Process for the production of cyclopropylmethyl halides

Disclosed is a process for the production of cyclopropylmethyl halides (CPMX) such as cyclopropylmethyl chloride (CPMCl) and cyclopropylmethyl bromide (CPMBr) wherein cyclopropanemethanol (CPMO) is contacted with an aqueous solution of a hydrogen halide (HX) at a temperature in the range of -30.degree. C. to 35.degree. C. Also disclosed is a three-step process wherein CPMO is converted to a CPMX, the CPMX is separated as a liquid organic phase from the aqueous hydrogen halide by decantation and then is subjected to fractional distillation to provide CPMX in high purity. Finally, a process for the co-production of a CPMX and a cyclobutyl halide (CBX) is disclosed.

This invention pertains to a process for the production of 
cyclopropylmethyl halides (CPMX) such as cyclopropylmethyl chloride 
(CPMCl) and cyclopropylmethyl bromide (CPMBr). The process involves 
treatment of cyclopropanemethanol (CPMO) with an aqueous solution of a 
hydrogen halide (HX) at a temperature in the range of -30.degree. C. to 
35.degree. C. Another embodiment of the invention involves a three-step 
process wherein CPMO is converted to a CPMX, the CPMX is separated from 
the aqueous hydrogen halide by decantation and then is subjected to 
fractional distillation to provide CPMX in high purity. Another embodiment 
of the present invention provides a process for the co-production of a 
CPMX and a cyclobutyl halide (CBX). 
The preparation of cyclopropylmethyl halides by reacting CPMO with a 
phosphorus trihalide is described in J. Med. Chem.-Chim. Therap. 15, 571 
(1980). The disclosed process requires very low temperatures, e.g. 
-65.degree. to -80.degree. C., in order to obtain acceptable selectivity 
to the desired CPMX. U.S. Pat. No. 3,385,857 describes a similar method 
for the preparation of CPMBr using diethyl ether as a solvent in order to 
achieve better recovery of the product. Again, the temperature was 
-78.degree. C. Published PCT Patent Application WO-97/30958 describes a 
process for the production of CPMX by reacting CPMO with excess chlorine 
or bromine in the presence of triphenylphosphine and dimethyl formamide 
solvent. In order to obtain the desired products in high purity, large 
amounts of triphenylphosphine are required for the process. Also, the 
reaction is carried out under very dilute condition requiring the use of a 
large amount of dimethyl formamide. The process of WO-97/30958 therefore 
results in poor throughput and the generation of large amounts of waste 
materials which make this process unattractive for commercial-scale 
production of CPMX. 
U.S Pat. No. 5,288,932 describes a process by a so-called one-pot, two-step 
process in which CPMO is reacted with methanesulfonic acid halides to form 
mesylates in the presence of trialkylamines. The mesylates are decomposed 
thermally in the presence of the amine hydrohalide salts to generate the 
CPMX along with large amounts of amine-sulfonic acid salts. Such formation 
of large amounts of salts makes product isolation difficult and presents 
disposal and environmental problems. The process also requires a 
complicated and costly measurement and temperature control technique and 
presents difficulties of operating on a commercial scale. Lee at al, Can. 
J. Chem., 1980, 58, 1075-79 discloses the reaction of CPMO with dilute, 
i.e., up to 2.0 Normal, aqueous hydrochloric acid at 60 or 85.degree. C. 
for 1.5 to 10 hours. The reaction gave 10 to 13 products with cyclobutanol 
as the major product. Only trace amounts CPMCl were observed. 
We have developed a simple and efficient process of the production of CPMX. 
One embodiment of the invention provides a process for the production of 
CPMX by contacting CPMO with an aqueous HX solution at a temperature of 
-30.degree. to 35.degree. C. The crude product obtained from the process 
comprises mainly CPMX along with cyclobutyl halide (CBX) and trace amounts 
of 4-halo-1-butene. The hydrohalide HX preferably is hydrogen bromide or, 
especially, hydrogen chloride. The initial reaction of CPMO and HX results 
in the formation of a two-phase liquid system comprising an organic phase 
comprising the halide products and an aqueous phase comprising the aqueous 
HX solution. The crude product thus can be recovered by decantation. 
Distillation of the product mixture, preferably in the presence of an acid 
scavenger or acceptor, gives CPMX having a purity satisfactory for use in 
other organic syntheses processes, e.g. a purity of 95% or greater. The 
concurrent addition of an acid scavenger during the distillation 
effectively prevents or minimizes decomposition of the desired CPMX 
product from prolonged heating, especially when the distillation column 
contain a metal, e.g., steel, packing material. 
Thus, a second embodiment of the present invention provides a process for 
the production of CPMX having a purity of 95% or greater, preferably 97% 
or greater, which comprises the steps of: 
(1) contacting CPMO with an aqueous HX solution at a temperature of 
-30.degree. to 35.degree. C. to obtain a reaction mixture comprising (i) 
an organic phase comprising CPMX, CBX and 4-halo-1-butene and (ii) an 
aqueous phase comprising the aqueous HX solution; 
(2) separating organic phase (i) from aqueous phase (ii) from step (1) by 
decantation; and 
(3) subjecting organic phase (i) to fractional distillation wherein organic 
phase (i) is fed to the mid-section of a distillation column operated at a 
temperature and pressure to provide (i) a column overhead vapor stream 
comprising a CBX and 4-halo-1-butene and (ii) a column base vapor stream 
comprising CPMX. 
The process of the present invention co-produces CPMX and CBX in CPMX:CBX 
mole ratios in the range of about 10:1 to 0.5:1, depending upon the 
conditions, particularly the temperature, of the process. Thus, a third 
embodiment of the present invention is the co-production of a CPMX and CBX 
in CPMX:CBX mole ratios in the range of about 10:1 to 0.5:1 by contacting 
CPMO with an aqueous HX solution at a temperature of -30.degree. to 
35.degree. C. Cyclopropylmethyl halides and cyclobutyl halides are useful 
intermediates for the production of pharmaceuticals. See, for example, 
Published PCT Patent Application WO 9304047, Spanish Patent ES 539110, 
U.S. Pat. No. 4,863,918, Czech Patent CZ 279821 and European Patent 
Publication EP 0380312 A1. 
In the first embodiment of our invention, a CPMX is produced by contacting 
CPMO with an aqueous HX solution at a temperature of -30.degree. to 
35.degree. C. wherein X is a halogen atom, preferably Cl or Br, most 
preferably Cl. The concentration of the aqueous HX solution may be in the 
range of about 20 to 80 weight percent HX, preferably about 30 to 60 
weight percent HX. Higher HX concentrations can be achieved or maintained 
by continuously introducing HX gas into the reaction zone of the process. 
The temperature at which the first embodiment is performed may be in the 
range of -30.degree. to 35.degree. C. but preferably is in the range of 
about -15 to 20.degree. C. and most preferably in the range of about -10 
to 5.degree. C. The crude product comprising CPMX and CBX with smaller 
amounts of 4-halo-1-butene forms a liquid organic phase which separates 
from the aqueous HX solution and may be recovered using conventional 
decantation procedures and equipment. Since CPMO is completely soluble in 
the aqueous HX solution and the halide products are insoluble in the 
aqueous phase, the separation of the product (organic phase) may be 
accomplished by simple decanting. Such differences of solubility between 
starting material CPMO and product halides in the aqueous HX solution is 
advantageous for commercial operations since the CPMX formed exists the 
organic layer while the unreacted CPMO remains in the aqueous layer. Thus, 
the reaction may be driven to completion while avoiding decomposition 
and/or isomerization of the CPMX product by prolonged contact with the 
acid. 
The second embodiment of the invention provides a process for the 
production of CPMX having a purity of 95% or greater, preferably 97% or 
greater, which comprises the steps of: 
(1) contacting CPMO with an aqueous HX solution at a temperature of 
-30.degree. to 35.degree. C. to obtain a reaction mixture comprising (i) 
an organic phase comprising CPMX, CBX and 4-halo-1-butene and (ii) an 
aqueous phase comprising the aqueous HX solution; 
(2) separating organic phase (i) from aqueous phase (ii) from step (1) by 
decantation; and 
(3) subjecting organic phase (i) to fractional distillation wherein organic 
phase (i) is fed to the mid-section of a distillation column operated at a 
temperature and pressure to provide (i) a column overhead vapor stream, 
i.e., a vapor stream removed from the upper section or top of the 
distillation column, comprising a CBX and 4-halo-1-butene and (ii) a 
column base vapor stream, i.e., a vapor stream removed from the lower 
section or bottom of the distillation column, comprising CPMX. 
Steps (1) and (2) of the three-step embodiment of the invention are carried 
out according to the procedures described above. The distillation column 
of step (3) typically is operated at a pressure of 100 Torr up to a 
pressure moderately above ambient pressure, e.g., up to about 2 to 3 bar 
absolute, and a column base temperature of about 30 to 115.degree. C. For 
example, when the distillation is carried out at approximately ambient 
pressure, the column base temperature normally will be in the range of 80 
to 115.degree. C. and an overhead vapor take-off temperature of 70 to 
84.degree. C. To achieve good separation of the CPMX, CBX and 
4-halo-1-butene which have similar boiling points, (CPMCl=86.degree. C., 
CBCl=83.degree. C., 4-chloro-1-butene=75.degree. C. at ambient pressure), 
a substantial portion of the overhead vapor is condensed and returned to 
the upper section of the column as reflux. Reflux ratios of about 10:1 to 
50:1 with 40 to 60 theoretical plates typically are required to achieve 
the desired separation. 
Heating the CPMX product in the presence of an acid can cause significant 
decomposition and/or isomerization of the product. Such catalytic amounts 
of acid can be generated as a result of the product halide contacting the 
materials of construction of the equipment, e.g., stainless steels, used 
for distillation. This acid-catalyzed decomposition/isomerization may be 
substantially overcome by performing the distillation in the presence of 
an acid scavenger or acceptor. This may be accomplished by the concurrent 
addition of an acid scavenger to the column during the distillation. 
Examples of acid scavengers which may be employed in the distillation 
include organic amines such as trialkylamines, pyridine and the likes), 
amides such as N-methylpyrrolidone and N-cyclohexylpyrrolidone, and/or 
inorganic bases such as sodium or potassium bicarbonate, sodium or 
potassium carbonates, and carboxylate salts of strong bases e.g., sodium 
acetate. The preferred acid scavengers are the trialkylamines having 
boiling points greater than the boiling point of any of the components of 
the crude product being distilled, e.g., trialkylamines having boiling 
points of about 100 to 250.degree. C. at ambient pressure. The amount of 
acid scavenger typically required gives an acid scavenger:crude product 
weight ratio in the range of about 0.001:1 to 0.1:1. 
Distillation step (3) is carried out by feeding the crude CPMX, i.e., 
organic phase (i) from step (2), to the mid-section of a distillation 
column operated at a temperature and pressure which provides a column 
overhead vapor stream comprising a CBX and 4-halo-1-butene and a column 
base vapor stream comprising CPMX. The distillation preferably is carried 
out while concurrently feeding an acid scavenger to the upper section of 
the distillation column. Operation of the distillation in a continuous 
manner has the advantage of limiting the heating time of the CPMX to 
minimize the possible thermal decomposition. The preferred acid scavenger 
having a higher boiling point remains in the base of the distillation set. 
The other effective way to reduce the isomerization during the distillation 
is to carry out the distillation under reduced pressure which allows the 
distillation to be carried out at lower temperature 30-50.degree. C. and 
to avoid the corrosion problems. The use of equipment such as glass column 
with packing, which is free of corrosion concerns, for the distillation of 
crude product can also effectively prevent the isomerization. 
The processes of this invention may be carried out in a continuous mode of 
operation. For example, CPMO may be introduced continuously into the lower 
part of a reaction zone wherein CPMO is halogenated by contact with an 
aqueous HX solution. The crude products which forms as an organic layer 
may be separated from the upper part of the reaction zone. HX gas is 
continuously introduced into the lower part of the reaction zone to 
maintain the concentration of the hydrogen halide solution constant. The 
advantage of continuous operation is to minimize the contact time of the 
product CPMX with the acid to avoid the further isomerization of CPMX to 
its isomers. 
The CPMO utilized in the present invention is readily obtained by the 
hydrogenation of cyclopropanecarboxaldehyde (CPCA) in the presence of a 
cobalt or nickel catalyst according to the process described in U.S. Pat. 
No. 5,475,151. The CPCA may be produced by the thermal isomerization of 
2,3-dihydrofuran as is described in U.S. Pat. No. 5,502,257. 
The processes provided by the present invention are further illustrated by 
the following examples. Gas chromatographic (GC) analyses were performed 
on a Hewlett-Packard 5890 series II gas chromatography with a 30 meter 
DB-Wax and a 30 meter DB-17 capillary columns. The identities of the 
products obtained were confirmed by nuclear magnetic spectrometry and gas 
chromatography-mass spectrometry by comparison to authentic samples. The 
percentages specified in the examples are by weight unless otherwise 
specified.

EXAMPLE 1 
To a 2-liter, jacketed flask was placed 36% hydrochloric acid (1577 g, 16 
mol, 1 liter) and cooled to 3.degree. C. CPMO (289.9 g, 4 mol, 99% purity) 
was added over a period of 1 hour while maintaining the temperature at 
3.degree. C. The reaction mixture was allowed to stand at this temperature 
for 16 hours. An organic phase which formed was separated to give 337.84 g 
of crude product which comprised 60.48% CPMCl, 35.28% CBCl and 4.24% 
4-chloro-1-butene. 
Distillation of the crude CPMCl was carried out in a column with stainless 
steel structure packing with about 50 theoretical plates and a reflux 
ratio of 30:1. The crude product was fed continuously to the middle 
section of the column while tributylamine was fed at the top of the 
column. Pure CPMCl was continuously removed as the base vapor after 
rectification with a short column section packed with Berl saddles. CPMCl 
was obtained in a purity of 97% assay and with 90% recovery. 
EXAMPLE 2 
36% Hydrochloric acid (1.4 liters) was cooled to -5.degree. C. and CPMO 
(288 g, 3.88 mol) was added while maintaining the temperature below 
0.degree. C. The reaction mixture was stirred for 3.5 hours at about 
-5.degree. C. and left to stand for 16 hours at -5 to 0.degree. C. The 
organic phase (top layer) was separated and washed with water to give 290 
g crude product comprised of 61.5% CPMCl, 35.6% CBCl and 2.9% 
4-chloro-1-butene. 
EXAMPLE 3 
36% Hydrochloric acid (1.4 liters) was cooled to 10.degree. C. and CPMO 
(288 g, 3.88 mol) was added while maintaining the temperature at 
9-11.degree. C. The reaction mixture was stirred for 3.5 hours at about 
10.degree. C. The organic phase (top layer) was separated and washed with 
water to give 282 g crude product comprised of 60.6% CPMCl, 35.8% CBCl and 
3.6% 4-chloro-1-butene. 
EXAMPLE 4 
36% Hydrochloric acid (1.4 liters) was cooled to 20.degree. C. and CPMO 
(288 g, 3.88 mol) was added while maintaining the temperature 
19-21.degree. C. The reaction mixture was stirred for 3.5 hours at about 
20.degree. C. The organic phase (top layer) was separated and washed with 
water to give 273 g crude product comprised of 58.9% CPMCl, 36.8% CBCl and 
4.3% 4-chloro-1-butene. 
EXAMPLE 5 
28% Hydrochloric acid (1.4 liters) was cooled to -5.degree. C. and CPMO 
(288 g, 3.88 mol) was added while maintaining the temperature below 
0.degree. C. The reaction mixture was stirred for 3.5 hours at about 
-5.degree. C. and left to stand for 16 hours at -5 to 0.degree. C. The 
organic phase (top layer) was separated and washed with water to give 193 
g crude product comprise of 54.7% CPMCl, 40.5% CBCl and 4.8% 
4-chloro-1-butene. 
EXAMPLE 6 
To a 2-liter jacketed flask was placed 48% hydrobromic acid (1490 g, 8.83 
mol, 1 liter) and the mixture was cooled to 3.degree. C. CPMO (151.62 g, 
2.085 mol, 99% purity) was added over a period of 30 minutes while 
maintaining the temperature at 3.degree. C. The reaction mixture was 
allowed to stand at 3.degree. C. for 24 hours. The organic phase was 
drained off to give 268.83 g of crude product comprised of 51.86% CPMBr, 
35% CBBr and 8.33% 4-bromo-1-butene. 
The crude product was distilled using a Teflon spinning band distillation 
system to give about 90% recovery of CPMBr having a purity of 98%. Small 
amounts (1% by weight of the total crude product) of N-methylpyrrolidone 
was added to the base of the distillation system to prevent the 
decomposition of CPMBr during the distillation. 
EXAMPLE 7 
48% Hydrobromic acid (1.4 liters) was cooled to -5.degree. C. and CPMO (300 
g, 4.04 mol) was added while maintaining the temperature below 0.degree. 
C. The reaction mixture was stirred for 3.5 hours at about -5.degree. C. 
and left to stand for 16 hours at -5 to 0.degree. C. The organic phase 
(bottom layer) was separated and washed with water to give 256 g crude 
product which comprises 59% CPMBr, 37% CBBr and 4% 4-bromo-1-butene. 
EXAMPLE 8 
62% Hydrochloric acid (0.25 liters) was cooled to -5.degree. C. and CPMO 
(50 g, 0.67 mol) was added while maintaining the temperature below 
0.degree. C. The reaction mixture was stirred for 3.5 hours at about 
0.degree. C. and allowed to stand for 16 hours at -5 to 0.degree. C. The 
organic phase (top layer) was separated and washed with water to give 71 g 
crude product comprised of 54% CPMBr, 37% CBBr and 7% 4-bromo-1-butene. 
The invention has been described in detail with particular reference to 
preferred embodiments thereof, but it will be understood that variations 
and modifications can be effected within the spirit and scope of the 
invention.