PROCESSES AND INTERMEDIATES FOR THE PREPARATION OF
ENZALUTAMIDE
Field of the Invention
The present invention provides processes for the preparation of enzalutamide.
Background of'the Invention
Enzalutamide is chemically described .as 4-(3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-
I dimethyl-4-0x0-2-sulfanylideneimidazolidin1- - yl}- 2-fluoro-N-methylbenzamide, and is depicted 1
I I
in Formula I.
FORMULA I
Processes for the preparation of enzalutamide are described in U.S. Publication Nos.
200710004753 and 200710254933; and PCT Publication Nos. WO 20071127010, WO
20061124 1 18, and WO 201 11106'570.
PCT Publication No. WO 201 11106570 discloses that the processes described in U.S.
Publication Nos. 200710004753 and 200710254933 result in only a 25% yield of enzalutamide in
the final step, which accounts for a 15% overall yield. PCT Publication No. WO 201 11106570
further discloses that the known processes for preparing enzalutamide involve the use of
extremely toxic reagents, for ,example, acetone cyanohydrin.
It is acknowledged in WO 201 11106570 [Para 001 01 and also a well known fact that
Acetone cyanohydrin is ,toxic and therefore its use as a reagent should be avoided for the
industrial production of a pharmaceutical ingredient.. Therefore, there is a need in the art to
develop a process for the preparation of enzalutamide that avoids the use of acetonecyanohydrin
as a reagent.
Summary of the Invention
1
The present invention provides a process for the preparation of enzalutamide that does
not involve the use of toxic reagents and, at the same time, results in a 'higher yield .of
enzalutarnide.
Detailed Description of the Invention
I
, . . . The term "about," as used herein, refers to any value which lies within the range defincd
I by a number up to %lo% of the value.
I .
A first aspect of the present invention provides a.process for the,preparation of
enzalutamide of Formula I,
FORMULA I
which comprises:
a) reacting a compound of Formula I1
FORMULA I1
with a compound of Formula 111
FORMULA 111
to prepare a compound of Formula IV; and
FORMULA IV
b) reacting the thus obtained compound of Formula IV obtained in above step a) with
a compound of Formula V,
FORMULA V
($1, / or p:
0
(Succinirnyl) wherein R is methyl, ethyl, benzyl, (Benzotriazol~l) ,
A second aspect of the present invention provides a process for the preparation of
enzalutamide of Formula I,
FORMULA I
which comprises reacting a compound of Formula IV with
FORMULA IV
a compound of Formula V,
FORMULA V
The reaction of the compound of Formula IV with the compound of Formula V is carried
out in a solvent. The solvent is selected from the group consisting of water, dimethyl sulfoxide,
esters, ethers, alcohols, hydrocarbons, halogenated hydrocarbons, and mixtures thereof.
Examples of preferred ester solvents include ethyl acetate, butyl acetate, and isopropyl acetate.
Examples of preferred alcohol solvents include methanol, ethanol, and n-butanol. Examples of
preferred hydrocarbon solvents include hexane and heptane. Examples of preferred ether
solvents include tetrahydrofuran and diisopropyl ether. An example of a preferred halogenated
hydrocarbon is dichloromethane.
The reaction of the compound of Formula IV with the compound of Formula V is carried
out for about 15 hours to about 20 hours, preferably about 15 hours to about 19 hours.
The reaction of the compound of Formula IV with the compound of Formula V is carried
out at about 60°C to about 100°C, preferably about 70°C to about 90°C.
The compound of Formula I obtained may be isolated by employing one or more
techniques selected from the group consisting of filtration, decantation, extraction, distillation,
evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or
recrystallization, and may further be dried using conventional techniques, for example, drying,
drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
A third aspect of the present invention provides a process for the preparation of a
compound of ~orrnulaIV ,
FORMULA IV
I which comprises reacting a compound of Formula I1
FORMULA I1
with a compound of Formula 111.
FORMULA I11
The compound of Formula 111 can be prepared by the methods known in the art, for
example, PCT Publication Nos. WO 20071127010 and WO 200611241 18. The compound of
Formula I1 can be prepared by the method disclosed in U.S. Patent No. 4,754,072 or by the
method as described herein.
The reaction of the compound of Formula I1 with the compound of Formula I11 to give
the compound of Formula IV is carried out in a solvent.
The solvent is selected fiom the group consisting of water, dimethyl sulfoxide, esters,
ethers, alcohols, hydrocarbons, halogenated hydrocarbons, amides, and mixtures thereof.
Examples of preferred ester solvents' include ethyl acetate, butyl acetate, and isopropyl acetate.
Examples of preferred alcohol solvents include methanol, ethanol, and 'n-butanol. Examples of
preferred hydrocarbon solvents include hexane and heptane. Examples of preferred ether
solvents include tetrahydrofuran and diisopropyl ether. An example of a preferred halogenated
hydrocarbon is dichloromethane. Examples of preferrcd amide solvent^ include N,N-dimethyl
formamide and acetamide.
The reaction of the compound of Formula I1 with the compound of Formula I11 is carried
out for about 15 hours to about 25 hours, preferably, about 16 hours to about 24 hours.
The reaction of the compound of Formula I1 with the compound of Formula III'is carried
out at about 10°C to about 40°C, preferably, about 1 5 " ~to' about 30°C.
The compound of Formula IV obtained by the reaction of the compound of Formula I1
with the compound of Formula I11 may optionally be isolated by employing one or more
techniques selected fiom the group consisting of filtration, decantation, extraction, distillation,
evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or
recrystallization, and may further be dried using conventional techniques, for example, drying,
drying under vacuum, spray d jing, fieeze drying, air drying, or agitated thin film drying.
A fourth aspect of the present invention provides a process for the preparation of a
compound of Formula V, .
FORMULA V
which comprises reacting a compound of Formula VI or a salt thereof
FORMULA VI
with a compound R-OH,
A fifth aspect of the present invention provides a process for the preparation of a
compound of Formula V,
FORMULA V
which comprises reacting a compound of Formula VI or a salt thereof
F 0
FORMULA VI
with a compound R-OH,
The compound of Formula VI can be .prepared by the methods ,known in art, for
. example, PCT Publication No. WO 201 1/106570.
The reaction of the compound of Formula VI with the compound R-OH to give the
compound of Formula V can be carried out in the presence of N,N-dimethylamino pyridine.
The reaction of the compound of Formula VI with the compound R-OH to give the
compound of Formula V is carried out in the optional presence of a coupling agent in a solvent.
The coupling agent can be selected from the group consisting of 1-ethyl-3-(3-
dimethylaminopropyl)carbodiimide hydrochloride, N,N1-dicyclohexylcarbodiimide, thionyl
chloride, and oxalyl chloride.
The solvent is selected from the group consisting of water, esters, halogenated
hydrocarbons, ethers, alcohols, hydrocarbons, amides, and mixtures thereof. Examples of
preferred ester solvents include ethyl acetate, butyl acetate, and isopropyl acetate. An example
of a preferred halogenated hydrocarbon. is dichloromethane. Examples of preferred alcohol
solvents include methanol,.ethanol, and n-butanol. Examples of preferred hydrocarbon solvents
include hexane and heptane. Examples of preferred ether solvents include tetrahydrofuran and
diisopropyl ether. Examples of preferred amide solvents include N,N-dimethyl formamide and
acetamide.
The reaction of the compound.of Formula VI with the compound R-OH is carried out
for about 2 hours to about 8 hours, preferrably about 3 hours to about 6 hours.
The reaction of the compound of Formula VI with the compound R-OH is carried out at
about 5°C to about 30°C, preferrably about 10°C to about 30°C.
The compound of Formula V may optionally be isolated by employing one or more
techniques selected from the group consisting of filtration, decantation, extraction, distillation,
evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or
recrystallization, and may further be dried using conventional techniques, for example, drying,
drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
A sixth aspect of the present invention provides a compound of Formula IV.
FORMULA IV
A seventh aspect of the.present invention provides a compound of Formula V,
FORMULA V
An eighth aspect of the present invention provides the use of a compound of Formula IV I for the preparation of enzalutamide. I
A ninth aspect of the present invention provides the use of a compound of Formula V for I
I the preparation of enzalutamide. !
i
A tenth aspect of the present invention provides a process for the preparation of I
enzalutamide of Formula I,
FORMULA I
which comprises reacting a compound of Formula V
FORMULA V
with a compound of Formula VII,
The compound of Formula VII can be prepared by the methods known in the art, for
, example, PCT Publication Nos. WO 200711270 10 and WO 200611 24 1 18.
The reaction of the compound of Formula V with the compound of Formula VII is
carried out in a solvent. The solvent is selected from the group consisting of water, dimethyl
sulfoxide, esters, ethers, alcohols, hydrocarbons, halogenated hydrocarbons, and mixtures
thereof. Examples of preferred ester solvents include ethyl acetate, butyl acetate, and isopropyl
acetate. Examples of preferred alcohol solvents include methanol, ethanol, and n-butanol.
Examples of preferred hydrocarbon solvents include, hexane and heptane. Examples of ether
solvents include tetrahydrofbran and diisopropyl ether. An example of a preferred halogenated
hydrocarbon is dichloromethane.
The reaction of the compound of Formula V .with the compound of.Formula VII is
carried out for about 10 hours to about 18 hours, preferably, about 12 hours to about 16 hours.
The reaction of the compound of Formula V with the compound of Formula VII is
carried out at about 60°C to about 1 OO°C, preferably, about 70°C to about 90°C.
The compound of orm mu la I may be isolated by employing one or more techniques
selected from the group consisting of filtration, decantation, extraction, distillation, evaporation,
chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization,
I
I and may hrther be dried using conventional techniques, for example, drying, drying under
1 . vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
An embodiment ofthe present invention provides a process according to the first, second
i -
I and tenth aspects, wherein enzalutamide obtained is free from the compounds of Formula IV and
I
Formula V.
An embodiment of the present invention provides a process according to the first, second
and .tenth aspects, wherein enzalutamide obtained is having less than 0.5% of the compound of
Formula IV.
An embodiment of the present invention provides a process according to the first, second
and tenth aspects, wherein enzalutamide obtained is having ,less than 0.5% of the compound of
Formula V.
An eleventh aspect of the present invention provides the use of enzalutamide free from
the compounds of Formula IV and Formula V for the manufacturing of a medicament used for
the treatment of metastatic castration-resistant prostate cancer.
A twelfth aspect of the present invention provides the use of enzalutamide having less
than 0.5% of the compound of Formula IV for the manufacturing of amedicament used for the
treatment of metastatic castration-resistant prostate cancer.
A thirteenth aspect of the present invention provides the use of enzalutamide having less.
than 0.5% of the compound of Formula V for the manufacturing of a medicament used.for the
treatment of metastatic castration-resistant prostate cancer.
A fourteenth aspect of the present invention provides the use of enzalutamide free from
the cornpor~nds of Formula IV and Formula V for the preparation of a pharmaceutical
composition.
Methods:
The IR spectrum was recorded using a ~erkin~lmeSr*pe ctrum One FTIR spectrometer.
The Mass spectrum was recorded using an Ab ~ciex*A PI 2000 LCMSIMS system.
The NMR spectrum was recorded using a ~ruker* Avance 111 400 MHz NMR
spectrometer.
. . . " .; , , .. . i . . while' the .present. .invention has been described in terms of its specific aspects, certain
. . ' '. . modifications and equivalents will be apparent to'those skilled in the art and are intended to be
. . .a ' included within the scope of the present invention.
Examples
Example 1 : Process for the preparation of 0-phenyl carbonochloridothioate (Formula 11)
. A solution of 5% aqueous sodium hydroxide (14.28 g) in phenol (30 g) was added to a
cooled solution of thiophosgene (24.3 mL) over 2 hours at 0°C to 5OC. The reaction mixture
was stirred for 1 hour to 2 hours'at 0°C to 5°C. The layers obtained were separated, and then the
I organic layer obtained was concentrated at 40°C to obtain the title compound.
Yield: 37.1 g.
Example 2: Process for the preparation of O-~henyl~4-c~ano-3-(trifluoromethyl~vhen~l~
carbamothioate (Formula IV)
4-Amino-2-(trifluoromethyl) benzonitrile (Formula 111; 20 g) was added to
dichloromethane (200 mL) and a solution of 0-phenyl carbonochloridothioate (Formula 11; 10 g)
in dichloromethane (100 mL) was added to the reaction mixture over 10' minutes at .20°C to
25°C. N,N-dimethyl formamide (20 mL;) was'added to the reaction mixture and the reaction
mixture was stirred for 18 hours at 20°C to 25°C. The reaction mixture was cooled to 0°C to
5°C and the solid obtained was filtered at O°C to 5°C. The filtrate obtained was concentrated at
40°C under vacuum and a solid material was obtained. A. mixture of hexanes (1 L) and
hydrochloric acid (1 L) was added to the solid material, and then the reaction mixture was stirred
for 20 minutes. The solid obtained was filtered, and then dried under vacuum at 40°C to obtain
the title compound. I
I
I
Yield: 12.8 g. I ,
'H NMR (400 MHz, CDCh), 6 (in ppm): 8.7 (s, lH), 8.05 (brs, 2H), 7.84 (d, j=8.36 Hz, lH), I
7.3-7.5 (m, 3H), 7.13 (d,j=7.8Hz, 2H). I
I I
Mass: [M + H]+=322.9; MSIMS: 322.9, 1 1 1.1,94.7.
IR in KBr, (in cm-I): 3433,3 196,3 159,3039,2232, 1707, 1613, 1592, 1538, 1504, 1490, 1456,
- 1411,1424,1370,1323,1308,1277,1220,1149,1196,1173,1149,1136,1070,1051,1022,
1003,940,903,841,774,752,734,691,677,638,628,613,554,528,493,452.
Example 3: Process for the preparation of 0-phenyl r4-cyano-3-(trifluoromethy1)phenyl~ . .
carbamothioate (Formula IV)
4-Amino-2-(trifluoromethyl) benzonitrile (Formula 111; 0.5 g) was added to
dichloromethane (5. mL). N,N-dimethyl formamide (1 'm~w)as added to the reaction mixture
and the reaction mixture was stirred for 5 minutes. 0-Phenyl carbonochloridothioate (Formula
11; 0.508 g) and neutral alumina (1 g) at 20°C to 25OC were added to the reaction mixture, and
then the reaction mixture was stirred for 24 hours. The solid obtained was filtered, and then
washed with dichloromethane (10 mL). The filtrate was washed with water (10 mL) for 5
minutes and the layers were separated. The organic layer was dried with sodium sulfate, and
, then filtered. The solution obtained was concentrated to yield a solid 'material, which was
crystallized using a dichloromethane and hexanes mixture to obtain the title compound.
Yield: 0.52 .g.
Example 4: Process for the preparation of 1 H-benzotriazol- 1 -yl N-r3-fluoro-4-(methyl
carbamoy1)phenyll-2-methylalaninate (Formula V; when R= benzotriazolyl)
N-[3-fluoro-4-(methylcarbamoyl)phenyl]-2-methylalanine hydrochloride (a salt of
Formula VI; ,1 g) was added to dichloromethane (10 mL) followed by the addition of 1Hbenzotriazol
(0.52 g) and 1-ethyl-3-(3-dimethy1aminopropyl)carbodiimide hydrochloride (0.64
g) at 20°C to 25OC. The reaction mixture was heated at 20°C to 25°C for 5 hours t'o 6 hours.
Water (10 mL) was added to the reaction mixture, and then the reaction mixture was stirred for
30 minutes. The layers obtained were separated and the organic layer was concentrated to
I obtain the title compound.
Yield: 1.4 g.
1 'H NMR (400 MHz, CDC13), 6 (in ppm): 8.03 (m, 2H), 7.4 (m, 2H), 6.98 (d, lH, j=8.24 Hz),
I 6.67 (brs, lH), 6.58 (dd, lH), 6.41 (dd, lH), 3.03 (d, lH), 1.88 (s, 1H).
!
.The compounds of Formula V (when R = methyl, ethyl, or benzyl) can be prepared by
the method disclosed in Example 4 by replacing lH-benzotriazol with the compound of Formula I R-OH (when R = methyl, ethyl, or benzyl).
.Example'.5: Process for the preparation of 2.5-dioxopyrrolidin- 1 -yl-N-(3-fluoro-4-
(methylcarbarnoyl)phenyll-2-methylalanine('F ormula V; when R= succinimvl)
N-[3-fluoro-4-(methylcarbamoyl)phenyl]-2-methylalanine hydrochloride (a salt of
Formula VI; 500. mg) was added to ethyl acetate (10 mL) at 24°C. The reaction mixture was
stirred and cooled to 0°C over 10 minutes. N,N'-dicyclohexylcarbodiimide (426 mg) was added
to the reaction mixture at O°C, followed by the addition of N,N-dimethylaminopyridine (24 mg),
I . and N-hydroxy succinamide (249 mg). The reaction mixture was stirred for 5 minutes, and then
the temperature was increased to 15°C. The reaction mixture was stirred at 12°C to 18°C for 3
hours. Water (10 mL) was added to the reaction mixture at 15°C to 20°C, and then the reaction
mixture was stirred for 5 minutes. The reaction mixture was filtered through celite, and then
washed with ethyl acetate (10 mL). The layers obtained were separated, and then the organic
layer was washed with sodium bicarbonate solution (7%) at 18°C to 20°C. The layers obtained
were separated, and then the organic layer was dried over sodium sulphate and filtered. The
organic layer was hrther distilled under vacuum at 18°C to 20°C for 1 hour to obtain the title
compound.
Yield: 625 mg.
'H NMR (400 MHz, CDCh), F (in ppm): 7.69 (m, lH), 7.48 (t, lH), 6.'45 (q, lH), 6.26 (q, lH),
2.8 (m, 4H), 2.74 (d, 311, j=4.52 Hz), 1.64 (s, 6H).
I
1 Mass: [M + HI+= 352.1, 321.2, 237,209.1, 195.1, 178, 169.1, 152.1, 138.1, 133.1, 11 1.9, 58.2.
Example 6: Process for the preparation of enzalutamide
Ethyl N-[3-Fluoro-4-(methylcarbamoyl)phenyl]-2-methylalaninate (Formula V when R =
ethyl; 0.5 g), dimethyl sulfoxide (0.5 mL), and 0-phenyl [4-cyano-3-(trifluoromethyl)phenyl]
1 carbamothioate (Formula IV; 2.26 g) were added to isopropyl acetate (1 ml,). The reaction
mixture was heated to 80°C to 85"C, and then stirred for 18 hours. Dichloromethane (20 mL)
and water (20 mL) were added to the reaction mixture, then the mixture was stirred for 15
minutes. The layers obtained were separated, and then the organic layer was concentrated at
25°C under vacuum to obtain the title compound.
Yield: 2.5 g
Enzalutamide can also be prepared by reacting 0-phenyl [4-cyano-3-(trifluoromethyl)
phenyl] carbamothioate (Formula IV) with the compound of Formula V (when R = methyl or
benzyl) by' following the method disclosed in Example 6.
I . . . : Example 7: Process for the preparation of enza'lutamide
. 1~-benzotriazol-l-~l-~-[3-fluoro-4-(meth~lcarbamo~l)~hen~l]-2-meth~lalaninate
(Formula V, when R = benzotriazolyl;' 0.5 g), dimethyl sulfoxide (0.5 mL), and 0-phenyl [4-
,cyano-3-(trifluoromethyl)phenyl] carbamothioate (Formula IV; 0.87 g) were added to isopropyl
acetate (1 mL). The reaction mixture was heated to 80°C to 85"C, and then stirred for 16 hours.
Dichloromethane (20 mL) and water (20 mL) were added to the reaction. mixture, and then the
.mixture was stirred for 15 minutes. The reaction mixture was filtered through celite, and then
washed with dichloromethane (10 mL). The layers obtained were separated, and then the
organic layer was concentrated at 25°C under vacuum to obtain the title compound.
Yield: 0.61 g
Example 8: Process for the preparation of enzalutamide
Enzalutamide can also be prepared by the method disclosed in Example 7 by replacing
lH-benzotriazol-1-yl N-[3-fluoro-4-(methylcarbamoyl)phenyl]-2-methylalaninate with 2,5-
dioxopyrrolidin- 1 -yl-N-[3-fluoro-4-(methy1carbamoyl)phenyl]-2-methylalaninate.
Example 9: Process for the preparation of enzalutamide
1 H-benzotriazol- 1 -yl-N-[3-fluoro-4-(methylcarbamoyl)phenyl]-2-methylalaninate
(Formula V when R' = benzotriazolyl; 0.5 g) and 4-isothiocyanato-2-(trifluoromethy1)-
benzonitrile (Formula VII; 0.62 g) were added to a mixture of dimethyl sulfoxide (0.5 mL) and
isopropyl acetate (1 mL). The reaction mixture was heated to 80°C to 85"C, and then stirred for
16 hours. Dichloromethane (20 mL) and water (20 mL) were added to the reaction mixture, and
then the mixture was stirred for 15 minutes. The reaction mixture was filtered through celite,
and then washed with dichloromethane (10 mL). The layers obtained were separated, and then
the organic layer was concentrated at 25" under vacuum to obtain the title compound.
Yield: 1.1 g.
Example 10: Process for the preparation of enzalutamide
Enzalutamide can also be prepared by reacting 4-isothi~c~anato-2-(trifluofomethyl)-
benzonitrile with ' 2,5-dioxopyrrolidin- 1 -yl-N-[3-fluoro-4-(methylcarbamoyl)phenyl]-2-
methylalaninate by following the method disclosed in Example 9.

WE CLAIM:
1. A process for the preparation of enzalutamide of Formula I,
FORMULA I
which comprises:
a) reacting a compound of Formula I1
FORMULA I1
with a compound of Formula I11
FORMULA I11
to obtain a compound of Formula IV;
FORMULA IV
and
b) reacting the thus obtained compound of Formula IV obtained in above step a) with .
a compound of Formula V,
FORMULA V
2. A process for the preparation of enzalutamide of Formula I,
I FORMULA I
which comprises reacting a compound of Formula IV with
FORMULA IV
.a compound of Formula V,
F . O
FORMULA V
A 'process for the preparation of a compound of Formula IV,
FORMULA IV
which comprises reacting.a compound of Formula I1
FORMULA I1
with a compound of Formula 111.
FORMULA III
4. . The process according to claim 1 or claim 3, wherein the reaction of the compound of
Formula I1 with the compound of Formula I11 to give the compound of Formula IV is
carried out in a solvent selected from the group consisting of water, dimethyl sulfoxide,
esters, ethers, alcohols, hydrocarbons, halogenated hydrocarbons, amides, and mixtures
thereof or the process according to claim 1 or claim 2, wherein the reaction of the
compound of Formula IV with the compound of Formula V is carried out in a solvent
selected from the group consisting of water, dimethyl sulfoxide, esters, ethers, alcohols,
hydrocarbons, halogenated hydrocarbons, and mixtures thereof.
5. A process for the preparation of a compound of Formula V,
' FORMULA V
~. - .. . , -..-- -, -, '.::,. -:.. - - .- .- --.- .- .- .- .- - - --
. -. - . . . . - - . - --- - - -.
18
I which comprises reacting a compound of Formula .VI or a salt thereof
I1 FORMULA VI
with a compound R-OH,
1 6. The process according to claim 5, wherein the reaction of the compound of Formula VI
with the compound R-OH to give the compound of Formula V is carried out in the
presence of a coupling agent selected from the group consisting of 1-ethyl-3-(3-
dimethylaminopropyl)carbodiimide hydrochloride, N, N'-dicyclohexylcarbodiimide,
thionyl chloride, and oxalyl chloride, in the presence of N,N-dimethylaminopyridine in a
solvent selected from thc group consisti~lgu f water, esters, halogenated hydrocarbons,
I ethers, alcohols, hydrocarbons, amides, and mixtures thereof.
7. . A compound of Formula IV.
FORMULA IV
or a compound of Formula V,
8. . Use of a compound of Formula IV or a compound of Formula V for the preparation of
enzalutamide.
A process for the preparation of enzalutamide of Formula I,
F
NHMe
FORMULA I
which comprises reacting a compound of Formula V
FORMULA V
with a compound of Formula VII,
FORMULA VII
10. The process according to claim 9, wherein the reaction of the cornpound of Formula V
with the compound of Formula VII is carried out in a solvent selected from the group
consisting of water, dimethyl sulfoxide, esters, ethers, alcohols, hydrocarbons,
halogenated hydrocarbons, and mixtures thereof.