Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
- 2 - 1066702
The present invention relates to benzofuran derivatives
and to a process for their preparation.
Compounds of the general formula:
HO ~ 1l 2
NR3R4
~ wherein Rl and R2 may be the same or different and each
is selected from hydrogen or an alkyl group (notably an alkyl
group, containing from 1 to 6 carbon atoms, for example a methyl,
an ethyl or a propyl group) or Rl and R2 together form an alkylene
chain (e.g. one containing from 2 to 5 carbon atoms) and R3 and
R4 may be the same or different and each is selected from a lower
alkyl group or R3 arld R4 together with the N atom form a
heterocyclic rin ~ find use as intermediates in the production of
herbicides. The term lower is used herein with respect to alkyl
and alkoxy groups to denote that these groups contain from 1 to 6
carbon atoms. It has been proposed that these compounds should
be prepared by reacting the appropriate enamine, i.e. a compound
of the general formula
: -
RlR2C = CH-NR3R4 II
with benzoquinone. However, herbicidal compounds prepared from ~ -
the compounds of formula I produced in this way are unsatisfactory
in that solutions of the herbicidal compounds develop precipitates
on standing. We have found that these precipitates are caus~d-by
the presence of hydroquinone derived materials in the intermediate
compounds from which the final compounds are prepared. Surpris-
- 2 -
.
. . . .
. . : .; ' ,, ' :
_ 3 _ 106670Z
ingly, the presence of an aldehyde of the formula RlR2CHCHO during
reaction of the benzoquinone and the enamine reduces the amount of
the hydroquinone materials in the product of formula I and hence
in products prepared therefrom. It is thus possible to produce
herbicidal compounds of the formula
R5S2 ~
wherein Rl and R2 have the values given above (notably
methyl or ethyl); M is an alkyl group containing from 1 to 6
carbon atoms (notably a methyl, ethyl, propyl or isopropyl group)
and R5 is an alkyl group, preferably containing from 1 to 6 carbon
atoms, e.g. a methyl, ethyl or propyl group) which are contaminated
with less than 1 molar percent of hydroquinone derived impurities.
Accordingly, the present invention provides a compound of
formula
11 ~ l0 IV
(wherein Rlo is a group OM or NR3R4; Rll is hydrogen or a
2 1' 2' R3, R4, R5 and M have the values given
above) characterised in that the compound contains less than 1
molar percent thereof of hydroquinone derived impurities.
The hydroquinone derived impurities which are present in
less than 1 molar percent are hydroquinone itself in the case of
compounds of formula I and compounds of the formula
''.
- 3 -
~ '''' .
' ` 4,~
'' ' . ; '. ' ' . ~ ,' " ':', '' : ' '.' '', '' .
. . .: , , .
,, : ' '' ' ,', '. ' ' ' ' ,:," -
" ~ _ 4 _ 1066702
R5 SO~
R5S02 -O
5 in the case of the compounds of formula III. The impurities are
readily detected in the compounds of formula IV by gas/liquid
chromatography. It is preferred that the impurities be present
in less than 0. 5 molar percent.
From another aspect, the present invention provides a
process for preparing a compound of formula I which comprises
reacting benzoquinone with a compound of formula II characterised
in that the reaction is carried out in the presence of a compound
of formula RlR2CHCHO wherein Rl and R2 have the values given above.
The process of the invention is of especial use in the
preparation of compounds of formula I in which Rl and R2 are the
same lower alkyl (notably methyl or ethyl) and the group -NR3R4 is
selected from piperidino, morpholino, and pyrrolidino. In this
case the compound of formula RlR2CHCHO will be an aliphatic
aldehyde, notably isobutyraldehyde.
The process of the invention will usuaily be carried out in
the presence of a liquid medium. Suitable liquid media for -
present use include aromatic hydrocarbons, e.g. benzene, toluene
or xylene; aliphatic hydrocarbons, e.g. cyclohexane or petroleum
ethers; halogenated hydrocarbons; and aliphatic ketones, -
25 e.g. acetone and........................................................ - -
~ 4 --
3j -
. . , . : .
. .
., - . .
07/B/135
` 106670Z
methyl ethyl ketone. If desired the liquid medium may be provided
wholly or in part by the compound RlR2CHCHO, e.g. when
isobutyTaldehyde is used. However, it is preferred to use a
liquid medium in which the compound of formula I and water are
only slightly soluble OT miscible. Exemplary of such liquid media
are the aromatic hydrocarbons.
The benzoquinone and compound of formula II are conveniently
used in the forms of solutions or slurries in one of the liquid
media specified above and the reaction is preferably carried out
with agitation and at a temperature of from 20 to 60C, e.g. 40 to
50C, although lower or higher temperatures, e.g. up to the reflux
temperature of the reaction mixture, may be used. Where the
reaction is not carried out under reflux, it may be desirable to
heat the reaction mixture, e.g. to 100-120C, in the final stages
to assist completion of the reaction.
~ he amount of the compound of formula ~ R2CHCffO which is
present is preferably at least 10, e.g. 10 to 200, lar percent,
based on the amount of the compound of formula II, and is typically
in the range 20 to 100 mol~r percent. The presence of the compound
2Q RlR2CHCHO may be achieved by separate addition of the compound to -
the reaction mixture or by the use of the compound as a solvent or
carrier for either or both of the other reagents. However, a
convenient method for incorporating the compound ~ R2CHCH0 is to
use the reaction mixture in which the compound of formNla II is
prepared. Thus, the compound of formula II may be prepared by
.
` 08/B/135
.
- 6 - 1066702
reacting a compound H-NR3R4 with an excess, e.g. 10 to 200~, notably
20-100~, molar excess, of the compound ~ R2CHoH0 and the reaction
product used directly in the process of the invention without
purification, although it will usually be necessary to remove water
therefrom, e.g. by distillation. The present invention therefore
also provides a process for preparing a compound of formula I or a
derivative thereof which comprises reacting a compound of formula
H-NR3R4 with an excess of a compound of fo~mula ~ R2CHoH0 to give
a neaction mixture containing a compound of formula II and the
compound RlR2CHoH0; and reacting this reaction mixture with
benzoquinone.
Whilst the preparation of the compound of formula I may be
carried out by adding a solution of the enamine of formula II to a
solution or slurry of the benzoquinone, we have found that the
product of such a reaction may be discoloured due to side reactions
and surprisingly that these side reactions are suppressed if the
ena~ine is present for ~ost or all of the reaction period in more
than the stoichiometric amount required to react with the -
benzoquinone. -~
The presence of the requisite amount of enamine in the reaction
mixture can be achieYed by, for example, adding the benzoquinone
either as a single addition or progressively over a period of time
to a reaction mixture containing the desired amount of enamine; or
by adding the benzoquinone and enamine in the desired proportions to
a continuously operated process. Preferably, the overall excess of
-- 6 --
~. . . -
.
.
.:
_ 7 _ 1~6~70~
the enamine employed is from 1 to 10%, notably 1 to 4~, molar
although higher excesses may be used if desired and during the
initial stages of a batch process where benzoquinone is added
progressively to the enamine much larger excesses may occur.
Thus, the present invention also provides a process for
preparing a compound of formula I which comprises reacting a
compound of formula H-NR3R4 with zn excess of a compound of
formula RlR2CHCHO in the presence of an organic solvent to form
a reaction mixture containing a compound of formula ~I; and
reacting this reaction mixture with benzoquinone, the compound of
formula II being present in the reaction mixture at substantially
all times in more than the stoichiometric amount required to react
with the benzoquinone present in the reaction mixture. The
invention also comprises a process for preparing a compound of
formula I which process comprises reacting benzoquinone with a
compound of formula II characterised in that the reaction is -~
carried out in the presence of a compound of formula RlR2CHCHO and
in that at substantially all times during the reaction the
compound of formula II is present in more than the stoichiometric
20 amount required to react with the benzoquinone present in the --
reaction mixture.
The processes of the invention may be carried out batchwise
or as a continuous process and the product of formula I may be
recovered using customary techniques, e.g. by filtering the
25 reaction mixture in which it is produced to recover the solid -
product which may thereafter....................................
. ,,.. ,~
,,, , ,, :. . : ,
.: . ...
,, , , :
- 8 - 106670Z
be washed. However, where the compound of formula I is used as
an int~rmediate in the production of other compounds, e.g. of
formulae III or IV, it may not be necessary to separate it from
the reaction mixture.
The intermediate compounds of formula IV are of especial
use in the preparation of the herbicidal compounds of formula III,
that is compounds of formula IV where Rlo is OM and Rll is R5SO2.
From another aspect the invention provides a process for
preparing a compound of formula III which comprises treating a
compound of formula IV (wherein R1o is OM or NR3R4 when Rll is
hydrogen or Rlo is NR3R4 when R11 is R5SO2 and which compound is
contaminated with less than 1 molar percent of hydroquinone based
impurities) so as to convert a 2-NR3R4 group to a 2-OM group
and/or a 5-OH group to a 5-R5SO20- group. This is conveniently
15 done by reacting a compound of formula IV with a compound
R5SO2Hal (where Hal is halogen - notably chlorine) to convert the
5-OH group into a R5SO2O- group; and/or converting the 2-NR3R4
group into an -OM group by hydrolysis and alkoxylation. These
conversions may be carried out in either order. Preferably the
20 compound of formula IV has itself been prepared from a compound
of formula I obtained by a process described above.
The present invention therefore also provides a process
for preparing a compound of formula
6 ~ R~lln2 VI
30 ~ wherein Rl and R2 may be the same or different and each is
selected from an alkyl group or R1 and R2 together form an
~ - 8 -
, . .
- . . , .................... .. : . , : . ~
. ,; . ,, ., . , ., .. ' :: :, :: . . ', . ' . : ',
- 9 - ~066702
alkylene chain; M is an alkyl group; and R6 is selected from
hydrogen or a group R5S02- where R5 is an alkyl grou~7 which
comprises:
Stage (a) reacting benzoquinone with an anamine of formula:
RlR2C=CH-NR3R4 II
~ wherein Rl and R2 have the values given above and R3 and R4 may
be the same or different and each is selected from a lower alkyl
group or R3 and R4 together with the N atom form a heterocyclic
ring~ in the presence of a compound of formula RlR2CHCHO, the
enamine preferably being present at substantially all times during
the reaction period in more than the stoichiometric amount required
to react with the benzoquinone; whereby there is produced a compound
of formula
~ c~\/Rl2 I
N 3 4 :
and optionally converting this compound into a compound of formula . :
IV where Rlo is NR3R4 and Rll is R5SO2 by reaction with a compound .
of formula HalSO2R5.
Stage (b) reacting a compound of formula . -
6 ~ ~ C_ ~ VII
3 4
with an acid as hereinafter defined and a compound of formula HOM
(where M has the values given above), preferably in a single stage, :--
whereby there is produced a compound of formula VI.
The conversion of the NR2R4 group to an OM group ! Q . g. in .
~ 9 .,,
. .. , , , . , ., , . . ., , - .
' ' ' " ' ' '' ' ' '' "'" .;'" " ' . '' , '" '. " '', ' " "' i " '' ' ' ' ' ' ' "'' ' '
.. . . .. . . . .... .. . ........... . . .
. .,: : , , , . ,,,, .:, . :., , . , ~,. : .
. ;, .: , ,,,, . ,, i. :. . . ...
- 10 - 1o667~2
Stage (b) of the process described above, is suitably achieved by
treatment with an acid and an alkanol. This treatment may be
carried out in a single stage and preferably Stage ~b) is carried
out in a single stage by using a mixture of acid and alkanol as is
described and claimed in our co-pending application No. 38817/76.
The term acid as used herein in respect of Stage (b) is to
denote a strong acid, which may be a mineral acid or an organic
acid; which does not take part in deleterious side reactions during
the Stage (b) of the process, apart from forming a salt with the
amine HNR3R4 released during the process; and which preferably
dissociates in water to give at least 1 gram equivalent of H per
gram mol of acid. Thus,suitable acids for present use include
hydrochloric, sulphuric and phosphoric acids, but do not include
nitric acid which may oxidize the reagents and/or products. The
acid may be used in the form of an aqueous solution thereof or in
an anhydrous form. The mineral acid for present use is preferably
hydrochloric acid which desirably provides not less than 20 parts
by weight of HCl per 80 parts of water in the reaction mixture.
me compound HOM is, as indicated in the preferred compounds
which it is desired to produce, preferably a lower alkanol, notably
methanol, ethanol, propanol or iso-propanol.
Stage (b) is preferably carried out in a liquid medium, which
may be merely an excess of the alkanol reagent. However, the process
is conveniently carried out by adding the solution of the compound
of formula I produced in Stage (a) of the process to an agitated
mixture of the acid and alkanol so as to form a two phase reaction
mixture. The addition may take place in one or..................
R - lo
~"y
,. . ., .. . . . . ~......... . . . . . .
. - .. . . .. ,... . ,. . . . i . - .
. ... . . ~ . ... ..
,, .
09/B/13S
066702
re stages or may be on a continuous basis where the process is
operated continuously. The reaction may be carried out at
elevated temperatures, although it is preferred to use temperatures
below 40C.
We have found that the relative proportions of acid, alkanol,
and compound of formula I affect the yield and quality of the
product. We prefer to employ more than 1.5 molar proportions of
alkanol and more than 1.2 molar equivalent proportions of acid per
lar proportion of compound of formula I. Whilst the process may
be carried out under substantially anhydrous conditions, as when
H2S04 is used as the acid, water may be preferred with some acids,
e.g. when HCl is present. In this case we prefer to use more than
0.35 parts by weight of HCl per part of water in the reaction mixture.
It is preferred to agitate the reaction mixture and it will
be appreciated that all weights and proportions a~e in respect of
the total reaction mixture not just the organic or aqueous phase.
Apart fro~ the reagents and solvents, the reaction mixture
may contain minor amounts of other non-deleterious materials.
Thus, the compound of formLla II need not be in pure fo~m but may
be used in the form of the reac~ion product from an earlier
process step as outlined below.
The compound of formula VI may be recovered from the ~eaction
mixtu¢e by allowing the mixture to separate into organic and
aqueous phases, removing the organic layer and recovering the
product therefrom, e.g. by distillation (to remQve excess alkanol
- 11 - '
, , , ', " ' ", ''": ' `; , . " ' ' ;' ' . .' ' ' '
- 12 ~0667~2
and solvent when present), washing with a mild alkali (e.g. sodium
carbonate) and further distillation, preferably under reduced
pressure, to remove final amounts of solvent. The isolated product
may then be purified by conventional techniques.
As indicated by formula VI, the product of the above process
may have the 5-position in the form of a 5-OH group or a derivative
thereof. However, it is preferred that the 5-position be in the
form of an R5SO2O- group, i.e. that the product be of tha general
formula III. This group is preferably a CH3SO2O- group and is
preferably introduced into the intermediate compound of formula
I by reacting this compound with HalSO2R5 in the presence of an
acid acceptor (Hal being halogen, notably chlorine) between
Stages (a) and (b). Alternatively, the R5SO2O-group may be
introduced by reacting a compound of formula VI wherein R6 is
hydrogen with Hal SO2R5 after Stage (b~ of the invention has been
carried out.
In reacting a compound of formula I or VI with Hal SO2R5,
the reaction is carried out in the presence of an acid acceptor
which term includes tertiary amines, notably trialkylamines,
e.g. trimethylamine or triethylamine; tertiary aromatic amines,
e.g. dimethyl-aniline; and pyridine and its homologues. Whilst
the reagents may be used in substantially the stoichiometric amounts,
we prefer to use a small excess, e.g. up to 20% molar excess, of
the compound R5SO2Hal based on the compound of formula I or VI
and an excess, e.g. 10 to 50% molar excess, of acid acceptor
based on the amount of H-Hal which would theoretically be
liberated.
-12-
.. .. : , . :. . . .. : : . . .. . .. . ,.. ~ . :~
.. . . . . .
:: , . . .
: . .
, .
- 13 ~06~702
The reaction may be carried out merely by mixing together
the R5SO2Hal and compound of formula I or VI simultaneously or
sequentially and in one or more stages. Desirably the reaction
temperature is less than 100C, preferably within the range 30 to
80C. However, to aid uniform reaction we prefer to carry out the
reaction in an organic solvent as reaction medium, or in an excess
of the acid acceptor. Suitable solvents include non-polar
organic solvents, e.g. benzene, toluene, xylene or hexane.
When the reaction is substantially complete, as evidenced
by analysis of a sample showing little or no remaining initial
compound of formula I or VI, the product may be recovered using
conventional techniques. However, where the product has not been
subjected to Stage (b) of the process of the invention, i.e.
is a compound of formula VII where R6 is R5S02-, we prefer not to
isolate the produc'~ but merely to extract the halogen salt of the
acid acceptor from the reaction mixture by water extraction and
to separate off the organic layer containing the compound of
formula VII for use in preparing the compound of formula VI where
R6 is R5SO2- (i.e. a compound of formula III) as described above.
From the above, it will be seen that the stages of
the process of the invention may be summarised as:
.. .. . . .
, , ' , , . , i . ' ' ' ' ~' ' ' , .' ' " ': ' ' ' ~
- . . . ; .: , : : .
. . .
., . , . , :
: , ,;
.
~ ~-, , . ,: ,
10/s/135
1 0 6 6 7 0 2
- 14 -
Stage 1 ~ R2CHCH0
l H ~ R4
Sta~ 2 RlR2C.C- ~ R4 II
¦ + benzoquinone
H0 ~ ~ l _ H
/ \ - R4
Sta~e_3A R5S02Hal ~ acid acceptor acid ~ Sta~e 3B
~ alkanol
R5 0~ ~ L Vlll~ IX ~
20 Sta~e 4A acid ~ alkanol ~ S02Hal ~ acid acc~e~ptor
R5S02o ~ ~ R2 III
ov, ~ H
, ~ . .. ... . . .
,; , . ..
ll/B/13S
- 15 - 1066702
The above process stages may be carried out as distinct and
separate steps but, as indicated above, readily lend the~selves
to sequential operation in that reaction products from one stage
may be used directly in a later stage. Furthermore, it is
possible to recover excess reagents and solvents for re-use.
Thus, acid acceptor may be recovered from the aqueous phase from
stage 3A or 4B by treatment of the halogen salt with alkali (e.g.
NaCH) and subsequent distillation; the organic phase of the
reaction mixtures from stages 3B, and/or 4A may be fractionally
distilled to recover alkanol and solvent, and the aqueous phases
may be distilled to recover alkanol and, possibly, acid, the
residue then being treated with alkali to liberate the amine
HNR3R4 and the acid acceptor which may have been carried over
in the organic phase from stage 3A to stage 4A and this residue is
fractionally distilled to recover amine for use in stage 1 and
acid acceptor for use in stages 3A or 4B.
The process of the invention will now be illustrated by the
following Examples, in which all parts and percentages are given
by weight unless stated otherwise:
ExamPle 1
Preparation of enamine of formula II
To a stirred mixture of 332 parts of isobutylaldehyde (100~
molar percent excess) with 867.5 parts of toluene were added 200.5
parts of moTpholine. The temperature rose from 20C to 41C. The
mixture was refluxed with continuous separation and removal of the
- 15 - --
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~. , ~, . ...
.~$ , ' , ,: , .
'~ , "' ' '' ~ .
12/B/135
_ , .
- 16 106670Z
aqueous phase from the returning solvent stream. To complete the
water removal, the final stages were carried out with a
fractionation column. The total time at reflux was 4.8 hours.
Preparation of 2,3-dihydro-3,3-dimethyl-5-hydroxy-2-morpholino-
S benzofuran of formula I
To 54 parts of technical benzoq~inone were added 51.5 partsof toluene and to this slurry was added sufficient of the enamine
solution as prepared above to be equal to a 4~ molar excess of
enamine to technical benzoquinone. The time of addition was 0.7
hours, reaction temperature 40-45C during addition. After a
further 0.7 hours the reaction mixture was raised to the boiling
point and maintained at reflux for 0.25 hours. After cooling to
25C the insoluble product was filtered off, washed with toluene,
and air dried to constant weight giving 2,3-dihydro-3,3-dimethyl-
5-hydroxy-2-morpholino-benzofuran.
$he yield of 2,3-dihydro-3,3-dimethyl-5-hydroxy-2-morpholino-
benzofuran was 89.3~ based on the benzoquinone starting material and
the purity was 98.7~ by analysis. The hydroquinone impurity in the
product was 0.2~.
Comparative example
The above steps were repeated, except that the enamine solution
was fractionally distilled to remove unreacted isobutyraldehyde so
that no significant amount of isobutyraldehyde should be present
during reaction of the enamine with the benzoquinone. In this case
the 2,3-dihydro-3,3-dimethyl-5-hydroxy-2-morpholino-benzofuran was
- 16 -
, . : , . . , .,:: . :. :
.. . .
- : .
- .
, . . .
~~ 13/B/135
.. ~
- 17 - 1(~6 6 7 0~
p~oduced in B9.2~ yield and at a purity of 96.1~. The hydroquinone
content was 1.6~.
Example 2
The process of the Cbmparative Example was repeated, except
that isobutyraldehyde in an equimolar amount based on the enamine
used, was added as a separate feed to the reaction vessel in which
the 2,3-dihydro-3,3-dimethyl-5-hydroxy-2-morpholino-benzofuran was
being prepared. The product was produced in 90~ yield, at a purity
of 97.8~ and with a hydroquinone content of 0.2~.
Example 3
To a stirred mixture of 332 parts of isobutyraldehyde
(100~ lar percent excess) with 867.5 parts of toluene were added
200.5 parts of morpholine. The temperature rose from 20C to 41C.
The mixture was refluxed with continuous separation and removal of
the aqueous phase from the returning solvent stream. To complete
the water re val, the final stages were carried out with a
fractionation column. The total time at reflux was 4.8 hours. To
this enamine solution was added a total of 238.2 parts of technical
benzoquinone (95.7~ molar on the morpholine assuming 100
conversion to enamine) over a period of 1.2 hours. The temperature
was maintained at 35-45C throughout the addition by heating or
cooling as required. When the heat of reaction was no longeT
observed, t`he reaction mixture was raised to the boiling point and
maintained at reflux for 0.5 hours. After cooling to 25C the
insoluble product was filtered off, washed with 670 parts of
- 17 -
- .
. , :, .
;.~ .
14/s/135
- 18 - 1066702
toluene, and air dried to constant weight giving 505.1 parts of
2,3-dihydro-3,3-dimethyl-5-hydroxy-2-morpholino-benzofuran, yield
91.7~ based on the technical benzoquinone used.
Ex~u~e 4
To a slurry of 108 parts of benzoquinone in 104 parts of
toluene was added 0.52 mo~ar equivalents of enamine dissolved in
toluene and isobutyraldehyde and prepared in a similar manner to
the enamine solution used in Example 3. The addition time was
0.75 hours, reaction temperature 40-45C. The reaction mixture
was left agitating for 16 hours before a further 0.52 molar
equivalents of enamine solution was added. After refluxing the
reaction mixture and isolating the product as described in
Example 1, 208.3 parts were obtained, equivalent to an 83.6~ yield
b æ ed on the technical benzoquinone used.
Whereas the product obtained in Example 3 was light tan in
colour, the product from this Example was grey.
Example 5
3-dihydro-3 3- ~ holino-benzofuran-S-
~1 methane sul~honate of formula VIII
The product from Example 1 (112.5 parts) was reslurried in
350 parts of toluene and heated to 40C with agitation. Methane
sulphonyl chloride (56.5 parts) and triethylamine (50.5 parts) were
~dded simLltaneously but separately to the reaction mixture,
which was maintained at 40-46C, over a period of 0.35 hours. A
25 further 5 parts of triethylamine were added, ~ollowed by 110 parts -
- 18 -
, - , . ~ ,, ~, ........................................ .
., , . ~ . . . . .
, : ~
- 19 - ~066702
of water. The two phase reaction mixture was heated to 50-55C
and then allowed to separate. me lower, triethylamine
hydrochloride, layer was removed. The upper organic layer was
evaporated to dryness to give solid 2,3-dihydro-3,3-dimethyl-2-
morpholino-benzofuran-5-yl methane sulphonate.
Preparation of 2,3-dihydro-3,3-dimethyl-2-ethoxy-benzofuran-5-yl
methane sulphonate of formula III
The product from the above stage (24.9 parts) was suspended
in water (50 parts) and anhydrous hydrochloric acid (22.4 parts).
The suspension was rapidly heated to 90-100C and then cooled
after 2 minutes. The crude product was extracted into ether
(3 x 60 parts) and the extracts washed with water (2 x 50 parts).
The extracts were dried with sodium sulphate and evaporated to
give a gum which crystallised to give 2,3-dihydro-3,3-dimethyl-
2-hydroxy-benzofuran-5-yl-methane sulphonate crystals. The
crystals were dissolved in ethanol containing 2 drops of sulphuric
acid and refluxed for one hour. The mixture was then cooled,
neutralised with triethylamine and evaporated to about one quarter
of its volume. Water was added to precipitate 2,3-dihydro-3,3-
dimethyl-2-ethoxy-benzofuran-5-ylmethane sulphonate. This product
contained 0.4% dimesylquinol impurity as compared to 2% in a
product produced from material derived from the Comparative Example
to Example 1.
Example 6
Stage (a) Preparation of enamine of formula II and its conversion
to a compound of formula I
-- 19 -- . -
~ ..
~., ~, , ~ ' . `. ' . ' :: :
..
. . . .
,
- 20 _ 1 O 6 6 7 ~ 2
To a stirred mixture of 332 parts of isobutyraldehyde
(100% molar per cent excess) with 867.5 parts of toluene were
added 200.5 parts of morpholine. The temperature rose from 20~C
to 41C. The mixture was refluxed with continuous separation and
removal of the aqueous phase from the returning solvent stream.
To complete the water removal, the final stages were carried out
with a fractionation column. The total time at reflux was
4.8 hours.
To the enamine solution thus produced was added a total of
238.2 parts of technical benzoquinone over a period of 1.2 hours.
The temperature was maintained at 35-45C throughout by heating
or cooling as required. When the heat of reaction was no longer
observed, the reaction mixture was raised to the boiling point
and maintained at reflux for 0.5 hours. After cooling to 25C
the insoluble product was filtered off, washed with 670 parts of
toluene, and air dried to constant weight giving 505.1 gms of
2,3-dihydro-3,3-dimethyl-5-hydroxy-2-morpholino-benzofuran.
Yield 91.7~ on the technical benzoquinone used.
Stage (b) Prepaxation of compound of formula VIII and its
conversion to a compound of formula III
Preparation of 2,3-d hydro-3,3-dimethyl-2-morpholino-benzofuran-5 - --
-yl methane sulphonate (Stage 3A)
The product from Stage (a) (505.1 parts) was reslurried in
1083 parts of toluene and heated to 40C with agitation. Methane
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- 20 -
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- 21 - 1066702
sulphonyl chloride (258 parts) and triethylamine (228 parts)
were added simultaneously but separately to the reaction mixture,
which was maintained at 40-46C, over a period of 0.35 hours.
A further 23 parts of triethylamine were added, followed by
585 parts of water. The two phase reaction mixture was heated
to 50-55C; and then allowed to separate. The lower, triethyl-
amine hydrochloride, layer was removed and the upper organic
was passed to stage 4A.
Pre~aration of 2,3-dihydro-3,3-dimethyl-2-ethoxy-benzofuran
-5-yl-methane sulphonate (Stage 4A)
To the solution from stage 3A were added 350 parts of
ethyl alcohol, 43 parts of water, and 655 parts of 30% w/w
hydrochloric acid. The temperature rose to 47C. The two-phase
reaction mixture was agitated for 16 hours with cooling to 20C
and after settling, the lower aqueous layer was removed.
me upper solvent layer was distilled to remove the bulk
of the unreacted ethyl alcohol, and washed with sodium carbonate
solution to remove traces of hydrochloric acid. The solution
was then distilled to remove the remaining toluene leaving
564 parts of product - yield 87.5% on the technical benzoquinone
used in Stage (a).
Example 7
Alternative method for carrying out Stage (b) in Example 6 -
Prep ration of 2,3-dihydro-3,3-dimethyl-5-hydroxy-2-ethoxy-
benzofuran of formula IX (Stage 3B)
- 21 -
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1066~02
- 22 -
97 parts of 2,3-dihydro-3,3-dimethyl-5-hydroxy-2
-morpholino-benzofuran prepared as in Stage (a) of Example 6
were allowed to air-dry after filtration and were added to
513 parts of ethyl alcohol and 32.5 parts of water. To this
were added 72 parts of concentrated sulphuric acid and the
mixture was refluxed for 4 hours.
The reaction mixture was cooled and poured into 3200
parts of ice and water to give an oil which solidified on
seeding with previously prepared product. This product was
filtered off and air dried. Yield: 57.7 parts, purity by
GLC 95%, equivalent to a molar yield of 67.5%. Continuous
ether extraction of the filtrate showed that a further 5.5%
of product had remained in solution.
Stage 4B - Preparation of 2,3-dihydro-3,3-dimethyl-2 -
-ethoxy-benzofuran-5-yl methane sulphonate of formula III
8.32 parts of the product from stage 3B were dissolved
in 20 parts of toluene and 6 parts of triethylamine. To this
were added 6.3 parts of methane sulphonyl chloride over 0.2
hours, the temperature being maintained at 40-45C. 15 parts
of water were added with agitation, and after separation of
the lower layer and evaporation to dryness, 11.7 parts of
product were obtained, purity 91% by GLC, equivalent to a
98~ molar yield.
- 22 -
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