JP2003510313A - Method for producing benzoic acid - Google Patents

Abstract

  (57) [Summary] 4-((2-piperidin-1-yl) An improved method for the production of [ethoxy] benzoic acid derivatives.

Description

Detailed Description of the Invention

TECHNICAL FIELD The present invention relates to the fields of medicinal chemistry and organic chemistry, and provides a novel method for producing a 4-[(2-piperidin-1-yl) ethoxy] benzoic acid derivative compound.

[0002] (Background technology)   Formula (I):

[Chemical 8] [Wherein R is C₁-C₆Alkyl; R¹And R^TwoAre each independently C
₁-C_FourTogether with the alkyl, or the nitrogen atom to which they are attached, the piperidines
Nyl, pyrrolidinyl, methylpyrrolidinyl, dimethylpyrrolidinyl, morpholino
Or forms 1-hexamethyleneimino; and n is 2 or 3] Is a compound represented by the formula (II):

[Chemical 9] [Where R^ThreeAnd R^FourAre independently hydrogen or a hydroxy protecting group; and R
¹, R^TwoAnd n are as defined above.] Important intermediate in the production of the compound represented by: or a pharmaceutically acceptable salt thereof
Is.

Compound (II), especially Raloxifene, wherein R ¹ and R ² together form a piperidinyl moiety, R ³ and R ⁴ are each hydrogen, and n is 2 is a disease state such as osteoporosis. Is known in the pharmaceutical industry as having activity for the treatment or prevention of. Typically, compound (I) is prepared, for example, by reacting β-chloroethylpiperidine hydrochloride and ethyl 4-hydroxybenzoate in methyl ethyl ketone in the presence of potassium carbonate (US Pat. No. 4,418,068). reference)
. An improved process for preparing compound (I) is disclosed in US Pat. No. 5,631,369, which is incorporated herein by reference in its entirety. The disclosures of both referenced patents teach the use of anhydrous powdered potassium carbonate as the preferred base to increase the reaction rate, which indicates that the particle size of anhydrous potassium carbonate is very important for the alkylation reaction. Means Powdered potassium carbonate is relatively more expensive than granular potassium carbonate hydrate,
Controlled air is required to maintain the anhydrous nature of powdered potassium carbonate. These factors add to the overall cost of producing compound (I) and compound (II).

Furthermore, the use of anhydrous potassium carbonate on a manufacturing industrial scale results in a heterogeneous mixture, thus limiting the ability to stir the mixture effectively. This also makes it difficult to carry out the reaction at high concentrations, resulting in ultimately low throughput. More efficient, robust, inexpensive compound (I) and ultimately compound (II)
Are needed. Such a method would ideally eliminate the use of powdered anhydrous potassium carbonate. Such a method also results in a homogeneous reaction mixture with increased reaction concentration and thereby increased throughput. Such methods represent an important and desirable advance over the current state of the art. The present invention is
Such a method is provided.

[0005] (Outline of the invention)   The present invention provides formula (I):

[Chemical 10] [Wherein R is C₁-C₆Alkyl; R¹And R^TwoAre each independently C
₁-C_FourTogether with the alkyl, or the nitrogen atom to which they are attached, the piperidines
Nyl, pyrrolidinyl, methylpyrrolidinyl, dimethylpyrrolidinyl, morpholino
Or forms 1-hexamethyleneimino; and n is 2 or 3] A method for producing a compound represented by:
Formula (III) in the presence of a hydrate:

[Chemical 11] [Wherein, X is halogen; and R ¹ , R ² and n have the same meanings as defined above], and a haloalkylamine represented by the formula (IV):

[Chemical 12] [Wherein, R is C ₁ -C ₆ alkyl].

[0006]   The invention further provides compounds of formula (II):

[Chemical 13] [Wherein R ¹ , R ² and n are as defined above; and R ³ and R ⁴ are each independently hydrogen or a hydroxy protecting group] or a pharmaceutically acceptable compound thereof. Provided is a method for producing a salt that can be dried.

DETAILED DESCRIPTION OF THE INVENTION General terms used in the description of chemical formulas herein have their ordinary meanings. For example, “C ₁ -C ₄ alkyl” means a straight or branched chain having 1 to 4 carbon atoms, and includes methyl, ethyl, propyl, isopropyl, butyl, n-butyl, isobutyl, and the like. C ₁ -C ₆ alkyl "includes pentyl, isopentyl, hexyl, in addition to groups such as isohexyl, a group included in the definition of" _C 1 -C ₄ alkyl ". “Halo” or “halogen” includes bromo, chloro, fluoro and iodo. As used herein, “suitable solvent” means a C ₁ -C ₆ alkyl acetate having the desired boiling point for a particular reaction substrate and suitable miscibility with the aqueous phase for the reaction substrate. To do.

As used herein, a “suitable aqueous acid” or “suitable acid” corresponds to the protonation of a basic group, such as an amino group or a carboxylate anion, without producing detrimental manipulation of the molecule. Means any one of an acid addition salt or an inorganic or organic acid capable of forming an acid. Examples of acids include, but are not limited to, aqueous hydrochloric acid, anhydrous hydrogen chloride, dilute phosphoric acid, dilute sulfuric acid, acetic acid, and the like. As used herein, “acid salt” refers to a water-soluble organic or inorganic acid, preferably an inorganic acid and a basic molecule (ie, typically, an amino group such as compound (I) or another nitrogen atom). Non-covalently attached compound formed by the reaction of a molecule containing an atom-containing group).

As used herein, "inorganic base hydrate" refers to, for example, a hydrate containing 1-20% water or a non-anhydrous inorganic such as sodium carbonate containing below the hydration limit for the particular base. Means base. Moisture content (and thus hydration) can be achieved by (1) addition of water as the bulk solvent or (2) introduction with potassium carbonate as the water of hydration of potassium carbonate. As hydrated potassium carbonate, commercially available potassium carbonate sesquihydrate can be obtained. As used herein, "hydroxy protecting group" and "-OH protecting group" are synonymous and have the commonly understood meaning, especially in avoiding reactions at the hydroxyl group and in bulk or other commonly understood terms. The group used for substituting the hydrogen atom of the hydroxyl group for the purpose of providing the purpose.

[0010]   In compound (II), R^ThreeAnd R^FourThe hydroxy protecting group is R^ThreeAnd R^Four Is generally not found in the final therapeutically active compound if is not hydrogen
However, in order to protect groups that may otherwise react during chemical
A group that is systematically introduced as part of the process and then removed at a later stage of the synthesis.
Means Compounds with such protecting groups can be treated with chemical intermediates (such derivatives
They are also important in the body)
The exact structure of is not very important. Formation and removal of such protecting groups
Many of the reactions to leave are, for example, “Protective Groups in Organic Chemist
ry ”, Plenham 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, Aka.
Numerous landmarks such as Demic Press (London and New York, 1965)
It is described in a quasi-book. Representative hydroxy protecting groups include, for example, -C ₁ -C_FourAlkyl, -CO- (C₁-C₆Alkyl), -SO_Two-(C_Four-C₆ Alkyl), and -CO-Ar (where Ar is an optionally substituted phenyl).
Nil).

“Substituted phenyl” means one or it selected from the group consisting of C ₁ -C ₄ alkyl, C ₁ -C ₅ alkoxy, hydroxy, nitro, chloro, fluoro and tri (chloro or fluoro) methyl. It means a phenyl group having the above substituents. “C ₁ -C ₅ alkoxy” means a C ₁ -C ₅ alkyl group bonded through an oxygen atom bridge such as methoxy, ethoxy, n-propoxy, isopropoxy and the like. Preferred R ³ and R ⁴ hydroxy protecting groups are C ₁ -C ₄ alkyl, especially methyl.

The present invention provides a method for producing the compound (I) represented by the reaction formula (1). Reaction process formula (1)

[Chemical 14] [Wherein, X, R, R ¹ and R ² have the same meanings as described above]

[0013]   In the novel method of the present invention, the halogen represented by the formula (III) in the presence of a suitable solvent is used.
4-alkylbenzoyl of the formula (IV) in about 1 molar equivalent
And hydrated inorganic base. Typically about 1-3 molar equivalents, preferred
Preferably about 1 to 1.5 molar equivalents and most preferably 1.05 molar equivalents of haloalcohol.
Killamine (III) is used. Similarly, about 1 to 3 molar equivalents, preferably about 1 to 1
． 5 molar equivalents, and most preferably 1.05 molar equivalents of base are used. R¹And R ^Two Are taken together to form piperidinyl, n is 2 and X is chloro.
(III) is preferred, and compound (IV) in which R is methyl is preferred.

Preferred solvents are C ₁ -C ₆ alkylacetate solvents in which the alkyl part of such solvents is a straight or branched chain alkyl part having 1 to 6 carbon atoms. Preferred alkyl acetate solvents include ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, amyl acetate, isoamyl acetate and the like.
The most preferred _C 1 -C ₆ alkyl acetate solvent is amyl acetate. In addition to the alkyl acetate solvent, the process of the present invention as well as the processes described below are carried out in the presence of a suitable inorganic base hydrate. Inorganic base hydrates such as carbonate or bicarbonate bases are preferred. Among these, granular potassium carbonate containing about 1 to 20% of water is preferable. Granular potassium carbonate with a water content of about 3-5% is most efficient for increasing the rate of completion of the reaction and is therefore most preferred for practicing the invention.

Furthermore, it is preferred to maintain the alkylation reaction mixture under an inert atmosphere, for example argon, or especially nitrogen. The present invention is carried out at a temperature of about 80 ° C to the reflux temperature of the solvent. The preferred temperature range is about 100
C. to about 150.degree. C., with about 118.degree. C. to about 125.degree. C. being especially preferred. The length of time for this reaction is substantially the time required for the reaction to occur. Typically, this reaction takes about 2-24 hours. The optimum time can be determined by monitoring the progress of the reaction by conventional chromatographic techniques. The preferred reaction time is 2 to 6 hours. A particularly preferred reaction time is
It is 4.5 to 5.5 hours. The most preferred reaction time is 4 to 4.5 hours.

When the reaction is complete, the alkylation mixture is cooled to between about 30 ° C. and about 70 ° C. and washed with water to dissolve the added basic salt. A suitable aqueous acid is then added to the mixture to extract compound (I). It is preferred to use aqueous hydrochloric acid in the extraction process to form the hydrochloride salt of Compound (I). For example, other aqueous acids such as sulfuric acid, phosphoric acid, acetic acid may be used to produce the corresponding acid salt of compound (I). Those skilled in the art will appreciate that compound (I) can be optionally isolated as the free base by methods known in the art such as chromatography, distillation and / or crystallization. It is preferred to use the acid salt of compound (I) in situ without isolation.

If desired, the aryl or alkyl ester of the desired compound (I) is cleaved by standard means to give formula (Ia):

[Chemical 15] [Wherein, R ¹ , R ² and n have the same meanings as defined above].

Typically, the acid compound (I) is heated to a range of about 80 ° C to about 150 ° C, but about 9
0 ° C to about 100 ° C is preferred. Acceptable concentration of compound in the preferred temperature range
(Ia) is produced in about 4 hours. Heating for 24 hours or less does not affect either quality or yield. If necessary, heat in the above temperature range,
Ester cleavage can be facilitated by distillation and removal of the alcohol formed in the acid hydrolysis. Acid compounds can be prepared using methods known to those skilled in the art (see US Pat. No. 5,631,369).
Isolation and purification of (Ia) is achieved. Generally, the mixture resulting from the ester cleavage step is cooled to a range of about -5 ° C to about 20 ° C. The product crystallizes or precipitates from solution in this range, but the optimum temperature range is from about 0 ° C to about 5 ° C. The desired compound (Ia) is then isolated by filtration or other techniques known to those skilled in the art.

According to the following reaction scheme (2), the compound (I) or its derivative is
II) can be converted. Reaction process formula (2)

[Chemical 16] [Wherein X is halogen, preferably bromine or chlorine; and R, R ¹ ,
R ² , R ³ and R ⁴ are as defined above.]

In general, compound (I) or a derivative thereof such as an amide, formyl or acid derivative is converted to an acid halide compound (V), preferably an acid chloride or acid bromide by methods known to those skilled in the art. As a general reference text for forming acid chlorides (acyl halides), see, for example, March, J. Advanced Org.
anic Chemistry, John Wiley and Sons, New York, New York, 1985; and Comprehensive Organic Transformations by Larock, RC.
(1989), VHC Publishers, Inc., New York, New York. A preferred procedure for the formation of an acyl halide (step 1) is to react the acid compound (Ia) with an acyl halide forming reagent in a solvent such as dichloromethane, 1,2-dichloromethane, toluene or tetrahydrofuran to give compound (V) Including providing. Representative acyl halide forming reagents include, but are not limited to, phosgene, thionyl chloride, oxalyl chloride, phosphorus trichloride, triphenylphosphine dibromide and acids such as hydrochloric acid and hydrofluoric acid. Preferred acyl halide forming reagents in the practice of the present invention are
Oxalyl chloride, anhydrous hydrogen chloride, and thionyl chloride. Most preferred is thionyl chloride.

In step 2, acyl halide compound (V) is acylated with compound (VI) to provide compound (II). Procedures for compound (VI) and the acylation step are known to those skilled in the art and are described, for example, by Peters in US Pat. No. 4,380,633.
5 and Jones et al., US Pat. Nos. 4,133,814 and 4418068; which are incorporated herein by reference in their entireties. Preferred compounds (I) for the acylation reaction of the present invention are compounds wherein R ¹ and R ² together with the nitrogen atom to which they are attached form piperidinyl and n is 2.

Those skilled in the art will appreciate that certain steps of the method of the invention can be reversed or omitted without adversely affecting the practice of the invention. Furthermore, certain steps, such as the formation of pharmaceutically acceptable salts, deprotection and / or exchange of protecting groups, may be carried out at different times, and such acts may depend on the particular starting materials used or It has an advantageous effect depending on its derivative. The reagents and all parameters necessary for performing the acylation, the deprotection performed as necessary, the salt formation step optionally performed in the reaction scheme (2), and the isolation / purification of the compound (II) are performed. , U.S. Pat. in this way,
According to the method of the present invention, the pharmaceutically active compound (II) and its acid addition salt are produced.

EXAMPLES The following examples are provided for the purpose of illustrating the invention and are not intended to limit the scope of the invention.

Example 1 Preparation of 4- (2-piperidinoethoxy) benzoic acid / hydrochloride In a 2000 gallon tank, amyl acetate (1320 L), methyl 4-hydroxybenzoate (167.42 kg), anhydrous potassium carbonate (408.6 kg) and β
-Chloroethylpiperidine hydrochloride (283.5 kg) was added. Mix 12
Heat at 0 ° C. to 125 ° C. for 5 hours, at which time HPLC analysis showed complete consumption of methyl 4-hydroxybenzoate. The tank was cooled below 50 ° C. Deionized water (880 L) was added to the tank. The layers were separated and the aqueous layer was discarded. In a glass lined tank, food grade hydrochloric acid (367 L) and deionized water (18
4 L) were mixed. The acid mixture was combined with the organic layer. The layers were separated and the organic layer was discarded. The mixture of intermediate ester in aqueous acid was heated until HPLC showed complete ester consumption (13 h). The mixture was cooled to below 40 ° C. and the mixture was mixed with acetone (
550 L) was added and the mixture was cooled to 0 ° C to 5 ° C and stirred for 1 hour. The product was collected by centrifugal filtration. The wet cake was rinsed by centrifugation with acetone (400 L).
The product is heated in a rotary vacuum dryer (double cone) at 50 ° C or less, 20 to 27 inches H
dried at g. The yield was 91% of theory.

Example 2 Preparation of 4- (2-piperidinoethoxy) benzoic acid hydrochloride hydrochloride Methyl 4-hydroxybenzoate (17.57 g) and amyl acetate (132 m)
l) were combined. To this slurry, at ambient temperature, potassium carbonate sesquihydrate (29.19 g) (particle size, 96% greater than 100 mesh, 100% 2
Larger than 00 mesh) and β-chloroethylpiperidine hydrochloride (20.
26 g) was added. The mixture was heated at 110-115 ° C for 4.5 hours. The solution was cooled below 50 ° C. and deionized water (88 mL) was added. The layers were separated and the aqueous layer was discarded. Deionized water (88 mL) was added to the organic layer and the bilayer mixture was stirred for 15 minutes,
The phases were separated. The aqueous layer was discarded. A diluted aqueous solution of aqueous hydrochloric acid was prepared by adding reagent grade hydrochloric acid (42.6 g) to deionized water (15 ml). This solution was added to the organic phase, stirred for 15 minutes and the phases separated. The organic phase was discarded. The aqueous phase was heated to reflux for 5 hours. About 1.5 hours after the start of reflux, the desired product started to precipitate. The product slurry was cooled below 40 ° C. and acetone (55 ml) was added. The mixture was cooled to 0-5 ° C and stirred for 1 hour. The product was collected by filtration and washed with a minimal amount of acetone precooled to 0 ° C. The product was dried in a vacuum oven at ambient temperature. The yield was 90.6% of theory. The potency of the product compared to the control by HPLC was 99.2%.

Example 3 Preparation of 4- (2-piperidinoethoxy) benzoic acid hydrochloride: Methyl 4-hydroxybenzoate (17.57 g) and amyl acetate (132 m)
l) were combined. To this slurry was added powdered potassium carbonate (29.1) at ambient temperature.
9 g) (water content 11% by Karl Fischer, particle size: 95% or more through 100 mesh sieve, 90% or more through 200 mesh sieve) and β-chloroethylpiperidine hydrochloride (20.26 g) were added. Mix the mixture at 110 ℃ ~ 11
Heated at 5 ° C. for 4.5 hours. The solution is cooled to below 50 ° C. and deionized water (88 mL
) Was added. The layers were separated and the aqueous layer was discarded. Deionized water (88 mL) was added to the organic layer, the bilayer mixture was stirred for 15 minutes and the phases were separated. The aqueous layer was discarded. Deionized water (
To 15 ml) was added reagent grade hydrochloric acid (42.6 g) to prepare a dilute aqueous solution of hydrochloric acid. This solution was added to the organic phase, stirred for 15 minutes and the phases separated. The organic phase was discarded. The aqueous phase was heated to reflux for 5 hours. About 1.5 from the start of reflux
After hours, the desired product started to precipitate. The product slurry was cooled below 40 ° C. and acetone (55 ml) was added. The mixture was cooled to 0-5 ° C and stirred for 1 hour.
The product was collected by filtration and washed with a minimal amount of acetone precooled to 0 ° C. The product was dried in a vacuum oven at ambient temperature. The yield was 93.4% of theory. The potency of the product by HPLC calibrated against a control was 99.2%.

Example 4 Preparation of 4- (2-piperidinoethoxy) benzoic acid hydrochloride hydrochloride Methyl 4-hydroxybenzoate (17.57 g) and amyl acetate (132 m)
l) were combined. To this slurry was added powdered potassium carbonate (29.1) at ambient temperature.
9 g) (water content 11% by Karl Fischer, particle size: 95% or more through 100 mesh sieve, 90% or more through 200 mesh sieve) and β-chloroethylpiperidine hydrochloride (20.26 g) were added. Mix the mixture at 118 ° C-12
Heated at 5 ° C. for 4.5 hours. The solution is cooled to below 50 ° C. and deionized water (88 mL
) Was added. The layers were separated and the aqueous layer was discarded. Deionized water (88 mL) was added to the organic layer, the bilayer mixture was stirred for 15 minutes and the phases were separated. The aqueous layer was discarded. Deionized water (
To 15 ml) was added reagent grade hydrochloric acid (42.6 g) to prepare a dilute aqueous solution of hydrochloric acid. This solution was added to the organic phase, stirred for 15 minutes and the phases separated. The organic phase was discarded. The aqueous phase was heated to reflux for 5 hours. About 1.5 from the start of reflux
After hours, the desired product started to precipitate. The product slurry was cooled below 40 ° C. and acetone (55 ml) was added. The mixture was cooled to 0-5 ° C and stirred for 1 hour.
The product was collected by filtration and washed with a minimal amount of acetone precooled to 0 ° C. The product was dried in a vacuum oven at ambient temperature. The yield was 91.3% of theory. The potency of the product by HPLC calibrated against a control was 101.0%.

Example 5 Preparation of 4- (2-piperidinoethoxy) benzoic acid hydrochloride: Methyl 4-hydroxybenzoate (50.22 g) and amyl acetate (198 m
l) were combined. To this slurry was added powdered potassium carbonate (122.
58 g) (water content by Karl Fischer 0.8%, particle size 95% or more through 100 mesh sieve, 90% or more through 200 mesh sieve) and β-chloroethylpiperidine hydrochloride (85.04 g) were added. The mixture at 118 ° C
Heated at 125 ° C. for 4.5 hours. The solution is cooled below 50 ° C. and deionized water (13
2 mL) was added. The layers were separated and the aqueous layer was discarded. Deionized water (132m)
L) was added, the biphasic mixture was stirred for 15 minutes and the phases were separated. The aqueous layer was discarded. A dilute aqueous solution of hydrochloric acid was prepared by adding reagent grade hydrochloric acid (127.8 g) to deionized water (45 ml). This solution was added to the organic phase, stirred for 15 minutes and the phases separated. The organic phase was discarded. The aqueous phase was heated to reflux for 5 hours. About 1.5 hours after the start of reflux, the desired product started to precipitate. The product slurry was cooled below 40 ° C. and acetone (123.7 ml) was added. Cool the mixture to 0 ° C to 5 ° C,
Stir for 1 hour. The product was collected by filtration and washed with a minimal amount of acetone precooled to 0 ° C. The product was dried in a vacuum oven at ambient temperature. The yield was 93.7% of theory. 100 potency of product relative to control by HPLC
． It was 0%.

Example 6 Preparation of 4- (2-piperidinoethoxy) benzoic acid hydrochloride hydrochloride Methyl 4-hydroxybenzoate (37.66 g) and amyl acetate (198 m)
l) were combined. To this slurry was added powdered potassium carbonate (91.9) at ambient temperature.
3 g) (water content by Karl Fischer 0.8%, particle size 95% or more through 100 mesh sieve, 90% or more through 200 mesh sieve) and β-chloroethylpiperidine hydrochloride (63.78 g) were added. Mix the mixture at 118 ° C to 1
Heated at 25 ° C. for 4.5 hours. The solution is cooled below 50 ° C. and deionized water (132
mL) was added. The layers were separated and the aqueous layer was discarded. Deionized water (132 mL) for the organic layer
) Was added, the bilayer mixture was stirred for 15 minutes and the phases were separated. The aqueous layer was discarded. A diluted aqueous solution of hydrochloric acid was prepared by adding reagent grade hydrochloric acid (95.85 g) to deionized water (33.75 ml). This solution was added to the organic phase, stirred for 15 minutes and the phases separated. The organic phase was discarded. The aqueous phase was heated to reflux for 5 hours. About 1.5 hours after the start of reflux, the desired product started to precipitate. The product slurry was cooled below 40 ° C. and acetone (123.7 ml) was added. The mixture was cooled to 0-5 ° C and stirred for 1 hour. The product was collected by filtration and washed with a minimal amount of acetone precooled to 0 ° C. The product was dried in a vacuum oven at ambient temperature. The yield was 93.2% of theory. 1 product potency against control by HPLC
It was 00.5%.

Example 7 Preparation of 4- (2-piperidinoethoxy) benzoic acid hydrochloride hydrochloride Methyl 4-hydroxybenzoate (50.22 g) and amyl acetate (198 m)
l) were combined. To this slurry was added powdered potassium carbonate sesquihydrate (122.58 g) and β-chloroethylpiperidine hydrochloride (85.0) at ambient temperature.
4g) was added. The mixture was heated at 118 ° C-125 ° C for 4.5 hours. Solution 5
Cool to below 0 ° C. and add deionized water (132 mL). The layers were separated and the aqueous layer was discarded. Deionized water (132 mL) was added to the organic layer, the bilayer mixture was stirred for 15 minutes and the phases were separated. The aqueous layer was discarded. A diluted aqueous solution of aqueous hydrochloric acid was prepared by adding reagent grade hydrochloric acid (63.9 g) to deionized water (45 ml). This solution was added to the organic phase, stirred for 15 minutes and the phases separated. The organic phase was discarded. The aqueous phase was heated to reflux for 5 hours. About 1.5 hours after the start of reflux, the desired product started to precipitate. The product slurry was cooled below 40 ° C. and acetone (123.7 ml) was added. The mixture was cooled to 0-5 ° C and stirred for 1 hour. The product is collected by filtration,
Wash with minimal acetone pre-cooled to 0 ° C. The product was dried in a vacuum oven at ambient temperature. The yield was 94.7% of theory. The potency of the product relative to the control by HPLC was 99.2%.

Example 8 Preparation of 4- (2-piperidinoethoxy) benzoic acid hydrochloride: Effect of water content and particle size on reaction Methyl 4-hydroxybenzoate (25.11 g) and amyl acetate (198 m
l) were combined. To this slurry was added powdered potassium carbonate (61.2
9 g) (water content by Karl Fischer 0.8%, particle size: 100% sieve pass 95% or more, 200 mesh sieve passage 90% or more) and β-chloroethylpiperidine hydrochloride (42.52 g) were added. Mix the mixture at 118 ° C to 1
Heat at 25 ° C. for 4.5 hours, at which time HPLC analysis showed complete consumption of methyl 4-hydroxybenzoate. The solution is cooled below 50 ° C. and deionized water (13
2 mL) was added. The layers were separated and the aqueous layer was discarded. Deionized water (132m)
L) was added, the biphasic mixture was stirred for 15 minutes and the phases were separated. The aqueous layer was discarded. A dilute aqueous solution of hydrochloric acid was prepared by adding reagent grade hydrochloric acid (63.9 g) to deionized water (22.5 ml). This solution was added to the organic phase, stirred for 15 minutes and the phases separated. The organic phase was discarded. The aqueous phase was heated to reflux for 5 hours. About 1.5 hours after the start of reflux, the desired product started to precipitate. The product slurry was cooled below 40 ° C. and acetone (123.7 ml) was added. The mixture was cooled to 0-5 ° C and stirred for 1 hour. The product was collected by filtration and washed with a minimal amount of acetone precooled to 0 ° C. The product was dried in a vacuum oven at ambient temperature. The yield was 90.8% of theory. 10 product potency against control by HPLC
It was 0.0%.

Example 9 4- (2-piperidinoethoxy) benzoic acid The particle size of potassium carbonate anhydride was as follows: 10 mesh sieve passing 94.4%, 20 mesh sieve passing 88.8%, The procedure was as in Example 8, except that 77.4% through 40 and 100 mesh sieves and not all 325 mesh sieves were passed through. After 4.5 hours of initial reaction at 118 ° C-125 ° C, less than 15% ethyl 4-hydroxybenzoate was converted to 4- (2-piperidinoethoxy) benzoic acid.

Example 10 4- (2-piperidinoethoxy) benzoic acid Deionized water immediately after loading with potassium carbonate (3% by weight of loaded potassium carbonate)
The procedure of Example 8 was followed except that (1.84 g) was added. 118 ° C-12
After initial reaction at 5 ° C. for 4.5 hours, HPLC analysis showed complete consumption of methyl 4-hydroxybenzoate. The yield was 91.6% of theory. The potency of the product relative to the control by HPLC was 99.3%.

Example 11 4- (2-piperidinoethoxy) benzoic acid Deionized water (16% by weight of potassium carbonate loaded) immediately after potassium carbonate loading
) (9.8 g) was added, but the procedure of Example 8 was followed. 118 ° C-12
After initial reaction at 5 ° C. for 4.5 hours, HPLC analysis showed complete consumption of methyl 4-hydroxybenzoate. The yield was 91.9% of theory. The potency of the product relative to the control by HPLC was 98.5%.

Example 12 Preparation of 6-methoxy-2- (4-methoxyphenyl) benzo [b] thiophene 3-Methoxybenzenethiol (100 g) in water (300 ml) was added to denatured ethanol (750 ml) and the flask was charged. Placed in cooling bath. Then α-bromo-
1-Methoxyacetophenone (164 g in total) was added little by little, and after the addition was completed,
The mixture was stirred in the cooling bath for 10 minutes and then at ambient temperature for 3 hours. Then the solvent was removed under reduced pressure and water (200 ml) was added. The mixture was extracted with ethyl acetate and the organic layer was washed twice with water, twice with aqueous sodium bicarbonate and twice with aqueous sodium chloride solution. The organic layer is then dried (magnesium sulfate), filtered,
Evaporation under reduced pressure with ethers afforded crude α- (3-methoxyphenylthio) -4-methoxyacetophenone (202 g) which was recrystallized from hexane to give the desired product (15
8 g) was obtained. mp 53 ° C.

The above intermediate (124 g) is added in portions to polyphosphoric acid (930 g) at 85 ° C. While adding, raise the temperature to 95 ° C and after the addition is complete, mix the mixture at 90 ° C for 3
The mixture was stirred for 0 minutes, and then for another 45 minutes while cooling without external heating. Then 1 liter of crushed ice was added to the mixture and an external ice bath was attached to control the temperature while the ice melted and the acid was diluted. In addition, water (500
ml) was added and the light pink precipitate was filtered and washed with water then methanol. The solid was dried under reduced pressure at 40 ° C. to obtain crude 6-methoxy-2- (4-methoxyphenyl) benzo [b] thiophene (119 g). The crude product was slurried with hot methanol, filtered, washed with cold methanol and the solid recrystallized from ethyl acetate (4 liters), filtered, washed with hexane and dried to give the desired intermediate product (68 g). ) Got. m. p. 187-190.5 ° C.

Example 13 Raloxifene hydrochloride [6-hydroxy-2- (4-hydroxyphenyl)-
3- [4- (2-piperidinoethoxy) benzyl] benzo [b] thiophene hydrochloride
Preparation of 4- (2-piperidinoethoxy) benzoic acid (3 g), dimethylformamide (2 drops), thionyl chloride (2.5 ml) and chlorobenzene (4 g) under a nitrogen blanket.
0 ml) was heated at 70 ° C to 75 ° C for about 1 hour. Then excess thionyl chloride and solvent (15-20 ml) were distilled off. The remaining suspension was cooled to ambient temperature, to which was added dichloromethane (100 ml), 6-methoxy-2- (4-methoxyphenyl) benzo [b] thiophene (this preparation being described in Example 14) and aluminum chloride. (10 g) was added. After stirring the solution for about 1 hour, ethanethiol (7
． 5 ml) was added and the mixture was stirred for a further 45 minutes. Tetrahydrofuran (40 ml) was then added with exothermic reflux, followed by 20% hydrochloric acid (15 ml). Water (50 ml) and saturated aqueous sodium chloride (25 ml) were added. The mixture was stirred and allowed to cool to ambient temperature. The precipitate was collected by filtration, water (30 ml), 2
It was washed successively with 5% aqueous tetrahydrofuran (40 ml) and water (35 ml). Then, the solid was dried under reduced pressure at 40 ° C. to obtain a product (5.05 g), which was subjected to 6-hydroxy-2- (4-hydroxyphenyl) -3-by nuclear magnetic resonance.
It was identified as [4- (2-piperidinoethoxy) benzyl] benzo [b] thiophene hydrochloride.

─────────────────────────────────────────────────── ─── Continued front page    (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, I T, LU, MC, NL, PT, SE), OA (BF, BJ , CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, K E, LS, MW, MZ, SD, SL, SZ, TZ, UG , ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, C A, CH, CN, CR, CU, CZ, DE, DK, DM , DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, K E, KG, KP, KR, KZ, LC, LK, LR, LS , LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, R U, SD, SE, SG, SI, SK, SL, TJ, TM , TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW

Claims (14)

[Claims] 1. Formula (I): [Chemical 1] [Wherein R is C₁-C₆Alkyl; R¹And R^TwoAre each independently C
₁-C_FourTogether with the alkyl, or the nitrogen atom to which they are attached, the piperidines
Nyl, pyrrolidinyl, methylpyrrolidinyl, dimethylpyrrolidinyl, morpholino
Or forms 1-hexamethyleneimino; and n is 2 or 3] A method for producing a compound represented by: or a pharmaceutically acceptable salt thereof, comprising:
Formula (III) in the presence of an inorganic base hydrate in a solvent: [Chemical 2] [Wherein, X is halogen; and R¹, R^TwoAnd n are as defined above.] A haloalkylamine represented by the formula (IV): [Chemical 3] [Wherein R is C₁-C₆Is alkyl] A method comprising reacting with a compound represented by: 2. A) extracting the reaction product of claim 1 with an aqueous acid; and then optionally b) cleaving the ester of the reaction product of step a) to give formula (Ia): Chemical 4] The method according to claim 1, further comprising the step of forming an acid compound represented by the formula; 3. The method according to claim 1, wherein the inorganic base hydrate is selected from the group consisting of potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and calcium carbonate. 4. The method according to claim 1, wherein the solvent is a C ₁ -C ₆ alkyl acetate solvent selected from the group consisting of amyl acetate, isopropyl acetate, isobutyl acetate and ethyl acetate. 5. The method according to claim 1, wherein the C ₁ -C ₆ alkyl acetate is amyl acetate. 6. The method according to claim 1, wherein the inorganic base hydrate is carbonate or bicarbonate. 7. The method of claim 6 wherein the carbonate is potassium carbonate hydrated with 1-20% water. 8. The method of claim 7, wherein the potassium carbonate hydrate is achieved by adding large amounts of water. 9. The method of claim 7 wherein the potassium carbonate hydrate is achieved with water of hydration. 10. The method according to claim 7, wherein the carbonate is potassium sesquihydrate. 11. A compound wherein R ¹ and R ² together with the nitrogen atom to which they are attached form piperidinyl; and n is 2 or a pharmaceutically acceptable salt thereof. The method according to item 1. 12. The method according to claim 2, wherein the aqueous acid is hydrochloric acid. 13. Formula (II): [Wherein R ³ and R ⁴ are each independently hydrogen or a hydroxy protecting group;
And R ¹ , R ² and n have the same meanings as defined above], wherein a) is a compound (I) or (Ia) which is an acyl halide. Reacting with a forming agent, the compound of formula (V): [Wherein X is a halogen], and b) compound (V) is converted to compound of formula (VI): [Wherein R ³ and R ⁴ are as defined above] or a pharmaceutically acceptable salt thereof; 14. A compound or a medicament thereof, wherein the compound is R ¹ and R ^{2 taken} together with the nitrogen atom to which they are attached to form a piperidinyl moiety; R ³ and R ⁴ are each hydrogen; and n is 2. 14. The method according to claim 1 or 13, which is a pharmaceutically acceptable salt, solvate or derivative.