Title of Invention | PROCESS FOR THE PREPARATION OF 3,5-BIS(TRIFLUOROMETHYL) BENZYLALCOHOL |
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Abstract | The present invention concerns a process for preparation for 3,5bis (trifluoromethyl)benzylalcohol by formylation in a solvent of an appropriate organo magnesium derivative with solid Para formaldehyde and optionally its conversion into a 3,5-bis(trifluromethyl)benzyl) halide. |
Full Text | WO2005/03472 PCT/IT2003/000616 It has now been surprisingly found that the fotmyiation reaction of organo- magnesium l,3-bis (trifluoromethyl) benzene derivatives with solid paraformaldebyde may be carried out with ease and allows to obtain on this substratum yields in 3,5- bis(trifluoromethyl)benzylalcohol comparable to those obtained with. gaseous formaldehyde DETAILED DESCRIPTION OP THE INVENTION So, according to one of its aspects, the invention concerns a process for preparing 3,5-bis (tnfluoromethyl)benzyl alcohol which, comprises reacting a 3,5- bis(tniluororaethyl)-plicnylmagnesium halide with solid paraformaldehytle in a- solvent According to the present invention, appropriate solvents are aliphatic ethers such, as, for example3 tetrahydroforam (THF), alone or, preferably, in admixture with aromatic hydrocarbons. For example mixtures of diethyl ether, THF, methyl-THF, isobutyl-ether, dimetoxyethane (DME), dimetoxyethane, diglyme, batyl-diglyme, ethyl-diglyme, triglyme with toluene o,m,p-xylenes, o,m,p-hexafluoroxylenes for example l,3-bis(trifluoromethyl)benzene, and similar may be used According to a preferred aspect, a mixture of THF and an aromatic hydrocarbon is used, for example toluene or 1,3-bis(trifluoromethyl) benzene, advantageously a mixture which comprises from 20 to 60% p/p of THF According to the invention the tetrahydrofuran is substantially anhydrous. The starting 3,5-bis(trifluoromethyl) phenylniagnesium halide according to the invention may be obtained from, the corresponding 3 5-bis(trifluoromethyl)-l- 2 WO2005/03472 PCT/IT2003/000616 3,5-bis(tnfluoromethyl)-I-brotnobenzerie and the starting 3,5- bis(tnfluoromethyl)-l-clitoroenzene are knowo-products, available on the market. In practice, after having prepared the organo-magnesium derivative according to the known techniques as indicated above, powdered paraformaldehyde is added to the reaction mass, advantageously in portions, and it is left to react for a period of between 1 and 5 hours, preferahly at a temperature between 30 and 90°C. According to the process of the invention, the amount of solid paraformaldehyde necessary to obtain the best yields is generally equmiolar or slightly in excess wita respect to the starting organo-magnesium derivative, for example an excess of not more than 5% In fect it was noted with surprise that a great excess of this reagent, contrary to what is normally remarked in organic chemical reactions, does not lead to an improvement of yields, but rather leads to a decrease of the same and to a more difficult processing of the final reaction mixture When the reaction is ended (winch can be checked by the techniques known to the skilled in the art for example "by gas-chromatography), the addact formed is hydrolysed with an aqueous solution of a nuneral acid, sucb. as sulphuric acid or hydrochloric acid, and the desired product, 3,5 bis(tnfluoromethyl) benzylalconol is obtained, which may be isolated and purified with the usual techniques, for example by crystallising ox distilling, or used as it is for further chemical transfcarnations. In feet 3,5-bus (tnfluoromethyl) benzylalconol isolated and purified or as a crude reaction product, cart in turu be used as the starting product for the prepsrafion 4 WO2005/03472 PCT/IT2003/000616 The reaction in step (c) may also be carried out according to any appropriate technique for the halogenation of benzjlalcohols, for example with, phosphorous tnbromide (PBr1) or NaBr and sulphuric acid, by heating Some preferred embodiments of the invention are given in the following cxpenmental part, The following example is given purely as illustration and is not {uniting in any way. EXPERIMENTAL PART EXAMPLE 1 (i) Preparation of 3.5-bis(trifluoromethyl)-phedyl magnesium.brornide In a 4-neck flask with. capacity 5 L equipped -with mechanical stirrnr, thermometer, bubble condenser add 250 ml filling filter at room temperature 5 9 g of Mg (1 888 moles); 3100 g of anhydrous THF. 50.0 g of 3,5- bis(trifluoromethyl)-l-bromo-benzene (0.1706 moles) are loaded. Stirring vigorously, with for the starting of the reaction (10 minutes approx) A temperature increase is noted and a variation in the coloum of the reaction mass from colourless to dark brown. A temperature increase up to about 600C is noted. The exothermic reaction is allowed to abate and, as soon as a fell in the internal temperature is noted, 826 % of anhydrous 1,3- bis(trifluoromethyl) benzene are loaded in the flask. The remaining' 451.0 g of 3,5-bis(trifluoromethyl)-l-bromo-benzene (1 539 moles) are mctered, 6 WO2005/03472 PCT/IT2003/000616 regulating the pouring rate so as to maintian the teniperature at 45°C (pouring duration 4.5 h) Once pouring is finished, 450C are maintained for 1-3 h. (ii)-Prenaration of 3 .S-bis(trifluoromethyl) – benzylalcohil 53.8 g of solid paraformaldehyde (1,7933 moles) are added to the reaction mixture obtained in the previous step (i), dosing it in two portions of about 27g The reaction is exothermic. It is left to react at 45°C for 6 hours and then the organo-magnesium adduct is hydrolysed -with 1002 3 g of H2SO4 at 20%, cooiing the system by means of an ice/water bath (Tmax=37°C), after which it is kept stimng vigorously for another hour, the mixture is left to settle, the two phases are separated, and. the solvents are eliminated from the organic phase, it is then distilled in a vacun (20 mbax) collecting 318 6 g of evaporated ornde aJcobol (ht > 92%) EXAMPLE 2 Preparation of 3,5-bis(trifluoromethyl)benzel bromide In a 4-neck flask with capacity 1000 ml equipped with mechanical agitator, thermometer, bubble condenser and 100 ml loading funnel, 262 2 g of the product of Example L (u) at 928% (0.988 moles), 550,2 g HBr 48% (3,2645 moles) aie loaded; this is nested at 50°C so as to melt the alcohol, then one starts to dose 113 g of concentrated H2SO4 (1.153 moles) Pouring is accomplished in 30 minutes, noting an increase of the internal temperature. this is heated to 100-105°C and left to react for 8 hours. The reaction is completed by reflux beating for per 1.5 hours the mixture is left to settle and 7 WO2005/03472 PCT/IT2003/000616 the phase are separated; the solvents are removed from the organic phase and the productt in the titie is obtained with a yield of 99-1%- 8 WO2005/03472 PCT/IT2003/000616 CLAIMS 1. Process for preparing 3,5-bis(trifl)ben2ylalc-obDl which comprises reacting a 3,5-bis((trifluoromethyl)-phenyimagnesrum halidc with solid paraformaldebyde in a solvent 2. 2 Process according to claim 1. characterised in that said solvent is an aliphatic ether 3- Process according to claim2, characterised in that said aliphatic elther is retrahydrofuran (THF). 4 Process according to claim 1, characterised in that said solvent is a mixture of alipliatic ethers and aromatic hydrocarbons 5 Process according to claim 4, characterised in that the aliphatic ether is selected from diethyl ether, THF, methel -THF, isobutyl-ether, dimetoxyethane (DME), diethoxyethane diglyme, butyl-diglynme, ethyl- diglyme and inglyme. 6 Process according to claim 4, characterised in that the aromatic hydrocarbon is selected from toluene, o,m,p-Xylenes, o,m,p-esafiuoioxylenes and 1,3- bis(trifluoromethyl) benzene, 7 Process according to claim A, characterised in that the reaction solvent is a mixture of THF and an aromatic hydrocarbon, 8. Process according to claim 7, characterised in that the reachon solvent is a mixture of THF and an aromatic hydrocarbon selected from. tolueae and 1,3- bis(trifluoromethyl) benzene 9 WO2005/03472 PCT/IT2003/000616 9 Process according to claim 7 or 8, characterised in. that said mixture comprising from 20 to 60% p/p of XHF 10 Process according to any one of the previous claims, characterised in that the 3,5-bis(trifluoromethyl)-phenylmagnesium balide is selected from 3,5- bis(tbis(trifluoromethyl)phenylmagnesuim bromide and 3,5-bisbis(trifluoromethyl)- phenylmagnesium chloride 11. Process according to any one of the previous claims characterised in that the solid paraformaldehyde is used in an approximately equnmolar amount or slightly in excess with respect to the 3,5-bis(trifluoromethyl)-phenyl magnesium halide 12 Process according to claim 11 characterised.in that the, molar excess of paraformaldehyde is less thanor equal to 5% with respect to the balide or 3,5- bis(trifluoromethyl)phenyl-mangnesium 13 Process according to any and of the previaus claims, characterised, in that the reacnon temperature is "between 30 and 900C. 14. Process according to any one of the previous claims characterised in feat at the end of the reaction the adduet is hydxolysed with an aqueous solution of a mineral acid. 15 Process according to claiun 14, characterised in that said mineral acid is selected from hydrochloric acid and sulphuric acid. 10 WO2005/03472 PCT/IT2003/000616 16 Process according to any one of the previous claims, characterised in that the 3,5-bis(trifluoromethyl)benzylalcohol isolated by distillation or crystallisation 17. Process according to any one of the previous claims, characterised in that the 3,5-bis(trifluoromethyl)benzylalcohol is used as a reagent to obtain a 3,5-bis(trifluoromethyl)benzyl halide 18 Process according to any one of the previous claims, characterised in that said 3,5-bis(trifluoromethyl)-phenyl-magnesium halide is obtained starting from the corresponding 3,5-bis(trifluoromethyl)-l-halobenzens by treatment with magnesium in a solvent selected from the solvents quoted in claims 2 to 9 19 Process according to claims 17 and 18, characterised in that. (a) a 3,5-bis(trifluoromethyl)-phenyl magnesium halide is formed from a 3,5-bis(trifluoromethyl)-hatobenzene in a solvent selected from the aliphatic ethers and a mixture of aliphatic ether; and aromatic hydrocarbons; (b) solid parafonnaldehyde is added to the reaction mixture thus obtained; (c) the 3,5-bis(trifluoromethyl)benzylcohol thus obtained is submitted to a halogenation reaction with HX where X is a halide, optionally in the presence of sulphuric acid; (d) the 3,5-bis(trifluoromethyl)benzyl halide thus obtained is isolated 11 The present invention concerns a p[rocessw for preparation for 3,5bis (trifluoromethyl)benzylalcohol by formylation in a solvent of an appropiate organo magnasium detivative with solid paraformaldehyde and optionally as conversion into a 3,5bis(in-fluromethyl/benzyl) halide. |
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00684-kolnp-2006-correspondence others.pdf
00684-kolnp-2006-correspondence-1.1.pdf
00684-kolnp-2006-description complete.pdf
00684-kolnp-2006-form-18-1.1.pdf
00684-kolnp-2006-international exm report.pdf
00684-kolnp-2006-international publication.pdf
00684-kolnp-2006-international search report.pdf
00684-kolnp-2006-pct others.pdf
00684-kolnp-2006-pct request.pdf
684-KOLNP-2006-AMENDED CLAIMS.pdf
684-KOLNP-2006-CANCELLED PAGES.pdf
684-KOLNP-2006-DESCRIPTION (COMPLETE).pdf
684-KOLNP-2006-PETITION UNDER RULE 137.pdf
684-KOLNP-2006-REPLY TO EXAMINATION REPORT.pdf
Patent Number | 242970 | ||||||||||||
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Indian Patent Application Number | 684/KOLNP/2006 | ||||||||||||
PG Journal Number | 39/2010 | ||||||||||||
Publication Date | 24-Sep-2010 | ||||||||||||
Grant Date | 22-Sep-2010 | ||||||||||||
Date of Filing | 23-Mar-2006 | ||||||||||||
Name of Patentee | MITENI S.P.A. | ||||||||||||
Applicant Address | VIA MECENATE, 90 1-20138, MILAN | ||||||||||||
Inventors:
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PCT International Classification Number | C07C 29/40 | ||||||||||||
PCT International Application Number | PCT/IT2003/000616 | ||||||||||||
PCT International Filing date | 2003-10-13 | ||||||||||||
PCT Conventions:
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