Title of Invention

PROCESS FOR THE PREPARATION OF 3,5-BIS(TRIFLUOROMETHYL) BENZYLALCOHOL

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-
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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
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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,
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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
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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%-
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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.
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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.

Documents:

00684-kolnp-2006-abstract.pdf

00684-kolnp-2006-claims.pdf

00684-kolnp-2006-correspondence others.pdf

00684-kolnp-2006-correspondence-1.1.pdf

00684-kolnp-2006-description complete.pdf

00684-kolnp-2006-form 1.pdf

00684-kolnp-2006-form 18.pdf

00684-kolnp-2006-form 3.pdf

00684-kolnp-2006-form 5.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-ABSTRACT.pdf

684-KOLNP-2006-AMENDED CLAIMS.pdf

684-KOLNP-2006-CANCELLED PAGES.pdf

684-KOLNP-2006-DESCRIPTION (COMPLETE).pdf

684-KOLNP-2006-FORM 1.pdf

684-KOLNP-2006-FORM 2.pdf

684-KOLNP-2006-FORM 3.pdf

684-KOLNP-2006-OTHERS.pdf

684-KOLNP-2006-PETITION UNDER RULE 137.pdf

684-KOLNP-2006-REPLY TO EXAMINATION REPORT.pdf


Patent Number 242970
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:
# Inventor's Name Inventor's Address
1 NARDELLO, ALESSANDRO C/O. MITENI S.P.A., LOC, COLOMBARA, 91 I-36070, TRISSINO(VI)
2 FACCIN, ANDREA C/O. MITENI S.P.A., LOC, COLOMBARA, 91 I-36070, TRISSINO(VI), ITALY
3 PRETTO, MARISA C/O. MITENI S.P.A., LOC, COLOMBARA, 91 I-36070, TRISSINO(VI), ITALY
PCT International Classification Number C07C 29/40
PCT International Application Number PCT/IT2003/000616
PCT International Filing date 2003-10-13
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA