82640-04-8

Usage

Uses

Used in Pharmaceutical Industry:
Raloxifene hydrochloride is used as a nonsteroidal, selective estrogen receptor modulator (SERM) for the prevention of postmenopausal osteoporosis. It helps to impede bone loss and reduce the risk of developing breast cancer.
Used in Quality Control:
Raloxifene hydrochloride is used as a pharmaceutical secondary standard for application in quality control, providing a convenient and cost-effective alternative to the preparation of in-house working standards.
Used in Mass Spectrometry:
Labeled Raloxifene hydrochloride is used as an internal standard for the quantification of Raloxifene by gas chromatography (GC) or liquid chromatography (LC) mass spectrometry.
Potential Future Applications:
Raloxifene hydrochloride has several extensions planned for different uses, such as growth disorder, obesity, colon tumor, and skin atrophy.

Biochem/physiol Actions

Raloxifene is a selective estrogen receptor modulator (SERM); acts as an anti-estrogen in both breast and uterine tissue while being estrogenic in bone. May have efficacy against estrogen-sensitive cancers.

Clinical Use

Treatment and prevention of osteoporosis in post menopausal women

Drug interactions

Potentially hazardous interactions with other drugs Anticoagulants: antagonism of anticoagulant effect of coumarins. Colestyramine: reduced absorption of raloxifene - avoid.

Metabolism

Raloxifene undergoes extensive first pass metabolism to the glucuronide conjugates: raloxifene-4'- glucuronide, raloxifene-6-glucuronide, and raloxifene-6, 4′-diglucuronide. Raloxifene undergoes enterohepatic recycling, and is excreted almost entirely in the faeces. Less than 6% of dose is excreted in the urine.

references

[1] obach rs.potent inhibition of human liver aldehyde oxidase by raloxifene.

InChI:InChI=1/C28H29NO4S/c30-21-8-4-20(5-9-21)28-26(24-13-10-22(31)18-25(24)34-28)27(32)19-6-11-23(12-7-19)33-17-16-29-14-2-1-3-15-29/h4-13,18,26,28,30-31H,1-3,14-17H2

Synthetic route

[2-(4-methoxyphenyl)-6-methoxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone hydrochloride (84541-36-6) → raloxifene hydrochloride

Conditions	Yield
Stage #1: [2-(4-methoxyphenyl)-6-methoxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone hydrochloride With boron trichloride In dichloromethane at 2 - 20℃; for 52.25h; Stage #2: With methanol In dichloromethane at 12℃; for 1.08333h; Product distribution / selectivity; Reflux;	95%
Stage #1: [2-(4-methoxyphenyl)-6-methoxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone hydrochloride With boron tribromide In dichloromethane at 2 - 20℃; for 52.25h; Stage #2: With methanol In dichloromethane for 0.75h; Product distribution / selectivity; Reflux;	95%
With boron trichloride In dichloromethane at 0 - 22℃; for 38.1h; Product distribution / selectivity; Reflux;	92.6%
With aluminium trichloride; ethanethiol In dichloromethane for 0.5h; Ambient temperature;	77.5%

[6-Methoxy-2-(4-Methoxyphenyl)benzo[b]thien-3-yl]-[4-[2-(1-Piperidinyl)ethoxy]phenyl] Methanone (84541-38-8) → raloxifene hydrochloride (82640-04-8)

Conditions	Yield
With N,N-diethylaniline; ethanethiol In dichloromethane at 32 - 34℃; for 2h; Solvent;	92%

+ 4-(2-piperidin-1-ylethoxy)benzoic acid hydrochloride (84449-80-9) → raloxifene hydrochloride (82640-04-8)

Conditions	Yield
Stage #1: 4-(2-piperidin-1-ylethoxy)benzoic acid hydrochloride With pyridine; thionyl chloride In dichloromethane for 1h; Heating / reflux; Stage #2: 6-acetoxy-2-(4-acetoxyphenyl)benzo[b]thiophene In dichloromethane Stage #3: With hydrogenchloride; sodium hydroxide; water; aluminum (III) chloride more than 3 stages;	70.4%

3-methoxybenzenethiol (15570-12-4) → raloxifene hydrochloride (82640-04-8)

Conditions	Yield
Multi-step reaction with 4 steps 1: 80.4 percent / KOH / ethanol; H2O; ethyl acetate / Ambient temperature 2: 69 percent / PPA / 1 h / 85 - 90 °C 3: AlCl3 / CH2Cl2 / 1.5 h / 27 - 29 °C 4: 77.5 percent / AlCl3, EtSH / CH2Cl2 / 0.5 h / Ambient temperature View Scheme
Multi-step reaction with 3 steps 1.1: bromine / methanol / 2.5 h / 10 °C 1.2: 4 h / 0 - 20 °C 2.1: polyphosphoric acid / 2 h / 65 - 90 °C 3.1: thionyl chloride / N,N-dimethyl-formamide; toluene / 2 h / 80 °C 3.2: 3 h / 20 °C View Scheme

2-(4'-methoxyphenyl)-6-methoxybenzothiophene (63675-74-1) → raloxifene hydrochloride (82640-04-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: AlCl3 / CH2Cl2 / 1.5 h / 27 - 29 °C 2: 77.5 percent / AlCl3, EtSH / CH2Cl2 / 0.5 h / Ambient temperature View Scheme

4-(2-(piperidin-1-yl)ethoxy)benzoyl chloride (166975-76-4) → raloxifene hydrochloride (82640-04-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: AlCl3 / CH2Cl2 / 1.5 h / 27 - 29 °C 2: 77.5 percent / AlCl3, EtSH / CH2Cl2 / 0.5 h / Ambient temperature View Scheme

α-(3-methoxyphenyl-thio)-4-methoxyacetophenone (63675-73-0) → raloxifene hydrochloride (82640-04-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: 69 percent / PPA / 1 h / 85 - 90 °C 2: AlCl3 / CH2Cl2 / 1.5 h / 27 - 29 °C 3: 77.5 percent / AlCl3, EtSH / CH2Cl2 / 0.5 h / Ambient temperature View Scheme

4-(2-piperidin-1-ylethoxy)benzoic acid hydrochloride (84449-80-9) → raloxifene hydrochloride (82640-04-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: SOCl2, DMF / toluene 2: AlCl3 / CH2Cl2 / 1.5 h / 27 - 29 °C 3: 77.5 percent / AlCl3, EtSH / CH2Cl2 / 0.5 h / Ambient temperature View Scheme
Multi-step reaction with 3 steps 1.1: thionyl chloride / dichloromethane / 40 °C 2.1: aluminum (III) chloride / dichloromethane / 10 - 35 °C 3.1: potassium hydroxide; water / 105 - 110 °C 3.2: 60 °C / pH 2 View Scheme

2-Bromo-4'-methoxyacetophenone (2632-13-5) → raloxifene hydrochloride (82640-04-8)

Conditions	Yield
Multi-step reaction with 4 steps 1: 80.4 percent / KOH / ethanol; H2O; ethyl acetate / Ambient temperature 2: 69 percent / PPA / 1 h / 85 - 90 °C 3: AlCl3 / CH2Cl2 / 1.5 h / 27 - 29 °C 4: 77.5 percent / AlCl3, EtSH / CH2Cl2 / 0.5 h / Ambient temperature View Scheme

2-(4'-methoxyphenyl)-6-methoxybenzothiophene (63675-74-1) + 4-[2-(piperidin-1-yl)ethoxy]benzoyl chloride hydrochloride → raloxifene hydrochloride (82640-04-8)

Conditions	Yield
With boron trichloride In 1,2-dichloro-ethane at 0 - 35℃; for 24h;

aqueous sodium chloride + 2-(4'-methoxyphenyl)-6-methoxybenzothiophene (63675-74-1) + 4-(2-piperidin-1-ylethoxy)benzoic acid hydrochloride (84449-80-9) → raloxifene hydrochloride (82640-04-8)

Conditions	Yield
With hydrogenchloride; thionyl chloride; ethanethiol; aluminium trichloride In tetrahydrofuran; N-methyl-acetamide; dichloromethane; water; chlorobenzene
With hydrogenchloride; thionyl chloride; ethanethiol; aluminium trichloride In tetrahydrofuran; N-methyl-acetamide; dichloromethane; water; chlorobenzene
With hydrogenchloride; thionyl chloride; ethanethiol; aluminium trichloride In tetrahydrofuran; N-methyl-acetamide; dichloromethane; water; chlorobenzene
With hydrogenchloride; thionyl chloride; ethanethiol; aluminium trichloride In tetrahydrofuran; N-methyl-acetamide; dichloromethane; water; chlorobenzene
With hydrogenchloride; CO; thionyl chloride; ethanethiol; aluminium trichloride In tetrahydrofuran; N-methyl-acetamide; dichloromethane; water; chlorobenzene

2-(4'-methoxyphenyl)-6-methoxybenzothiophene (63675-74-1) + 4-(2-piperidin-1-ylethoxy)benzoic acid hydrochloride (84449-80-9) → raloxifene hydrochloride (82640-04-8)

Conditions	Yield
With thionyl chloride; ethanethiol; aluminium trichloride In tetrahydrofuran; N-methyl-acetamide; dichloromethane; chlorobenzene
With thionyl chloride; ethanethiol; aluminium trichloride In tetrahydrofuran; N-methyl-acetamide; dichloromethane; chlorobenzene
Stage #1: 4-(2-piperidin-1-ylethoxy)benzoic acid hydrochloride With thionyl chloride; N,N-dimethyl-formamide In chlorobenzene at 70 - 75℃; for 1h; Stage #2: 2-(4'-methoxyphenyl)-6-methoxybenzothiophene With aluminum (III) chloride In dichloromethane; chlorobenzene at 20℃; for 1.75h;
Stage #1: 4-(2-piperidin-1-ylethoxy)benzoic acid hydrochloride With thionyl chloride In N,N-dimethyl-formamide; toluene at 80℃; for 2h; Stage #2: 2-(4'-methoxyphenyl)-6-methoxybenzothiophene With aluminum (III) chloride In dichloromethane at 20℃; for 3h;

Raloxifen (84449-90-1) → raloxifene hydrochloride (82640-04-8)

Conditions	Yield
With hydrogenchloride In tetrahydrofuran; isopropyl alcohol at 5 - 35℃; for 2.25h;
With ammonium chloride In water at 70 - 75℃; for 8.45h; Product distribution / selectivity;
With hydrogenchloride In tetrahydrofuran Product distribution / selectivity;
With hydrogenchloride In methanol; water pH=2;
Stage #1: Raloxifen In methanol; acetone at 25 - 30℃; for 0.166667h; Stage #2: With hydrogenchloride In methanol; water; acetone pH=1.5 - Ca. 2;

<6-<(methylsulfonyl)oxy>-2-<4-<(methylsulfonyl)oxy>phenyl>benzothien-3-yl><4-<2-(1-pyrrolidinyl)ethoxy>phenyl>methanone hydrochloride (84449-85-4) → raloxifene hydrochloride (82640-04-8)

Conditions	Yield
Stage #1: <6-<(methylsulfonyl)oxy>-2-<4-<(methylsulfonyl)oxy>phenyl>benzothien-3-yl><4-<2-(1-pyrrolidinyl)ethoxy>phenyl>methanone hydrochloride With water; potassium hydroxide at 105 - 110℃; Stage #2: With hydrogenchloride In water; acetone at 60℃; pH=2;

Ethyl 4-hydroxybenzoate (120-47-8) → raloxifene hydrochloride (82640-04-8)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: tetra(n-butyl)ammonium hydrogensulfate; potassium carbonate / ethyl acetate; water / 13 - 35 °C / Reflux 2.1: formic acid; sulfuric acid / acetic acid 3.1: thionyl chloride / N,N-dimethyl-formamide / toluene / 5 h / 65 - 70 °C 4.1: iron(III) sulfate pentahydrate; iron / toluene / 99 - 114 °C 4.2: 62 - 66 °C / Inert atmosphere 5.1: sodium hydroxide / tetrabutylammomium bromide / toluene; water / 6 h / Reflux 5.2: 20 °C 6.1: sodium hydroxide; tetrabutylammomium bromide / dichloromethane; water / 16 h / 20 °C 6.2: 2 - 51 °C 7.1: boron trichloride / dichloromethane / 52.25 h / 2 - 20 °C 7.2: 1.08 h / 12 °C / Reflux View Scheme

N-chloroethylpiperidine hydrochloride (2008-75-5) → raloxifene hydrochloride (82640-04-8)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium hydroxide; tetrabutylammomium bromide / dichloromethane; water / 16 h / 20 °C 1.2: 2 - 51 °C 2.1: boron trichloride / dichloromethane / 52.25 h / 2 - 20 °C 2.2: 1.08 h / 12 °C / Reflux View Scheme

[6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl](4-hydroxyphenyl)methanone (63676-19-7) → raloxifene hydrochloride (82640-04-8)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium hydroxide; tetrabutylammomium bromide / dichloromethane; water / 16 h / 20 °C 1.2: 2 - 51 °C 2.1: boron trichloride / dichloromethane / 52.25 h / 2 - 20 °C 2.2: 1.08 h / 12 °C / Reflux View Scheme

ethyl 4-((phenylsulfonyl)oxy)benzoate → raloxifene hydrochloride (82640-04-8)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: formic acid; sulfuric acid / acetic acid 2.1: thionyl chloride / N,N-dimethyl-formamide / toluene / 5 h / 65 - 70 °C 3.1: iron(III) sulfate pentahydrate; iron / toluene / 99 - 114 °C 3.2: 62 - 66 °C / Inert atmosphere 4.1: sodium hydroxide / tetrabutylammomium bromide / toluene; water / 6 h / Reflux 4.2: 20 °C 5.1: sodium hydroxide; tetrabutylammomium bromide / dichloromethane; water / 16 h / 20 °C 5.2: 2 - 51 °C 6.1: boron trichloride / dichloromethane / 52.25 h / 2 - 20 °C 6.2: 1.08 h / 12 °C / Reflux View Scheme

p-benzenesulfonyloxybenzoyl chloride → raloxifene hydrochloride (82640-04-8)

Conditions

Yield

Multi-step reaction with 4 steps 1.1: iron(III) sulfate pentahydrate; iron / toluene / 99 - 114 °C 1.2: 62 - 66 °C / Inert atmosphere 2.1: sodium hydroxide / tetrabutylammomium bromide / toluene; water / 6 h / Reflux 2.2: 20 °C 3.1: sodium hydroxide; tetrabutylammomium bromide / dichloromethane; water / 16 h / 20 °C 3.2: 2 - 51 °C 4.1: boron trichloride / dichloromethane / 52.25 h / 2 - 20 °C 4.2: 1.08 h / 12 °C / Reflux View Scheme

benzenesulfonic acid-4-[6-methoxy-2-(4-methoxy-phenyl)-benzo[b]thiophene-3-carbonyl]-phenyl ester (1293362-49-8) → raloxifene hydrochloride (82640-04-8)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium hydroxide / tetrabutylammomium bromide / toluene; water / 6 h / Reflux 1.2: 20 °C 2.1: sodium hydroxide; tetrabutylammomium bromide / dichloromethane; water / 16 h / 20 °C 2.2: 2 - 51 °C 3.1: boron trichloride / dichloromethane / 52.25 h / 2 - 20 °C 3.2: 1.08 h / 12 °C / Reflux View Scheme

4-benzenesulfonyloxy-benzoic acid (7507-41-7) → raloxifene hydrochloride (82640-04-8)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: thionyl chloride / N,N-dimethyl-formamide / toluene / 5 h / 65 - 70 °C 2.1: iron(III) sulfate pentahydrate; iron / toluene / 99 - 114 °C 2.2: 62 - 66 °C / Inert atmosphere 3.1: sodium hydroxide / tetrabutylammomium bromide / toluene; water / 6 h / Reflux 3.2: 20 °C 4.1: sodium hydroxide; tetrabutylammomium bromide / dichloromethane; water / 16 h / 20 °C 4.2: 2 - 51 °C 5.1: boron trichloride / dichloromethane / 52.25 h / 2 - 20 °C 5.2: 1.08 h / 12 °C / Reflux View Scheme

1-(4-methoxyphenyl)ethanone (100-06-1) → raloxifene hydrochloride (82640-04-8)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: bromine / methanol / 2.5 h / 10 °C 1.2: 4 h / 0 - 20 °C 2.1: polyphosphoric acid / 2 h / 65 - 90 °C 3.1: thionyl chloride / N,N-dimethyl-formamide; toluene / 2 h / 80 °C 3.2: 3 h / 20 °C View Scheme

1-(4-(2-(piperidin-1-yl)ethoxy)phenyl)-2-(2-benzylthio-4-methoxyphenyl)ethanone → raloxifene hydrochloride (82640-04-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: trifluoroacetic acid / 6 h / 80 °C 2: N,N-diethylaniline / dichloromethane / 12 h / 40 °C 3: N,N-diethylaniline; ethanethiol / dichloromethane / 2 h / 32 - 34 °C View Scheme

benzyl-(3-methoxyphenyl)-sulfide → raloxifene hydrochloride (82640-04-8)

Conditions	Yield
Multi-step reaction with 5 steps 1: periodic acid; iron(III) chloride / toluene / 4 h / 27 °C / Cooling with ice 2: trifluorormethanesulfonic acid / 6 h / 70 °C 3: trifluoroacetic acid / 6 h / 80 °C 4: N,N-diethylaniline / dichloromethane / 12 h / 40 °C 5: N,N-diethylaniline; ethanethiol / dichloromethane / 2 h / 32 - 34 °C View Scheme

Upstream product

• 84541-36-6 [2-(4-methoxyphenyl)-6-methoxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone hydrochloride 
• 15570-12-4 3-methoxybenzenethiol 
• 63675-74-1 2-(4'-methoxyphenyl)-6-methoxybenzothiophene 
• 166975-76-4 4-(2-(piperidin-1-yl)ethoxy)benzoyl chloride 
• 63675-73-0 α-(3-methoxyphenyl-thio)-4-methoxyacetophenone 
• 84449-80-9 4-(2-piperidin-1-ylethoxy)benzoic acid hydrochloride 
• 2632-13-5 2-Bromo-4'-methoxyacetophenone 
• 84449-90-1 Raloxifen 
• 84449-63-8 6-acetoxy-2-(4-acetoxyphenyl)benzo[b]thiophene 
• 84449-85-4 <6-<(methylsulfonyl)oxy>-2-<4-<(methylsulfonyl)oxy>phenyl>benzothien-3-yl><4-<2-(1-pyrrolidinyl)ethoxy>phenyl>methanone hydrochloride 
• 120-47-8 Ethyl 4-hydroxybenzoate 
• 2008-75-5 N-chloroethylpiperidine hydrochloride 
• 63676-19-7 [6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl](4-hydroxyphenyl)methanone 
• 1286990-00-8 ethyl 4-((phenylsulfonyl)oxy)benzoate 

Downstream Products

• 158985-97-8 [6-(N-cyclohexylcarbamoyl)-2-[4-(N-cyclohexylcarbamoyl)phenyl]benzo[b]thienyl-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone 
• 1020061-04-4 [6-hydroxy-2-(4-hydroxyphenyl)-benzothiophen-3-yl]-[4-[2-(1-piperidyl)ethoxy]phenyl]-methanone hydrochloride monohydrate 
• 676636-17-2 [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl]-4-[2-(1-piperidinyl)ethoxy]phenyl malonate 
• 676636-09-2 [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl]-4-[2-(1-piperidinyl)ethoxy]phenyl succinate 
• 676635-74-8 [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl]-4-[2-(1-piperidinyl)ethoxy]phenyl L-lactate 
• 676635-78-2 [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl]-4-[2-(1-piperidinyl)ethoxy]phenyl DL-lactate 
• 1326716-58-8 [6-hydroxy-2-(4-hydroxyphenyl)-benzothiophene-3-yl]-[4-[2-(1-piperidyl)ethoxy]phenyl]methanone sulfamate 
• 174264-47-2 (6-((tert-butyldimethylsilyl)oxy)-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)(4-(2-(piperidin-1-yl)ethoxy)phenyl)methanone 
• 195454-31-0 raloxifene N-oxide 
• 84449-90-1 Raloxifen 

Relevant academic research and scientific papers

Preparation method of raloxifene hydrochloride and intermediate thereof

The preparation method comprises the following steps: preparing a raloxifene hydrochloride precursor (intermediate 2) from 1-{4-[2-(piperidine-1-yl)ethyoxyl]phenyl}-2-(2-sulfydryl-4-methoxyphenyl)ethanone (intermediate 1) and 4-methoxybenzoyl halide, performing demethylation protection, and preparing raloxifene hydrochloride from the demethylated raloxifene hydrochloride precursor and hydrochloricacid. Herein, the intermediate 1 is generated by removing benzyl protection from an intermediate 3 (1-{4-[2-(piperidine-1-yl)ethoxy]phenyl}-2-(2-benzylthio-4-methoxyphenyl)ethanone) in trifluoroacetic acid through a reaction; (3-methoxyphenyl) benzyl sulfide is oxidized to generate a sulfoxide compound, and then the sulfoxide compound reacts with 1-[2-(4-ethynylphenoxy)ethyl]piperidine to generate an intermediate 3. The method has the advantages of mild reaction conditions, few side reactions, high yield, cheap reagent raw materials, easy recovery and easy preparation, and is suitable for industrial large-scale production.

Novel solvated crystalline of Raloxifene hydrochloride and process for preparing Raloxifene hydrochloride monohydrate

The present invention relates to a raloxifene hydrochloride acetone solvate which is a novel solvate of raloxifene hydrochloride, namely, [6-hydroxy-2-(4-hydroxyphenyl)-benzo thiophen-3-yl]-[4-[2-(1-piperidyl)ethoxy]phenyl]-methanone hydrochloride; and a method to manufacture high purity raloxifene hydrochloride monohydrate using the same. The manufacturing method of raloxifene hydrochloride monohydrate comprises the following steps: a) make a crystalline raloxifene hydrochloride acetone solvate into a slurry in top water; b) adding and mixing concentrated hydrochloric acid into the solution; and c) obtaining raloxifene hydrochloride monohydrate by separating solids obtained from the step b) and drying the solids.COPYRIGHT KIPO 2016

PREPARATION OF RALOXIFENE AND ITS SALTS

The invention provides processes for the preparation of pure raloxifene or its salts, involving hydrolyzing 6-methylsulfonyloxy-2-[(4-methylsulfonyloxy)-phenyl]-3-[4(2-(piperidinyl)ethoxy)benzoyl]benzothiophene hydrochloride, using an aqueous base.

A PROCESS FOR PREPARING BENZO[B]THIOPHENE DERIVATIVES

The present invention relates in general to the field of organic chemistry, and in particular to the preparation of benzo[b]thiophene derivatives. These benzo[b]thiophene derivatives are useful as intermediates in the synthesis of pharmaceutically active agents such as raloxifene or derivatives thereof.

A process for preparing benzo[b]thiophene derivatives

The present invention relates in general to the field of organic chemistry, and in particular to the preparation of benzo[b]thiophene derivatives. These benzo[b]thiophene derivatives are useful as intermediates in the synthesis of pharmaceutically active agents such as raloxifene or derivatives thereof.

A PROCESS FOR PREPARING BENZO[B]THIOPHENE DERIVATIVES

The present invention relates in general to the field of organic chemistry, and in particular to the preparation of benzo[b]thiophene derivatives. These benzo[b]thiophene derivatives are useful as intermediates in the synthesis of pharmaceutically active agents such as raloxifene or derivatives thereof.

PROCESS FOR THE PREPARATION OF RALOXIFENE HYDROCHLORIDE

The present invention provides an improved process for the preparation of α-(3- methoxyphenylthio)-4-methoxyacetophenone. The present invention also provides a process for the preparing free flowing solid of 6-methoxy-2-(4-methoxyphenyl)- benzo[b]-thiophene. The present invention further provides a process for the preparation of substantially pure 6-methoxy-2-(4-methoxyphenyl)-benzo[b]-thiophene. The present invention further provides a process for purification of raloxifene hydrochloride.

A PROCESS FOR THE PREPARATION OF 6-HYDROXY-2-(4-HYDROXYPHENYL)-3-[4-(2-PIPERIDINO ETHOXY) BENZOYL]BENZO[B]THIOPHENE

The present invention related to a process for preparing 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2- piperidinoethoxy)benzoyl]benzo[b]thiophene, compound of formula (I), said process comprising: deprotecting compound of formula (II) with base in dimethyl sulfoxide to yield substantially pure compound of formula (I) with HPLC purity of 99 % or more by area and optionally converting to its pharmaceutically acceptable salt.

CRYSTALLINE FORM OF BENZOTHIOPHENE COMPOUND AND PROCESS FOR PREPARATION THEREOF

Crystalline raloxifene hydrochloride in hydrated form, particularly the monohydrate, processes for its preparation, pharmaceutical compositions comprising it and uses thereof.

PROCESS FOR PREPARING RALOXIFENE HYDROCHLORIDE

Process for preparing raloxifene hydrochloride with a purity greater than 98% and low aluminium content comprising the following stages a) demethylation of 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene in pyridine and hydrochloric acid to obtain 6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene in pyridine hydrochloride, b) acetylation of 6-hydroxy-2-(4-hydroxyphonyl)benzo[b]thiophene with an acetylating agent to obtain the corresponding 6-acetoxy-2-(4 acetoxyphenyl)benzo[b]thiophene, c) acylation of 6-acetoxy-2-(4-acetoxyphonyl)benzo[b]thlophene with 4-(2 piperidinoethoxy)benzoylchloride hydrochloride with aluminium trichloride in halogenated solvent to obtain 6-acetoxy-2-(4-acetoxyphenyl)-3-[4-(2 piperidinoethoxy)benzoyl]-benzo[b]thiophene, d) hydrolysis of 6-acetoxy-2-(4-acetoxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyll benzo[b]thiophene according to the following operating conditions: dl) treatment of 6-acetoxy-2-(4-acetoxyphonyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene with alkaline hydroxide in alcohol solvent, d2) acidification of the product obtained in the preceding stage (dl) with a strong acid, to obtain the corresponding raloxifene salt with the strong acid, characterised in that the strong acid used in stage (d2) is concentrated hydrochloric acid.