Process for preparing benzoic acid derivative intermediates and benzothiophene pharmaceutical agents

Processes for producing benzothiophenes employing ethylene carbonate or propylene carbonate are provided.

FIELD OF THE INVENTION 
The present invention relates to the fields of pharmaceutical and organic 
chemistry and provides novel processes for preparing compounds of formula 
I 
##STR1## 
wherein 
R is C.sub.1 -C.sub.4 alkyl; 
R.sup.1 and R.sup.2 each are independently C.sub.1 -C.sub.4 alkyl, or 
combine to form piperidinyl, pyrrolidinyl, methylpyrrolidinyl, 
dimethylpyrrolidinyl, morpholino, dimethylamino, diethylamino, or 
1-hexamethyleneimino; and 
n is 2 or 3; 
or a pharmaceutically acceptable salt thereof; and compounds of formula II 
##STR2## 
wherein 
R.sup.3 and R.sup.4 each are H or a hydroxy protecting group; and 
R.sup.1, R.sup.2, and n are as defined above; or a pharmaceutically 
acceptable salt thereof. 
Compounds of formula II, particularly raloxifene, in which R.sup.1 and 
R.sup.2 combine to form a piperidinyl moiety, R.sup.3 and R.sup.4 each are 
H, and n is 2, are well known in the pharmaceutical art as having activity 
for the treatment of certain disease states including, for example, 
osteoporosis. 
BACKGROUND OF THE INVENTION 
Typically, compounds of formula I are prepared by reacting, for example, 
.beta.-chloroethylpiperidine hydrochloride and ethyl 4-hydroxybenzoate in 
methyl ethyl ketone, in the presence of potassium carbonate (see, U.S. 
Pat. No. 4,418,068.) However, the referenced synthetic route has certain 
undesirable aspects. Firstly, the solvent, methyl ethyl ketone, is 
hazardous and requires expensive handling and disposal procedures. 
Secondly, use of this solvent sets a limit of 80.degree. C. as a reaction 
temperature during formation of an ester, thus limiting the rate of the 
potassium carbonate catalyzed alkylation reaction. Furthermore, the 
organic layer containing the ester must be stripped to an oil prior to 
dissolution of the oil in aqueous sodium hydroxide and methanol. This oil 
preparation step is time consuming and could reduce the ultimate yield 
with large-scale production. 
Thus, a more efficient, less expensive process for preparing compounds of 
formula I, and, ultimately, compounds of formula II, especially if such an 
efficient process did not require the use of hazardous solvents, would be 
a significant and desirable advance over the current state of the art. The 
present invention provides such a process. 
Analogously, Yoshino, et al, Bulletin of the Chemical Society of Japan, 
4:553-556 (1973), disclose condensation reactions of ethylene carbonate 
with a variety of phenols in the presence of tetraethylammonium halides or 
a metal hydride such as lithium or sodium hydride. These reactions 
generally are run in the presence of dimethylformamide (DMF) as a solvent, 
the presence of which creates considerable limitations. Most importantly, 
the use of DMF would require the isolation of each intermediate compound 
prepared by the process of the present invention prior to the commencement 
of the subsequent step. The replacement of DMF with a solvent which would 
allow each step of the present processes to be run without isolating each 
intermediate would provide a significant advance to the present state of 
the art. Such an advance is provided by the present processes. 
SUMMARY OF THE INVENTION 
The present invention provides a novel process for preparing compounds of 
formula I 
##STR3## 
wherein 
R is C.sub.1 -C.sub.4 alkyl; 
R.sup.1 and R.sup.2 each are independently C.sub.1 -C.sub.4 alkyl, or 
combine to form piperidinyl, pyrrolidinyl, methylpyrrolidino, 
dimethylpyrrolidino, morpholino, dimethylamino, diethylamino, or 
1-hexamethyleneimino; and 
n is 2 or 3; 
or a pharmaceutically acceptable salt thereof, comprising 
a) condensing (C.sub.1 -C.sub.4 alkyl) 4-hydroxybenzoate with ethylene 
carbonate or propylene carbonate in the presence of a condensation 
catalyst and a moderately polar, water immiscible solvent having a high 
boiling point; 
b) reacting the product of step a), a compound of formula III 
##STR4## 
wherein 
R and n are as defined above, with a leaving group donor; and 
c) reacting the product of step b), a compound of formula IV 
##STR5## 
wherein 
R and n are as defined above; and 
X is a leaving group, with a base selected from the group consisting of 
piperdine, pyrrolidine, methylpyrrolidine, dimethylpyrrolidine, 
morpholine, dimethylamine, diethylamine, and 1-hexamethyleneimine. 
The present invention also provides a novel process for preparing compounds 
of formula II 
##STR6## 
wherein 
R is C.sub.1 -C.sub.4 alkyl; 
R.sup.1 and R.sup.2 each are independently C.sub.1 -C.sub.4 alkyl, or 
combine to form piperidinyl, pyrrolidinyl, methylpyrrolidino, 
dimethylpyrrolidino, morpholino, dimethylamino, diethylamino, or 
1-hexamethyleneimino; and 
n is 2 or 3; 
or a pharmaceutically acceptable salt thereof, comprising 
a) condensing (C.sub.1 -C.sub.4 alkyl) 4-hydroxybenzoate with ethylene 
carbonate or propylene carbonate in the presence of a condensation 
catalyst and a moderately polar, water immiscible solvent having a high 
boiling point; 
b) reacting the product of step a), a compound of formula III 
##STR7## 
wherein 
R and n are as defined above, with a leaving group donor; 
c) reacting the product of step b), a compound of formula IV 
##STR8## 
wherein 
R and n are as defined above; and 
X is a leaving group, with a base selected from the group consisting of 
piperdine, pyrrolidine, methylpyrrolidine, dimethylpyrrolidine, 
morpholine, dimethylamine, diethylamine, and 1-hexamethyleneimine; 
d) reacting the product of step c) with a compound of formula IV 
##STR9## 
wherein R.sup.3 and R.sup.4 are as defined above, or a pharmaceutically 
acceptable salt thereof; 
e) optionally removing the hydroxy protecting groups from the reaction 
product from step d); and 
f) optionally forming a salt of the reaction product from either step d) or 
step e). 
Further provided are novel compounds of formula I above, which are useful 
as intermediates for preparing compounds of formula II above. 
DETAILED DESCRIPTION OF THE INVENTION 
One aspect of the present invention provides a process for preparing a 
compound of formula I 
##STR10## 
wherein 
R is C.sub.1 -C.sub.4 alkyl; 
R.sup.1 and R.sup.2 each are independently C.sub.1 -C.sub.4 alkyl, or 
combine to form piperidinyl, pyrrolidinyl, methylpyrrolidino, 
dimethylpyrrolidino, morpholino, dimethylamino, diethylamino, or 
1-hexamethyleneimino; and 
n is 2 or 3; 
or a pharmaceutically acceptable salt thereof, comprising 
a) condensing (C.sub.1 -C.sub.4 alkyl) 4-hydroxybenzoate with ethylene 
carbonate or propylene carbonate in the presence of a condensation 
catalyst and a moderately polar, water immiscible solvent having a high 
boiling point; 
b) reacting the product of step a), a compound of formula III 
##STR11## 
wherein 
R and n are as defined above, with a leaving group donor; and 
c) reacting the product of step b), a compound of formula IV 
##STR12## 
wherein 
R and n are as defined above; and 
X is a leaving group, with a base selected from the group consisting of 
piperidine, pyrrolidine, methylpyrrolidine, dimethylpyrrolidine, 
morpholine, dimethylamine, diethylamine, and 1-hexamethyleneimine. 
General terms used in description of chemical formulae herein bear their 
usual meanings. For example, the term "C.sub.1 -C.sub.4 alkyl" refers to 
straight or branched chains of 1 to 4 carbon atoms including, methyl, 
ethyl, propyl, isopropyl, butyl, n-butyl, and isobutyl. 
The term "halo" includes bromo, chloro, fluoro, and iodo. 
In formula II compounds, the R.sup.3 and R.sup.4 hydroxy protecting groups, 
when R.sup.3 and R.sup.4 are not H, denote groups which generally are not 
found in final, therapeutically active compounds, but which are 
intentionally introduced during a portion of the synthetic process to 
protect a group which otherwise might react in the course of chemical 
manipulations, and is then removed at a later stage of the synthesis. 
Since compounds bearing such protecting groups are of importance primarily 
as chemical intermediates (although some derivatives also exhibit 
biological activity), their precise structure is not critical. Numerous 
reactions for the formation and removal of such protecting groups are 
described in a number of standard works including, for example, Protective 
Groups in Organic Chemistry, Plenum Press (London and New York, 1973); 
Green, T. W., Protective Groups in Organic Synthesis, Wiley (New York, 
1981); and The Peptides, Vol. I, Schrooder and Lubke, Academic Press 
(London and New York, 1965). 
Representative hydroxy protecting groups include, for example --C.sub.1 
-C.sub.4 alkyl, --CO--(C.sub.1 -C.sub.6 alkyl), --SO.sub.2 --(C.sub.4 
-C.sub.6 alkyl), and --CO--Ar in which Ar is optionally substituted 
phenyl. The term "substituted phenyl" refers to a phenyl group having one 
or more substituents selected from the group consisting of C.sub.1 
-C.sub.4 alkyl, C.sub.1 -C.sub.5 alkoxy, hydroxy, nitro, chloro, fluoro, 
and tri(chloro or fluoro) methyl. The term "C.sub.1 -C.sub.5 alkoxy" 
represents a C.sub.1 -C.sub.5 alkyl group attached through an oxygen 
bridge such as, for example, methoxy, ethoxy, n-propoxy, isopropoxy, and 
the like. Preferred R.sup.3 and R4 hydroxy protecting groups are C.sub.1 
-C.sub.4 alkyl, particularly methyl. 
In the present, novel process (C.sub.1 -C.sub.4 alkyl) 4-hydroxybenzoate is 
condensed with ethylene carbonate or propylene carbonate, preferably the 
former, in the presence of an appropriate condensation catalyst and a 
moderately polar, water immiscible solvent having a high boiling point. 
Each of the starting materials used in the first step of the present 
process step a)! are commercially available or can be prepared via 
procedures well known to the skilled artisan. 
The amount of reactants used in this reaction is that amount necessary to 
affect coupling. Typically, an equivalent amount to, preferably, a slight 
excess of the ethylene carbonate or propylene carbonate is used for each 
equivalent of (C.sub.1 -C.sub.4 alkyl) 4-hydroxybenzoate, preferably ethyl 
4-hydroxybenzoate, substrate. 
Appropriate condensation catalysts include tetra(C.sub.1 -C.sub.4 
alkyl)ammonium halides and metal hydrides such as, for example, lithium 
hydride. Preferably, an equivalent of (C.sub.1 -C.sub.4 alkyl) 
4-hydroxybenzoate substrate. 
The solvent employed in the present reaction is a moderately polar, water 
immiscible solvent having a high boiling point. The term "moderately 
polar" means a solvent having a functional ester, ether, or halogen moiety 
and include, for example, amyl acetate, diethoxyethane, chlorobenzene, 
methyl benzoate, and anisole. Of these, anisole is especially preferred. 
The term "having a high boiling point" means those moderately polar, water 
immiscible solvents which have boiling points greater than 100.degree. C. 
Because the present reaction step, and each reaction step of the present 
process can be run at temperatures in the range from about a minimum of 
100.degree. C. to reflux of the given reaction mixture, the upper 
temperature limit of the selected solvent is unlimited, provided the 
solvents boiling point is greater than 100.degree. C. However, when 
anisole, the preferred solvent, is employed, it is preferred to run the 
first step of the present reaction in the temperature range from about 
130.degree. C. to about 150.degree. C. 
The solvents used in the present process provide distinct advantages over 
the prior art ketone and highly polar solvents such as DMF. Compared to 
ketone solvents such as methyl ethylketone, the solvents used in the 
present process require less expensive handling and disposal procedures. 
Equally important, the solvents used in the present process allow the 
process steps to be run at a higher temperature than the solvents 
disclosed in the prior art. Furthermore, when compared to highly polar 
solvents such as DMF, the solvents of the present process allow each step 
of the process to be run without isolating each intermediate. Thus, the 
solvents used in the present process provide a distinct and unexpected 
advantage over the solvents discussed in the prior art for analogous 
reactions. 
The length of time for this reaction to run is that amount necessary for 
the desired intermediate to be prepared. Typically, the first reaction 
step of the present process takes from about 15 hours to about 60 hours. 
The optimal time can be determined by monitoring the progress of the 
reaction via conventional chromatographic techniques such as thin layer 
chromatography. 
In addition, it is preferred to maintain each reaction step of the present 
process under an inert atmosphere such as, for example, argon, or, 
particularly, nitrogen. 
The first step of the present process provides a compound of formula III 
##STR13## 
wherein R and n are as defined above, which then is reacted with a leaving 
group donor via well known procedures. Typically, the hydrogen of the 
hydroxy moiety of a formula III compound, in which R preferably is ethyl, 
is substituted with a leaving group such as, for example, a sulfonate such 
as methanesulfonate, 4-bromobenzenesulfonate, toluenesulfonate, 
ethanesulfonate, isopropanesulfonate, 4-methoxybenzenesulfonate, 
4-nitrobenzenesulfonate, 2-chlorobenzenesulfonate, triflate, and the like, 
halogens such as iodo or bromo, and other related leaving groups. A 
leaving group donor, therefore, is a compound which will substitute a 
formula III compound with a leaving group to provide a compound of formula 
IV 
##STR14## 
wherein X is a leaving group. 
For the present reaction step, an equivalent to, preferably, a slight 
excess of a leaving group donor, preferably sulfonyl chloride, is used for 
each equivalent of a formula III compound. The reaction generally is run 
in the presence of an appropriate base, such as pyridine, under an inert 
atmosphere. 
The present reaction may be run at a temperature from about 60.degree. C. 
to about 90.degree. C., preferably, at about 75.degree. C., and is run in 
a relatively short period of time; typically from about one-half hour to 
two hours. Of course, conventional chromatographic techniques may be used 
to determine the progress of the reaction. Additional compounds of formula 
IV may be provided by allowing the reaction mixture to sit for about 
another 6 to about 18 hours after the above-heating period, adding about 
one-half equivalent of the desired leaving group donor per each equivalent 
of formula III substrate, heating for about one-half hour to about two 
hours, and allowing the mixture to cool to ambient temperature. 
In the third step of the present process, a compound of formula IV above is 
reacted with at least 2 equivalents of a base selected from the group 
consisting of piperidine, pyrrolidine, methylpyrrolidine, 
dimethylpyrrolidine, morpholine, dimethylamine, diethylamine, or 
1-hexamethyleneimine per equivalent of a formula IV compound, in the 
presence of an appropriate base, via well known procedures. 
Appropriate bases include organic and inorganic bases, but inorganic bases, 
particularly a carbonate or bicarbonate base, is preferred. Of these, 
powdered potassium carbonate is especially preferred. 
Furthermore, it is preferred to maintain the present reaction step under an 
inert atmosphere such as, for example, argon or, particularly, nitrogen. 
The present reaction may be run at a temperature from about 60.degree. C. 
to about 100.degree. C. Preferably, this reaction is run at about 
80.degree. C. 
Typically, this reaction is run in from about 2 to about 18 hours, and the 
progress of the reaction can be monitored using standard chromatographic 
techniques. 
The product of the present process is isolated and purified via procedures 
well known to one of ordinary skill in the art, particularly as 
hereinafter described. 
The reaction products from steps a) and b) of the present process may be 
isolated and purified, via standard techniques, prior to commencement of 
the next step of the present process, or, preferably, each step, a), b), 
and c), is run in the same vessel. 
The product of the present process, a compound of formula I, is novel and 
useful as an intermediate for preparing pharmaceutically active compounds 
of formula II. 
Another aspect of the present invention provides a process for preparing a 
compound of formula II 
##STR15## 
wherein 
R is C.sub.1 -C.sub.4 alkyl; 
R.sup.1 and R.sup.2 each are independently C.sub.1 -C.sub.4 alkyl, or 
combine to form piperidinyl, pyrrolidinyl, methylpyrrolidino, 
dimethylpyrrolidino, morpholino, dimethylamino, diethylamino, or 
1-hexamethyleneimino; and 
n is 2 or 3; 
or a pharmaceutically acceptable salt thereof, comprising 
a) condensing (C.sub.1 -C.sub.4 alkyl) 4-hydroxybenzoate with ethylene 
carbonate or propylene carbonate in the presence of a condensation 
catalyst and a moderately polar, water immiscible solvent having a high 
boiling point; 
b) reacting the product of step a), a compound of formula III 
##STR16## 
wherein 
R and n are is as defined above, with a leaving group donor; 
c) reacting the product of step b), a compound of formula IV 
##STR17## 
wherein 
R and n are as defined above; and 
X is a leaving group, with a base selected from the group consisting of 
piperidine, pyrrolidine, methylpyrrolidine, dimethylpyrrolidine, 
morpholine, dimethylamine, diethylamine, and 1-hexamethyleneimine; 
d) reacting the product of step c) with a compound of formula V 
##STR18## 
wherein R.sup.3 and R.sup.4 are as defined above, or a pharmaceutically 
acceptable salt thereof; 
e) optionally removing the reaction product from step d); and 
f) optionally forming a salt of the reaction product from either step d) or 
step e). 
For the present, novel process, steps a), b), and c) are the same as steps 
a), b), and c) in the above described process, plus additional steps d) 
(acylation of formula V compound with a formula I compound), step e) 
(optional removal of any hydroxy protecting group), and step f) (optional 
salt formation of a protected or deprotected compound of formula II). 
In step d), the reaction product from step c) which, preferably, is 
isolated and purified prior to the initiation of this step, is reacted 
with a compound of formula V 
##STR19## 
wherein R.sup.3 and R.sup.4 are as defined above. 
Compounds of formula V, are known in the art and are prepared, for example, 
as described by Peters in U.S. Pat. No. 4,380,635, or Jones, et al., in 
U.S. Pat. Nos. 4,133,814 and 4,418,068, each of which is herein 
incorporated by reference. Although the R.sup.3 and R.sup.4 protecting 
groups are not required for this step, thus allowing a compound of formula 
V in which R.sup.3 and R.sup.4 are hydrogen to be acylated with a compound 
of formula I in which R.sup.3 and R.sup.4 each are hydrogen, one skilled 
in the art would recognize that a hydroxy protecting group, particularly 
methyl, would be preferred. A preferred formula I compound for one present 
acylation reaction is that in which R.sup.1 and R.sup.2 are combined to 
form piperidinyl and n is 2. 
Reagents and all parameters necessary to carry out the acylation step of 
step d), the optional deprotection step of step e), the optional salt 
formation step of step f), and isolation and purification of formula II 
compounds are described in the afore-incorporated United States patents. 
Thus, pharmaceutically active compounds of formula V, including their acid 
addition salts, are prepared via the instant process of the present 
invention. 
The following examples are provided for the purpose of illustrating the 
present invention and are not intended to be limiting upon the scope of 
the invention.

EXAMPLE 1 
Ethyl 4-(2-piperidinoethoxy)benzoate 
##STR20## 
To a 250 mL 3 neck flask with mechanical stirring, condenser, and a 
resistant thermal device (RTD probe) connected via temperature controller 
to a heating mantle and under nitrogen atmosphere are added: 8.31 g of 
ethyl 4-hydroxybenzoate, 4.84 g of ethylene carbonate, 0.05 g of 
tetrabutylammonium iodide, and 60 mL of anisole. The mixture was heated to 
140.degree. C. for about 48 hours. Thin layer chromatography (conducted in 
an ethyl acetate solvent system) revealed the presence of only a small 
amount of starting material. 
To 11 mL of the resulting solution (containing about 10.0 mmol of ethyl 
4-(2-hydroxyethoxy)benzoate) was added 1.78 mL (22 mmol) of pyridine and 
0.85 mL (11 mmol) of methane sulfonyl chloride under nitrogen. The mixture 
was heated to 75.degree. C. for 24 hours. An additional 0.04 mL (5 mmol) 
of methane sulfonyl chloride was then added and heating was continued. 
After 1 hour, the mixture was cooled to ambient temperature and 10 mL of 
water was added followed by the addition of 10 mL of ethyl acetate. The 
layers were separated and the aqueous layer discarded. NMR analysis 
revealed that the organic layer contained ethyl 
4-(2-methanesulfonylethoxy)benzoate. 
To a 25 mL round bottom flask with magnetic stirring and condenser and 
under nitrogen were added the following: the solution from step 2 
containing about 10.0 mmol of ethyl 4-(2-methanesulfonylethoxy)benzoate, 2 
mL (20 mmol) of piperidine, and 1.5 g K.sub.2 CO.sub.3. The mixture was 
heated to 80.degree. C. for 24 hours and then to 125.degree. C. for an 
additional 24 hours to yield product. The yield was estimated to exceed 
90%. The product was identical by chromatography and .sup.1 H--NMR to that 
found by published methods. 
EXAMPLE 2 
Methyl (2-piperidinoethoxy)benzoate 
##STR21## 
To a 250 mL round bottom flask with magnetic stirring and a condenser, 
under nitrogen atmosphere were added the following: 7.61 g of (0.05 mol) 
methyl 4-hydroxybenzoate, 5.32 g of (0.06 mol) ethylene carbonate, 0.05 g 
(1.4 mmol) of tetrabutylammonium iodide, and 60 mL of anisole. The mixture 
was heated to 147.degree. C. for about 48 hours. After the flask was 
cooled to ambient temperature, the following were added: 8.9 mL (0.11 mol) 
and 6.25 mL (0.08 mol) methane sulfonyl chloride. The resulting mixture 
was heated to 75.degree. C. for 20 hours and 100 mL of ethyl acetate was 
added. The mixture was washed twice with 100 mL aliquots of water and then 
dried over magnesium sulfate. 
The flask contents were transferred to a 250 mL, 3 neck flask with 
mechanical stirring, condenser, and RTD probe hooked through a temperature 
controller to a heating mantle. 7.5 g of potassium carbonate and 10 mL 
(100 mmol) of piperidine were added. The reaction was heated to about 
85.degree. C. for about 5 days, and the resulting mixture was then 
quenched with water, and ethyl acetate was added until two distinct layers 
appeared. The aqueous layer was separated and discarded and the organic 
layer was washed twice with brine. The resulting organic layer was dried 
over magnesium sulfate and the solvent was removed under reduced pressure, 
yielding a solution of the title product in anisole. .sup.1 H--NMR 
chromatography confirmed the presence of the desired product. The yield 
was grater than 95% of theory. 
EXAMPLE 3 
Ethyl 4-(2-piperidinoethoxy)benzoic acid hydrochloride 
##STR22## 
To the product solution from Example 1 is added 25 mL of 8N hydrochloric 
acid, and the resulting layers are separated. The aqueous acid layer is 
then heated to between 95.degree. C. and reflux for about 4 hours to about 
24 hours. The solution is cooled to about 0.degree. C. to 5.degree. C. and 
the crystalline product is collected by filtration and dried. 
EXAMPLE 4 
6-Hydroxy-2-(4-hydroxyphenyl)-3-4-(2-piperidinoethoxy)benzyl!benzob!thiop 
hene hydrochloride 
##STR23## 
Under nitrogen atmosphere, a mixture of 3 g of ethyl 
4-(2-piperidinoethoxy)benzoic acid hydrochloride, 2 drops of 
dimethylformamide, 2.5 mL of thionyl chloride, and 40 mL of chlorobenzene 
is heated to about 70.degree. C. for about one hour. The excess thionyl 
chloride and about 15 mL to about 20 mL of solvent are then distilled off. 
The remaining suspension is cooled to ambient temperature and to it are 
added 100 mL of dichloromethane, 2.7 g of 
6-methoxy-2-(4-methoxyphenyl-benzob!thiophene (as prepared via the 
procedures described in the above incorporated U.S. patents), and 10 g of 
aluminum chloride. The solution is stirred for about 1 hour, 7.5 mL of 
ethanethiol is added, and the mixture is stirred for an additional 45 
minutes. Then 40 mL of tetrahydrofuran is added, followed by 15 mL of 20% 
hydrochloric acid, and heated to reflux. 50 mL of water and 25 mL of 
saturated aqueous sodium chloride are added. The mixture is stirred and 
allowed to cool to ambient temperature. The precipitate is collected by 
filtration and washed successively with 30 mL of water, 40 mL of 25% 
aqueous tetrahydrofuran, and again with 35 mL of water. The solids are 
then dried at 40.degree. C., under vacuum, to obtain the title product.