IL115855A - Process for the preparation of disubstituted benzophenones, their novel intermediates and process for the preparation of said intermediates - Google Patents

Abstract

A process for preparing disubstituted benzophenones of the formula wherein R and R' are independently selected from hydrogen, C1-C6 alkyl, substituted or unsubstituted aryl, alkoxy, aryloxy, halogen, or a group COOR" ', wherein R" ' is hydrogen, C1-C6 alkyl, or substituted or unsubstituted aryl, provided that R and R' are not both fluorine in the para position, comprising the steps of: (a) (1) when R and R' are the same, reacting a compound of the formula 33 ז' באייר התשס" א - April 30, 2001 with an acrylic acid ester of the formula wherein R" is C1 to C8 alkyl in the presence of a palladium, ruthenium, or platinum catalyst, to yield a compound of the formula or, (2) when R and R' are not the same, reacting a compound of formula (II) with a compound of the formula wherein R' and R" are as hereinbefore described in the presence of a palladium, ruthenium, platinum catalyst to yield a compound of the formula (III); (b) preferably, converting the said compound of formula (III) into a derivative of the formula 34 ז' באייר התשס" א - April 30, 2001 wherein R and R' are as defined above, and R" is H, CH3 or Na; and (c) oxidizing the said compound of formula (III) obtained from step (a), or the said derivative thereof of formula (IIIa), to yield the corresponding disubstituted benzophenone. Intermediates of formula (III) wherein, either R and R' are identical and selected from F, -O-C6H5, -C6H5, Br-C6H4 - and H2N-C6H4 - provided that R and R' are not both F in the para position or R and R' are non identical and R is F, OCH3, CH3 or COOR" ', wherein R" ' is hydrogen, C1-C6 alkyl, or substituted or unsubstituted aryl; and R' is p-CH3O-C6H4-, p-CH3-C6H4-, or -O-C6H5;- and R" is H, C1-C8 alkyl, or Na are claimed as novel.

Description

115855/2 Τ7Π3Π /ππ7ω Ό"·ωττι WTI ■nnm Λπηιηη-π ETnaim Π.3Π7 Τ7πη Π7« Γττη τ ππ ηηπ"7 PROCESS FOR THE PREPARATION OF DISUBSTITUTED BENZOPHENONES, THEIR NOVEL INTERMEDIATES AND PROCESS FOR THE PREPARATION OF SAID INTERMEDIATES 3125/94 115855/2 -1- Field of The Invention The present invention relates to a process for preparing disubstituted benzophenones, and to novel intermediate compounds therefor.

BACKGROUND OF THE INVENTION Disubstituted benzophenones are important materials having a variety of uses and applications. For instance, 4,4'-difluorobenzophenone (DFBF) is used as a precursor for high performance polymers, e.g., polyether ketones, as well as pharmaceuticals, e.g. Lidoflazine, Mioflazine, Funarizine and Fluspirilene; 4,4'-diphenoxybenzophenone (DPBP) is used as a monomer for the preparation of poly(arylene ether ketones), and the 4,4'-diarylbenzophenones are candidates for a variety of polymers.

The Prior Art According to the known art, compounds of this type are prepared in a variety of ways, all of which are expensive and complicated. For instance, JP 61-22146 [C.A. 106. 66911m] discloses the reaction of fluorobenzene with CO in the presence of O2, using a catalytic system comprising PdCl2 and FeCl3. JP 61-172845 [CA. 106, 32580η], and JP 61-183245 [CA. 106, 4659b] describe the preparation of DFBP from difluorodiphenylmethane via oxidation, using a variety of oxidizing reagents. JP 61-47438 [CA. 105, 114737η] relates to the preparation of 4-fluoro-dibenzophenone from 4-chloro-dibenzophenone. JP 2- 240042 and EP 178,184 disclose a Friedel Crafts reaction, employing 3125/94 115855/2 -2- AICI3 and LiCl as the catalysts, between p-fluorobenzoylchloride and fluorobenzene as the main reaction components. EP 323,897 and US 3,366,601 describe the production of DPBP in a similar manner by the reaction between two molecules of diphenylether and CO2, in the presence of a Friedel- Crafts catalyst and promoter such as POCI3 or phosgene. Other related reactions are disclosed in the following references: EP 147,299, relating to a catalyzed reaction between COCI2 and fluorobenzene; EP 4710, describing the preparation of DFBP from diaminodiphenylme thane, a known carcinogen; JP 2-40340 [C.A. 113, 23373q] relates to the oxidation of 1,1-diarylethylene with HNO3; EP 395,446 concerns coupling reactions; FR 2,647,107 describes the preparation of DFBP from diphenylcarbonate in the presence of HF/SbF5; and FR 2,647,108 relates to the electrophilic attack of fluorobenzene by acylhaloformate.

It has now been found, and this is an object of the present invention, that it is possible to prepare disubstituted benzophenones by a simple and economic coupling process using inexpensive starting materials, to obtain a highly pure product in high yields.

SUMMARY OF THE INVENTION The process for preparing disubstituted benzophenones of formula (I): 94 Π5355/4 -3- wherein E and R* are independazitl -selected from H, Cz-C$ alkyl, STibatrttctad or unsxibstitutad aryl, al&txsy, arylaxy, halogen, or & group COOS'", wherein Rm is hydrogen, C1-Ce alkyl, or substituted or unsubstituted aryl provided that R and R' are not both fluorine in the para position , according to the invention, is iUustrated by the following scheme: optional acidification oxirtarion or trans* esteri&at!on iyt^ comprises the steps of (a) (1) when R and £' are the same, reacting a compound of formula (Π) wherein R is as defined above with an acrylate of formula (TV): 3125/94 115855/2 -4- wherein R" is to Cg alkyl, H or Na in the presence of a supported or unsupported catalyst selected from Ru, Pd and Pt, to yield a compound of formula III: or, (2) when R and R' are not the same, reacting a compound of formula V: wherein R* and R" as defined above with a compound of formula II, in the presence of a supported or unsupported catalyst selected from Ru, Pd and Pt, to yield a compound of formula III; 3125/94 115855/2 -δ- (b) preferably, converting the said compovmd of formula (III) into a derivative of formula (Ilia): wherein R" may be H, CH3 or Na; and (c) oxidizing the said compound of formula (III) obtained from step (a), or the said derivative thereof of formula (Ilia) obtained from step (b), to yield the corresponding disubstituted benzophenone of formula (I).

Brief Description of the Drawings Fig. 1 is the !H-NMR of 3,3'-bis-(p-fluorophenyl) octyl acrylate, obtained from its mixture with the undesired isomer bis-2,3'-(p- fluorophenyl) octyl acrylate; Fig. 2 is the GC of the same product as in Fig. 1; Fig 3 is the mass spectrum of 3,3'-bis-(p-fluorophenyl) octyl acrylate; Fig. 4 is the !H-NMR of 3,3'-bis-(p-fluorophenyl) acrylic acid; 3125/94 115855/2 -6- Fig. 5 is the 1H-NMR of 4,4'-difluoro-benzophenone, in CDC13, Fig. 5(b) being an enlargement of Fig. 5(a).

Detailed Description of Preferred Embodiments According to a preferred embodiment of the invention, the catalyst is selected from the group consisting of Ru, Pd and Pt. Preferably the catalyst is palladium or ruthenium, more preferably the catalyst is supported on carbon, preferably a 0.4 wt. to 5 wt.% Pd/C or 0.4 wt.% to 5 wt.% Ru/C catalyst, or the catalyst is an unsupported palladium salt, e.g. PdCl2, PdBr2, or palladium acetate, optionally in the presence of tertiary phosphines. The reaction is preferably carried out in an aprotic solvent, more preferably in N-methylpyrrolidone.

In order to neutralize hydrogen bromide (HBr) liberated during the coupling reaction, the reaction medium further comprises a base such as Na2CC>3 or triethylamine. Optionally, an antioxidant, such as BHT (2,6-di-tert-butyl-p-cresol) or methylhydroquinone, can also be added in amounts of about 1%, to avoid polymerization of the acrylate via a free radical mechanism.

In order for the coupling reaction to proceed at an acceptable speed, it is preferred to carry it out at a temperature between 130°C and 200°C, more preferably between 150°C and 160°C. At lower temperatures the reaction may proceed more slowly than at higher temperatures; the skilled person will appreciate when raising the temperature will be necessary for the reaction to proceed at a desirable rate.

In the consecutive step, oxidation of the intermediate of formula (III), or preferably (Ilia), can be carried out in any convenient way which does not give rise to undesirable side-reactions. In an embodiment of -7- Π5355 3 the invention, oxidation of the compound of formula (ΓΕΓ) is (.arrzed out by catalytic reaction with oxygen. Conveniently, the reaction can be carried ont in air as the rm mrtg environment, optionally enriching it with oxygen. Suitable oxygenation catalysts will be apparent to the skilled chemist. An example of snch catalytic systems are those containing mixtures of Co and Mn cations, optionally together with bromide. Other examples of oxidation processes of compounds of formula (HE) and (Ilia) are the reaction of these compounds with nitric acid, typically m a 70% aqueous solution, , as well as the reaction of these compounds with a suitable catalyst and reagents containing active chlorine, for example NaOCl (which has low environmental impact) in the presence of Ru(¾ or Ru02« The compounds of formula (ΕΠ): wherein, either R and R* are identical and selected from F, -O-CgHg, -CgHg, Br-Cel-U- and H2N-C6H4- provided that R and R' axe not both F in the para position ox R and R' are nan identical and R is F, OCH3, CH3 or COOR'M, wherein Rm is hydrogen, Ci-Ce al¾rl, or substituted or tmsubstrtuted aryl; and R' is P-CH3O-C6H4-, p-CHs-Celk-,- or -Ο-ΟβΗδ,'- andR" is H, Ci-Cg aUcyl, or a. -7a- The compounds of formula (ΙΠ) are prepared, as noted, by reacting compound of formula (II) with an acrylate in the presence of a transition metal catalyst. Compounds of formula (Π) are .known per se.

The derivatives of the formula (ID) compound, having the formula wherein B ancLE' are as defined above, andB" is Ξ, CH3 ox Na; are also novel compounds, and thus also form a part of the invention. These compounds are obtained by saponification, acidification and esterification reactions, starting from the formula (HI) compounds, as will be exemplified hereinafter, and by means known to the skilled chemist which, therefore, are not discussed here in, detail, for the sake ofbrevity: Examples The above and other characteristics and advantages of the invention will be better understood through the following illustrative and non-limitative description of preferred embodiments.

The following nomenclature is used throughout this description: pFBB: j?cra-fluorobromobenzene mFBB: jneia-fluorobromobenzene BDPE: bromodiphenyiether BFPAA: bis(fluorophenyl) acrylic acid DFBP: difLuorobenzophenone 3,4'-DFBP 3,4'-difluorobenzophenone DFOA: 3,3'-bis-(p-fluorophenyl)octyl acrylate DFPSA: 3,3'-bis-(p-fluorophenyl)sodi m acrylate salt DPBP: diphenoxybenzophenone DTBP: ditolylbenzophenone DCBP : dicarboxybenzophenone FMeBP: 4-fluoro-4'-methylbenzophenone FMBP: 4-fluoro-4'-methoxybenzophenone PFBP: 4-fluoro-4'-benzoxyphenone BBBP: bis-biphenybenzophenone OMe: -OCH3 EtOH: ethanol EtOAc: ethyl acetate MA: methylacrylate OA: octylacrylate BHT: (2,6-di-tert-butyl-p-cresol) MEK: methylethylketone OFC: octylfluorocinnamate OMC: octyl-4-methoxy cinnamate FPBP: (4-fluorophenyl-4'-phenoxy)benzophenone HPLC: high-performance liquid chromatography DSC: differential scanning calorimetry GC: gas chromatography DCM: dichloromethane NMR: nuclear magnetic resonance NMP: N-methyl-pyrrolidone -10- AcOH: acetic acid EDC: dichloroethane Example 1 Preparation of p-FBB using Fe powder Fluorobenzene (250 g, 2.6 mmol) and 2.5 g Fe powder were placed into a 1 liter round bottom flask equipped with an efficient stirrer. The mixture was cooled to 10°C and bromine (416 g, 2.6 mmol) was fed in over 2 hrs. After 10% of the bromine was added, HBr started to evolve and the temperature rose to 19°C. During the rest of the addition the temperature was kept below 25°C. After all the bromine had been added the reaction mixture was stirred at this temperature for a further 1 hr. Traces of bromine were decomposed with ~25 ml of 1 molar aq. sodium sulfite, then 200 ml of water was added. The lower organic phase was separated to give 438 g (96% yield) of pFBB containing 1.7% of the ortho isomer.

Example 2 Preparation of p-FBB using FeCla Fluorobenzene (250 g, 2.6 mol) and 2.5 g FeCl3 were placed into a 1 liter round bottom flask equipped with a mechanical stirrer. The mixture was cooled to 5°C and bromine (416 g, 2.6 mol) was fed in over 2 hrs. During the addition the temperature was kept at 5°C. Traces of bromine were decomposed with ~25 ml of 1 molar aq. sodium sulfite and 100 ml of water was added. The lower organic phase was separated to give 442 g (97% yield) of pFBB containing 1.5% of the ortho isomer. -11- Example 3 Preparation of 4.4'-difluorobenzophenone (DFBP) Step A: Preparation of 3,3'-bis-(p-fluorophenyl)octyl acryiate (DFOA) Preparation 1 (Pd/C catalyst): This preparation was effected by coupling between pFBB and octyl acryiate (OA) in a ratio of 2:1. 350 g pFBB (2 mol), 184 g OA (2 mol), 110 g anhydrous sodium carbonate (1.04 mol), 4 g BHT, 23 g Pd/C (Pd content 0.43%) and 692 ml NMP (ratio pFBB/[pFBB + OA + NMP] = 32% v/v) were charged into a 2-liter, 5-necked flask. The contents were flushed with N2 for 15 min. at room temperature then heated gradually to 151°C (the b.p. of pFBB) under vigorous mechanical stirring (450-500 rpm). The total duration of the process, to completion, was 6-10 hrs.

The reaction progress was monitored by GC, the samples being quenched in aq. acid and extracted with EtOAc.

After the reaction was completed, determined by the absence of octylfluorocinnamate (OFC) in the reaction mixture, the mixture was cooled to 60-80°C and filtered to remove the catalyst, unreacted Na2CO3 and NaBr produced. The filter cake was further washed with 100 ml NMP and the filtrate evaporated under reduced pressure to recover the solvent together with unreacted pFBB.

The residue was subjected to high vacuum distillation where the major fraction was collected at 188-200°C/0.4-0.6 mbar, to give 90% of the desired isomer (DFOA) and 3% of a by-product isomer, bis-2,3'-(p-fluorophenyl)octyl acryiate. -12- The Pd/C catalyst was separated from the inorganic salt by means of a The NMR spectrum of this intermediate is shown in Fig. 1, its mass-spectra in Fig. 2, and its GC spectrum in Fig. 3, along with the undesired 2,3-isomer.

Preparation 2 (PdCL catalyst): A mixture of 35 g pFBB (0.2 mol), 22 g OA (0.12 mol), 10.6 g Na2CO3, and 5.7 mg PdCl2 (0.028 mmol), in 53 ml NMP, was heated to 150°C under nitrogen and with vigorous stirring. After 6 hours, the conversion was 75%, based on pFBB according to GC. GC of the crude reaction mixture revealed a composition of OFC 5.5%, DFOA 77%, pFBB 12.5%. Work-up was as described in Preparation 1.

Step B: Preparation of 3,3'-bis-(p-fluorophenyl) sodium acrylate (DFPSA) The crude reaction mixture from Step A, after removal of the volatiles, was subjected to alkaline hydrolysis as follows: A mixture of the above residue (~1 mol crude ester), 150 ml ethanol, 250 ml water and 40 g NaOH (1 mol) was heated to 80°C for 3 hrs. The reaction mixture was cooled to room temperature under vigorous stirring upon which a heavy crystalline precipitate occurred.

The mixture was filtered and washed with 100 ml distilled water, and 2 x 100 ml ethyl acetate leading to a decolorization of the solid. This -13- precipitate was designated "crop a", and comprised 227.9 g, (representing a yield of 80.8%) of m.p. 105-106°C.

Evaporation of the filtrate (mainly the EtOAc layer) led to a further deposition of the acrylate salt, designated "crop b", in a purity of 89.4% and a yield of 13.6%.

The sodium salt can be easily recrystallized from hot water to give very pure material (determined by acid-base titration) in a yield of close to 80%. Acidification of the aqueous layer of the evaporated filtrate can improve the total yield of the acrylate (in the form of the acid), by 7%. Acidification of the above salt with an aq. acid (such as HC1 or HBr) leads quantitatively to the correspond ng acid 3,3'-bis-(p-fluorophenyl) acrylic acid.

Step C; Oxidation of 3,3'-bis-(p-fluorophenyl) sodium acrylate (DFPSA) with 70% HNO3 at atmospheric pressure.

A reactor, equipped with a condenser and a strong mechanical stirrer and attached to a gas-trap (scrubber charged with NaOH), was placed in a cooling bath and charged with 210 ml HNO3 (70%). 141 g (0.5 M) DFPSA was gradually added to the vigorously stirred acid, in portions, while maintaining the internal temperature in the range 20-39°C. The duration of the salt addition was 2.5 hrs. The resultant suspension was stirred for 1.5 hrs at 20°C. At this stage, a GC of the crude product (after extraction with DCM), indicated the following composition: DFBP 62.4% 4,4'-p-Difluoro-benzil 1.8% Mono-nitro derivative 26.3% -14- Di-nitro derivative 2.6% Difluorophenyl octylacrylate 1.2% The liquid phase was pumped out of the reactor and the remaining solids were refluxed with 200 ml aq. Na2CC>3 (21.2 g) for 4 hrs. The reaction mixture was cooled to room temperature and the powdered solids were filtered and washed with distilled water. At this stage, GC of the mixture revealed the following composition: DFBP 95.0% 4,4'-p-Difluoro-benzil 1.9% Mono-nitro derivative 1.8% Di-nitro derivative 0.8% Crystallization of the crude solid, from ethanol/water (95:5) yielded crop a: 51 g (47% yield) of a pure product (100% purity, by HPLC and DSC).

Extraction of the aq. filtrate with EtOAc yielded 25.4 g crude material containing 36.6% DFBP, 12% Di-F-benzil and ~20% mono-and di-nitro derivatives.

The NMR spectrum of DFBP so obtained is shown in Fig. 5. ~ Example 4 Preparation of 3.3'-bis-(p-fluorophenvnacrylic acid (BFPAA) 3,3'-bis-(p-fluorophenyl) sodium acrylate was suspended in water and acidified to pH = 1. After stirring for one hour, the mixture was filtered, and the solid washed with water and then dried. The recovery -15- of acid from the sodium salt was quantitative. The NMR spectrum of this compound is shown in Fig. 4.

Example 5 Oxidation of 3.3'-bis-(p-fluorophenyl) acrylic acid (BFPAA) with air A mixture of BFPAA (20.6 g, 79 mmol), cobalt acetate tetrahydrate (800 mg, 3.2 mmol), manganese acetate tetrahydrate (200 mg, 0.8 mmol), 47% aqueous HBr (396 mg, 2.3 mmol) and AcOH (0.2% water, 160 ml) was heated to 160°C under a stream of air at 200 psi in a 450 ml PARR Titanium Pressure Reactor. Methyl ethyl ketone (MEK - 16 ml, 178 mmol) in AcOH (20 ml) was added via a high pressure metering pump (ELDEX B-100-S2) over 3 hrs. Good oxygen absorption was observed - down to 9-11% O2 in the exit gas - during the addition of the MEK. One and a half hrs after completion of the MEK addition the exit gas contained 20% oxygen and a sample of the reaction mixture was examined by GC. The reaction mixture at this time contained: 6.1% fluorobenzoic acid, 92.5% DFBP and 0.1% BFPAA.

The reaction mixture was evaporated (60°C/30 mm Hg) to remove the HOAc solvent and 100 ml water was added. The mixture was stirred and heated to 60°C for one hour after which it was cooled and the solid was collected by filtration and dried. This solid contained 11 ppm Co and 5 ppm Mn and was identified as DFBP by GC-MS (M+ = 218) and proton NMR (7.15 ppm, t, 4H, JRH = JHF = 8.6 Hz and 7.77-7.84 ppm, dd, 4H, JRH = 8.6 Hz, JRF = 5.5 Hz - see Figs. 5a, 5b). The yield of isolated product was 14.9 g (86%). From the aqueous washings, 0.35 g of a precipitate of 4-fluorobenzoic acid was obtained (3% yield). -16- Example 6 Oxidation of S.B'-bis-fp-fluorophenvDoctyl acrylate (Octyl BFPAA) This example shows that it is possible to oxidize the octyl (2-ethylhexyl) ester of BFPAA directly to DFBP without the use of MEK. It is assumed that the octyl chain co-oxidizes during the oxidation and provides a steady source of peroxides (which, in the absence of the octyl chain, are supplied by the co-oxidation of added MEK).

A mixture of Octyl BFPAA (31 g, 83.3 mmol), cobalt acetate tetrahydrate (800 mg, 3.2 mmol), manganese acetate tetrahydrate (200 mg, 0.8 mmol), 47% aqueous HBr (396 mg, 2.3 mmol) and AcOH (0.2% water, 160 ml), was heated to 140°C under a stream of air at 500 psi in a 450 ml PARR Titanium Pressure Reactor. Very strong oxygen absorption was observed -down to only 1.5-2.0% O2 in the exit gas -over a period of 20 minutes only, and then the oxygen concentration began to rise. One and a half hours later the exit gas contained 18% oxygen and a sample of the reaction mixture was examined by GC. The reaction mixture at this time contained: 1.1% fluorobenzoic acid, 21.7% DFBP, 4.9% BFPAA and 43.6% octyl BFPAA. The temperature was now raised to 165°C over 15 minutes, and strong oxygen absorption was again observed -down to 4-6% O2 in the exit gas. After another 3 hours, the oxygen content of the exit gas was 13% and a GC sample of the reaction mixture showed: 6.7% fluorobenzoic acid, 82.3% DFBP, 2.6% BFPAA and 0.1% Octyl BFPAA. -17- Example 7 Oxidation of 3.3'-bis(p-fluorophenyl) sodium salt (DFPSA) with NaOCl in the presence of RuCla 141 g of DFPSA (0.5 mole) was added portionwise to 1450 ml NaOCl solution (10.7%, 2 mole) containing 94 mg RuCl32]¾0 (0.38 mmols), over 1-2 hours, while maintaining the temperature of the reaction mixture in the range 29-45°C.

After completion of the addition, all of the starting material was consumed and uncalibrated GC analysis revealed 97.5% of the desired product (DFBP).

The crude solid was purified by continuous liquid-solid extraction (in a Soxhlet apparatus) using ethanol: water (95:5) as the solvent. Cooling, followed by filtration of the receiver contents, produced 98.7 g DFBP (with a purity of 99.4% by DSC) in a yield of 90.5%.

Example 8: Preparation of octyl 3.3'-bis(p- fluorophenvDacrylate using Ru/C as catalyst A 250 ml glass reactor was charged with 28 g (0.16 mol) pFBB, 16.6 g OA (0.08 mol), 8.8 g anhydrous Na2C03, 0.08 g BHT, 0.65 g Ru/C (2.5% Ru), and 32 ml NMP. The vessel was flushed with nitrogen for 15 min., and the mixture was then heated to 150 °C with vigorous stirring and maintained at this temperature. Samples were withdrawn from the reaction mixture at fixed intervals for GC analysis. After 12 hours, the reaction mixture contained 9.7% of the required product and 60% of the mono adduct (octyl 3-(4'-fluorophenyl)acrylate). -18- Example 9 Synthesis of 4.4'-Ditolylbenzophenone (DTBP): Step A: Synthesis Of octyl 3,3'-bis(p-tolyl)acrylate (OBTA) A mixture of 4-bromotoluene (34 g, 198.8 mmol), OA (20.8 ml, 100 mmol), Na2CO3 (10.6 g, 100 mmol), BHT (0.2 g), 2% Pd C (530 mg) and NMP (30 ml) was flushed with N2 for 15 minutes. The mixture was heated to 180 °C for 7 hours to give 6.2% unreacted bromotoluene, ca. 1.5% octyl 4-methylcinnamate and 85% OBTA.

Step B: Oxidation of OBTA with 70% HNO3 at room temperature A solution of OBTA (5.11 g) in 10 ml EDC was stirred with 10 ml 70% HNO3 at room temperature for 2.5 hr. The major product of this oxidation was identified as the mononitro derivative (by NMR and GC/MS), accompanied with ca. 5% 4,4'-dimethylbenzophenone. Carrying out the reaction at 110-130°C led almost exclusively to the desired DTBP (purified by crystallization from ethanol/H2O 95:5). -19- Step C: Oxidation of sodium 3,3'-bis(p-tolyl)acrylate with NaOCl Sodium 3,3'-bis(4-tolyl)acrylate (27.4 g, 100 mmol), obtained from OBTA by the method of Example 3, Step B, was added portionwise to 400 ml 10% NaOCl solution containing 28 mg RuCl3.nH20 (n varying according to supplier). The temperature rose to 48-49°C. The white suspension was filtered to give 70% DTBP together with 27.1% 2,2*-bis(4-tolyl)vinyl chloride. DTBP was crystallized from hexane.

Example 10 Preparation of 4.4,-dicarboxybenzophenone (DCBP) bv oxidation of 3.3'-bis(p-tolyl)acrylic acid with air A mixture of 3,3'-bis(p-tolyl)acrylic acid (24.5 g, 89 mmol) (obtained by acidification of the sodium salt in a manner analogous to Example 4), cobalt acetate tetrahydrate (1000 mg, 4 mmol), manganese acetate tetrahydrate (250 mg, 1 mmol), monobromoacetic acid (70 mg, 0.5 mmol), MEK (0.4 g, 0.5 mmol) and AcOH (0.2% water, 180 ml) was place in a 450 ml PARR Titanium Pressure Reactor, pressurized with air to 200 psi and then heated to 160 °C. The stirrer speed was set at 700 rpm. After stabilization of the temperature at 160 °C, air was passed through the reactor (via a dip-tube) at 600 ml/min. Samples were periodically removed from the reactor. After 5 hours, complete conversion of the starting material was achieved. Crystallization from the cold reaction mixture yielded a white solid (23.5 g) containing (HPLC) DCBP (43%), terephthalic acid (38%) and several unidentified by-products. The two major components were identified by esterification of the products with acidic methanol and examination of the esterified products by GC-MS and proton NMR. -20- Example 11 Preparation of 4.4'-diphenoxybenzophenone (DPBP): Step A: Preparation of octyl-3,3'-bis(4-phenoxyphenyl)acrylate (DPPOA) by the coupling of 4-bromodiphenyl ether (BDPE) and octyl acrylate: A mixture of BDPE (249 g, 1.0 mol, purity of 95%), OA (104 ml, 0.5 mol), Na2CO3 (56 g, 0.53 mol), 0.5% Pd/C (2.70 g, 0.14 mmol) and NMP (640 ml) were charged into a two liter 4-necked reactor. The reactor was heated to 180°C under an N2 atmosphere for 5 hours. The crude reaction mixture contained 1.48% unreacted BDPE, 0.1% mono adduct, and 93.4% DPPOA, as determined by GC. The contents of the reactor were cooled to 80 °C and filtered through a sintered glass filter. The residual cake contained Na2CO3, NaBr and catalyst. The filtrate was evaporated under reduced pressure to give a viscous, oily residue which was subjected to the next stage without further treatment.

Step B: Alkaline hydrolysis of DPPOA to sodium 3,3'-bis(4-phenoxyphenyl)acrylate The oily residue from Step A was dissolved in 90 ml absolute EtOH and 120 ml H2O. NaOH (24 g, 0.6 mol) was added and the mixture refluxed for 2 hours. The EtOH was then evaporated under reduced pressure. It is possible to isolate the salt as a solid by removal of the water and released octanol. The salt can be crystallized from hot water. -21- Step C; Oxidation of sodium 3,3'-bis(4-phenoxyphenyl)acrylate with NaOCl to DPBP The Na salt from Step B (28.3 g, 66 mmol) was added portionwise to a solution of NaOCl (342 ml, active chlorine=6.4%) containing RuCl3.nH20 (0.17 mmol, n varying according to supplier). The exothermic reaction raised the temperature from 22°C to 50°C. The solids were separated by filtration to give 27.4 g wet material (92% purity by uncalibrated GC). The product was purified by continuous extraction (Soxhlet) using 200 ml EtOAc, to yield 14 g DPBP (58%) with a purity of 96-97%. The m.p. was 147.5-148.0°C.

Step D: Preparation of DPBP via ozonolysis of DPPOA A solution of DPPOA (20 g) in DCM was stirred at -50 to -60°C as ozone was passed through the solution. After two hours, the initially light brown mixture acquired the characteristic blue-gray color of ozone. Oxygen was then passed through for 20 minutes. The reaction mixture was treated with 3 ml of triethylamine (quenching agent), contacted with 5% aqueous NaHS03 and the phases were separated. The DCM product layer was passed through Celite and the DCM was removed by distillation under reduced pressure to leave a crude product containing (GC) 87% of the desired product. Purification of the material was performed by crystallization from hot EtOAc to give 10.3 g of the ketone (71% isolated yield) with a purity of 97%.

Step E: Preparation of DPBP by oxidation of DPPOA with air A mixture of DPPOA (32.3 g, 62 mmol), cobalt acetate tetrahydrate (800 mg, 3.2 mmol), manganese acetate tetrahydrate (200 mg, 0.8 mmol) 47% aqueous HBr (417 mg, 2.4 mmol), MEK (1 ml, 11 mmol) -22- and AcOH (0.2% water, 120 ml) was placed in a PARR Titanium Pressure Reactor, flushed with nitrogen, pressurized with this gas to 200 psi and then heated to 160°C. After stabilization of the temperature at 160°C, air was slowly fed through the reactor (via a dip-tube) at 600 ml/min. An exothermic reaction commenced within 20 minutes, and strong oxygen absorption was observed as evidenced by the presence of only 2-4% oxygen in the exit gas. After one hour, the oxygen content of the exit gas was 1.7% and, after another 5 minutes, the exit gas oxygen content had risen to 2.9%. The air pressure was then raised to 500 psi in order to complete the oxidation. After another 40 minutes, the exit gas oxygen content had risen to 10% and, after a further 3 hours, the exit gas oxygen content was steady at 19%. The air flow was then stopped and the reactor was flushed with nitrogen, cooled to 100°C and depressurized. The reaction mixture contained 6% unreacted starting material, 86% DPBP and 2% 4-phenoxybenzoic acid (cleavage product from the benzophenone). Mixture components were identified by GC-MS.

Example 12: Production of 4-fluoro-4-methoxybenzophenone (FMBP) Step A: Heck Reaction between 4-bromofluorobenzene (pFBB) and Octyl 4-methoxycinnamate (OMC) A mixture of OMC (145 g, 0.5 mol), pFBB (87.5 g, 0.5 mol), Na2CO3 (27.5 g, 259 mmol), BHT (1 g), 0.5% Pd/C (3.1 g) and NMP (400 ml) was heated under N2 at 151 °C for 10 hours. A mixture of Z and E isomers of octyl 2-(4'-fluorophenyl)-2-(4-methoxyphenyl)acrylate (1:1 ratio) was obtained with a conversion of 95%, based on the initial OMC concentration. The reaction mixture was allowed to cool to room temperature, the solids (Na2CO3, NaBr and Pd/C) were filtered off and -23- the solvent was evaporated under reduced pressure. The residue was subjected to alkaline hydrolysis without further purification.

Step B: Alkaline hydrolysis to sodium 2-(p-fluorophenyl)-2-(p-methoxyphenyl)acrylate The residue from Step A was dissolved in a mixture of 75 ml EtOH and 175 ml H2O, and then treated with 29.5 g NaOH for 2 hours at reflux. The liquids (EtOH, H2O, octanol) were then removed to leave a paste. Crystallization from this paste in 400 ml of hot water gave the desired sodium salt as a mixture of E and Z isomers.

Step C: Oxidation of sodium 2-(p-fluorophenyl)-2-(p-methoxy-phenyl)acrylate with NaOCl The sodium salt of Step B (57.8 g, 196 mmol) was added portionwise to a solution of 8% NaOCl (750 ml) and RuO2 (56 mg, 0.4 mmol). The exothermic reaction raised the temperature from 22°C to 50 °C. Pure FMBP (25.8 g, 112 mmol, 57% yield) was obtained after crystallization from EtOH/H2O 95:5. The m.p. was 93.2°C and the spectral results (NMR, GC, GC/MS) were compatible with the required structure.

Example 13: Production of 4.4,-(biphenyl)benzophenone Step A: Preparation of 3,3'-bis-(4-biphenyl)octyl acrylate A mixture of 4-bromobiphenyl (46.6 g, 0.2 mol), OA (20 g, 0.11 mol), Na2CO3 (11 g), 0.5%-Pd/C (2.43 g) and BHT (1 g) in NMP (79 ml) was heated for 6 hours at 180° C. Uncalibrated GC showed this gave 91.6% of the desired bis-adduct and 3.5% of a 2',3-product, together with 1.5% bromobiphenyl. Work-up of the reaction mixture was the same as in Example 3, Step A. -24- Step B: Alkaline hydrolysis to sodium 3,3'-bis-(4-biphenyl) acrylate Hydrolysis was carried out on the residue resulting from Step A (55.35 g) using 54 g NaOH, 30 ml ethanol and 50 ml water, at 70°C for 6 hours. The Na salt was transferred to the next step.

Step C; Oxidation with an RuC13/NaOCl system Oxidation of the corresponding Na salt with an RuC13/NaOCl system analogous to Example 11, Step C, gave a yellowish solid material. This was further purified by recrystallization from ethyl acetate to give a product with 91% isomeric purity, m.p. 237.5°C.

Example 14 Preparation of 3.4'difluorobenzophenone (3.4 -DFBP) Step A: Preparation of 3,3'-(p-fluorophenyl)-(m-fluorophenyl)-octylacrylate.

A mixture of m-fluorobromobenzene (mFBB, 17.5 g, 0.1 mol)), OFC (27.8 g, 0.1 M), Na2CO3 (5.6 g, 0.05 mol), and 5%-Pd/C (1.05 g), in NMP (85 ml) was heated to 150-160°C for 25 hours. GC shows the presence of 3.2% m-FBB, 4.6% OFC, 84.3% bis-adduct and 3.2% of the isomeric bis-adduct in the crude product mixture. Work-up was performed according to the procedure given in Step A of Example 3.

Step B: Alkaline Hydrolysis 3,3'-(p-fluorophenyl)-(m-fluorophenyl)octylacrylate was hydrolyzed to sodium 3,3'-(p-fluorophenyl)-(m-fluorophenyl)acrylate in a mixture of NaOH, H2O, and EtOH (relative ratios 5:25:25 g) at 80°C for 2.5 hours. After removal of most of the liquid (ethanol and 2-ethyl hexanol) by vacuum distillation, the residue was subjected to oxidation. -25- Step C: Oxidation The residue from Step B was redissolved in 75 ml H20 and slowly added to 125 ml NaOCl (12%) in which 13 mg of Ru02 was predissolved. The temperature of the oxidation medium was raised to 60-70°C. The precipitate formed was filtered and crystallized from ethanol-H20 to give 3,4'-DFBP at 96% purity, m.p. 55.7°C. IH-NMR and GC/MS spectra confirmed the structure of the product.

Example 15; Preparation of (4-fluorophenyl-4'-phenoxy)benzophenone (FPBP) Step A: Preparation of 3,3'-(p-fluorophenyl)(p-phenoxyphenyl) octylacr late A mixture of OFC (125 g, 0.5 mol), p-BDPE (139 g, 0.5 mol) and 0.5% Pd C catalyst (1.6 g) in NMP (400 ml) was heated to 180°C for 2 hours. The conversion was >98% based on GC and the crude reaction product showed the presence of Z&E isomers of the product in a ratio of 32/60. Work-up was per Step A, Example 3. !H-NMR as well as GC/MS of the isomeric mixture confirmed the structure of the product.

Step B: Alkaline hydrolysis to sodium 3,3'-(p-fluorophenyl)(p-phenoxyphenyl)acrylate Alkaline hydrolysis of the crude product from Step A was carried out in a manner analogous to that of Example 3, Step B.

Step C: Oxidation of sodium 3,3'-(p-fluorophenyl)(p-phenoxy-phenyl)acrylate Ten grams of the salt (0.11 mol) were added portionwise to a solution of NaOCl 9.2% (90 ml) and 0.0116 g of RuCl3 (keeping the ratio of the -26- salt/Ru=500). Filtration of the product followed by crystallization from hot EtOAc gave FPBP in a purity >97%, m.p. 101.8°C.

Example 16 Preparation of methylfluorocinnamate Procedure 1: A mixture of pFBB (35 g, 0.2 mol), MA (10.3 g, 0.12 mol), Na2C03 (11.2 g, 0.11 mol) and PdCl2 (5 mg, 2.82 x 10-5 mol) in NMP (38 ml) was heated in a three-necked flask in an oil bath at 125°C for 6 hours; GC of the crude reaction mixture shows the presence of the monomelic adduct (methylfluorocinnamate=MFC) together with the desired double adduct in a ratio of 24.3 to 36.5 respectively.

Procedure 2: Instead of heating in an open flask, the above mixture was heated in a pressure bottle at 150°C (2 hours) and at 175°C for 1 hour. A pressure of 2-6 atm developed. GC revealed the presence of the mono-adduct accompanied by traces of the double adduct (at a ratio of 39 : 0.5%).

All the above examples have been given for the purpose of illustration, and are not intended to limit the invention in any way. As will be apparent to the skilled chemist, many alternative procedures are available to carry out the invention; different solvents, catalysts and additives can be employed, in different proportions; all without exceeding the scope of the invention.

Claims (45)

3125/94 115855/2 -27- CLAIMS:

1. A process for preparing disubstituted benzophenones of formula (I): wherein R and R' are independently selected from hydrogen, C \-CQ alkyl, substituted or unsubstituted aryl, alkoxy, aryloxy, halogen, or a group COOR"', wherein R'" is hydrogen, C^-Cg alkyl, or substituted or unsubstituted aryl, provided that R and R' are not both fluorine in the para position. comprising the steps of: (a) (1) when R and R* are the same, reacting a compound of formula (II) with an acrylic acid ester of formula (TV) wherein R" is C \ to Cg alkyl in the presence of a palladium, ruthenium, or platinum catalyst, to yield a compound of formula (HI): 3125/94 Π5855/3 -28- or, (2) when R and R' are not the same, reacting a compound of formula Π) with a compound of formula (V) wherein R* and R" are as hereinbefore described in the presence of a palladium, ruthenium, platinum catalyst to yield a compound of formula (HI); (b) preferably, converting the said compound of formula (HE) into a derivative of formula (EUa): wherein R and R' are as defined above, and R" is H, CH3 or Na; and 3125/94 115855/2 -29- (c) oxidizing the said compound of formula (III) obtained from step (a), or the said derivative thereof of formula (Ilia), to yield the corresponding disubstituted benzophenone of formula (I).

2. A process according to claim 1, wherein the catalyst is a supported catalyst.

3. A process according to claim 2, wherein the catalyst is supported on carbon.

4. A process according to claim 3, wherein the catalyst is palladium or ruthenium catalyst.

5. A process according to claim 4, wherein the ratio of catalyst to carbon support is between about 0.4 wt.% and 5 wt.%.

6. A process according to claim 1, wherein the catalyst is an unsupported catalyst.

7. A process according to claim 6, wherein the catalyst is Ρά(¾, PdBr2, or palladium acetate, optionally in the presence of tertiary phosphines.

8. A process according to clai 7, wherein the catalyst is PdCl2.

9. A process according to claim 1, wherein the reaction is carried out without a solvent. 3125/94 115855/2 -30-

10. A process according to claim 1, wherein the reaction is carried out in solution.

11. A process according to claim 10, wherein the solvent is an aprotic solvent.

12. A process according to claim 11, wherein the aprotic solvent is N-methylpyrrolidone.

13. A process according to claim 1, wherein the reaction mixture further comprises a base and, optionally, an antioxidant.

14. A process according to claim 13, wherein the base is Na2C03.

15. A process according to claim 14, wherein the antioxidant is BHT.

16. A process according to claim 1, wherein step (a) is carried out at a temperature between about 130°C and about 200°C.

17. A process according to claim 16, wherein step (a) is carried out a temperature between about 150°C and about 160°C.

18. A process according to claim 1, wherein oxidation of the compound of formula (ΠΙ) is carried out by catalytic reaction with oxygen.

19. A process according to claim 18, wherein the oxygen source is air, optionally enriched with oxygen. 3125794 115855/4 -31-

20. A process according to claim 18· o claim 19, wherein the catalyst comprises Co and Mn as cations.

21. A process according to claim 1, wherein oxidation of the compound of formula (EH) is carried out by reaction with nitric acid.

22. A process according to claim 18, wherein the oxidation reaction is carried out using NaOCl in the presence of a Ru(UI) or Ru(IV) compound.

23. A process according to claim. 22, where the ruthenium compound is selected from RuCl3 or R11O2.

24. A process according to claim 1, wherein the oxidation reaction is carried out using ozone.

25. The novel compound of formula (ΕΠ): wherein, either R and ' are identical and selected from F, -O-CQRQ, -C6H5, Br-C6H4- and H2N-C6H4- provided that R and R' are not both F in the para position or R and R' are non identical and R is F, OCH3, CH3 or COORm, wherein Rm is hydrogen, Ci-Cg alkyl, or substituted or unsubstituted aryl; and R' is p-CHaO-CeKtv P-CH3-C6H4-,- or -O-CgHs;- and R" is H, C i-Ga alkyl, or Na. 3125/94 115855/2 -32-

26. A process for preparing a compound of formula (ΠΙ): wherein R and R' are independently selected from hydrogen, Οχ-Ορ alkyl, substituted or unsubstituted aryl, alkoxy, aryloxy, halogen, or a group COOR"', wherein R'" is hydrogen, Ci-Cg alkyl, or substituted or unsubstituted aryl; provided that R and R' are not both F in the para position;and R" is H, C -C^ alkyl, or Na comprising the steps of: (a) (1) when R and R' are the same, reacting a compound of formula (II) with an acrylic acid ester of formula (TV) in the presence of a palladium, ruthenium, platinum or rhodium catalyst; or, 3125/94 115855/2 -33- (b) when R is not the same as R\ reacting a compound of formula (II) with a compound of formula (V) in the presence of a palladium, ruthenium, platinum or rhodium catalyst.

27. A process according to claim 26, wherein the catalyst is a palladium or ruthenium catalyst.

28. A process according to claim 26, wherein the catalyst is a supported catalyst.

29. A process according to claim 28, wherein the catalyst is supported on carbon.

30. A process according to daim 29, wherein the catalyst is a palladium or ruthenium catalyst.

31. A process according to claim 30, wherein the ratio of catalyst to carbon support is between about 0.4 wt.% and 5 wt.%.

32. A process according to claim 26 wherein the catalyst is an unsupported catalyst. 3125/94 115855/3 -34-

33. A process according to claim 32, wherein the catalyst is Ρά(¾, PdBr2, or palladium acetate, optionally in the presence of tertiary phosphines.

34. A process according to claim 33, wherein the catalyst is PdCl2-

35. A process according to claim 26, wherein the reaction is carried out without a solvent.

36. A process according to claim 26, wherein the reaction is carried out in solution.

37. A process according to claim 36, wherein the solvent is an aprotic solvent.

38. A process according to claim 37, wherein the solvent is N-methylpyrrolidone.

39. A process according to claim 26, wherein the reaction mixture further comprises a base and, optionally, an antioxidant.

40. A process according to claim 39, wherein the base is Na2C03.

41. A process according to claim 39, wherein the antioxidant is BHT.

42. A compound according to claim 25 of formula (Ilia): 115855/3 wherein, either R and R' are identical and selected f om F, -O-CgHs, -C^H5, Br-CeH4- and H2N-C6H4- provided that R and R' are not both F in the para position, or R and R* are non identical and R is F, OCH3, CH3 or COOR"', wherein R'" is hydrogen, Οχ-Οβ aDcyl, or substituted or unsubstituted aryl; and R' is P-CH3O-C6H4-, P-CH3-C6H4-," or -O-C6H5; and R" is H, CH3 or Na.

43. A process for preparing a compound of formula CD, essentially as described and with particular reference to the examples.

44. A process for preparing a compound of formula OH), essentially as described and with particular reference to the examples.

45. A process for preparing a compound of formula (Ha), essentially as described and with particular reference to the examples. LUZZATTO & LUZZATTO