmole of iso-100 amyl nitrite, and 76 mmole of trichloroacetic acid and 15 mmole Cu powder are added. The period of addition is 45 minutes and the temperature is 3-1 S°C. In Example 2, 83 mmole of anhydrous MgS04 are added and 105 the yield is 87%. In Example 4, without MgS04, the yield is 88%.
Example 4 4-Bromo-2-fluorobiphenyl
A slurry containing 1.0 grams (15 milli-110 moles) copper powder, 12.5 grams (76.5 millimoles) trichloroacetic acid and 125 millil-itres benzene is stirred at 23-26°C under a nitrogen blanket for 4^ hours. The slurry is cooled to 6°C and 10.5 millilitres (78.5 milli-115 moles) isoamyl nitrate are added. After waiting 90 seconds, a solution containing 9.5 grams (50 millimoles) 4-bromo-2-fluoroanili-ne in 50 millilitres benzene is added dropwise over 30 minutes to the slurry, keeping the 120 temperature of the slurry pot between 8 and 1 7°C. When the addition is complete, the green slurry is allowed to warm to 25°C and is stirred at 23-25°C overnight.
Analysis by gas liquid chromatography 125 shows a chemical yield of 88%.
Claims (1)
1. A process for preparing a biphenyl compound of the formula
3
GB2 087 886A
3
wherein R-, and R2 are independently selected *15 from hydrogen, halogen, alkoxy, (C,_4 alkoxy)carbonyl, nitro, alkyl, C4_7 cycloal-kyl, phenyl, cyano and (T'OOC)xC(T)3_:,
wherein x is one or two, T is hydrogen or C,_4 alkyl, the T's being the same or different 20 when x is one, and either each T' is C,_4 alkyl or (COOT')2 forms a cyclic diester, and R3 and R4 are independently selected from hydrogen, hydroxyl, halogen, nitro, C.,_4 alkyl, C,_4 alkoxy, (C, _ 6 alkoxy)carbonyl, aryloxycarbonyl 25 phenyl, cyano and C4_7 cycloalkyl, which comprises simultaneously adding a alkyl nitrite and an aniline compound of the formula wherein R, and R2 are as defined above, to an excess of a benzene compound of the formula wherein R3 and R4 are as defined above.
2. A process according to claim 1 wherein the biphenyl compound has the formula
50
55 \
R 3 Rz
4. A process according to claim 3 wherein the 4-bromo-2-fluoroaniline has been prepared by reacting 2-fluoroaniline with a brominating agent in a solvent comprising dimethylfor-
70 mamide or dimethylacetamide.
5. A process according to claim 1 for preparing 2,4-difluorobiphenyl, in which the aniline compound is 2,4-difluoroaniline and the benzene compound is benzene.
75 6. A process according to any preceding claim wherein the nitrite is isoamyl nitrite.
7. A process according to any preceding claim which is conducted at from 20 to 80°C.
8. A process according to any preceding
80 claim which is conducted in the absence of water.
9. A process according to any preceding claim which is conducted in the presence of copper.
85 10. A process according to claim 1 substantially as described in any of the Examples.
Printed for Her Majesty's Stationery Office by Burgess & Son (Abingdon) Ltd.—1982.
Published at The Patent Office, 25 Southampton Buildings,
London, WC2A 1AY, from which copies may be obtained.
p~
in which R,, R2, R3 and R4 are independently 60 selected from hydrogen, chlorine, bromine and fluorine, but is not biphenyl itself.
3. A process according to claim 1 for preparing 4-bromo-2-fluorobiphenyl, in which the aniline compound is 4-bromo-2-fluoroanil-65 ine and the benzene compound is benzene.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US10506279A | 1979-12-19 | 1979-12-19 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2087886A true GB2087886A (en) | 1982-06-03 |
| GB2087886B GB2087886B (en) | 1983-06-08 |
Family
ID=22303848
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8040293A Expired GB2065655B (en) | 1979-12-19 | 1980-12-16 | Preparing biphenyl compounds by coupling |
| GB8134869A Expired GB2087886B (en) | 1979-12-19 | 1980-12-16 | Preparing biphenyl compounds by coupling |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8040293A Expired GB2065655B (en) | 1979-12-19 | 1980-12-16 | Preparing biphenyl compounds by coupling |
Country Status (6)
| Country | Link |
|---|---|
| JP (1) | JPS5697236A (en) |
| DE (1) | DE3046512A1 (en) |
| FR (1) | FR2471962A1 (en) |
| GB (2) | GB2065655B (en) |
| IT (1) | IT8050411A0 (en) |
| NL (1) | NL8006497A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101704723B (en) * | 2009-11-02 | 2013-04-24 | 上海万溯化学有限公司 | Preparation method of hydroxymethyl substitutent o-alkyl biphenyl and intermediate thereof |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL8006496A (en) * | 1979-12-19 | 1981-07-16 | Upjohn Co | PROCESS FOR PREPARING ARYL-PROPIONIC ACIDS. |
| DE3216851A1 (en) * | 1981-05-18 | 1982-12-02 | The Upjohn Co., 49001 Kalamazoo, Mich. | METHOD FOR PRODUCING SUBSTITUTED BIPHENYL COMPOUNDS |
| IT1210910B (en) * | 1982-07-23 | 1989-09-29 | Blaschim Spa | IMPROVEMENT OF THE PROCEDURE TO PREPARE BIARYL COMPOUNDS BY COPULATION OF AN ARILAMINE WITH AN ARENE. |
| US4482502A (en) * | 1983-04-25 | 1984-11-13 | Ethyl Corporation | Preparation of biaryl compounds |
| US4539397A (en) * | 1983-04-25 | 1985-09-03 | Ethyl Corporation | (Alkoxydiazo)halobenzeneacetonitriles |
| US4544509A (en) * | 1983-08-15 | 1985-10-01 | Ethyl Corporation | Aryl coupling process |
| FR2811664B1 (en) * | 2000-07-17 | 2002-09-13 | Rhodia Chimie Sa | PROCESS FOR THE PREPARATION OF A POLYAROMATIC COMPOUND |
| CN103936551B (en) * | 2013-01-21 | 2015-10-28 | 北京交通大学 | A kind of method preparing 3-bromo biphenyl |
| CN113620774A (en) * | 2021-08-17 | 2021-11-09 | 上海应用技术大学 | Method for synthesizing biphenyl compounds by adopting microchannel reactor |
| CN116003216B (en) * | 2023-01-17 | 2024-08-06 | 沈阳药科大学 | Preparation method of ibuprofen |
-
1980
- 1980-11-28 NL NL8006497A patent/NL8006497A/en not_active Application Discontinuation
- 1980-12-10 DE DE19803046512 patent/DE3046512A1/en not_active Withdrawn
- 1980-12-16 GB GB8040293A patent/GB2065655B/en not_active Expired
- 1980-12-16 GB GB8134869A patent/GB2087886B/en not_active Expired
- 1980-12-18 IT IT8050411A patent/IT8050411A0/en unknown
- 1980-12-18 FR FR8026939A patent/FR2471962A1/en not_active Withdrawn
- 1980-12-19 JP JP17915280A patent/JPS5697236A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101704723B (en) * | 2009-11-02 | 2013-04-24 | 上海万溯化学有限公司 | Preparation method of hydroxymethyl substitutent o-alkyl biphenyl and intermediate thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| GB2065655A (en) | 1981-07-01 |
| GB2065655B (en) | 1983-07-06 |
| GB2087886B (en) | 1983-06-08 |
| NL8006497A (en) | 1981-07-16 |
| JPS5697236A (en) | 1981-08-05 |
| IT8050411A0 (en) | 1980-12-18 |
| FR2471962A1 (en) | 1981-06-26 |
| DE3046512A1 (en) | 1981-08-27 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |