84449-90-1

Basic information

• Product Name: Raloxifene
• Synonyms: [4-[2-(1-Piperidinyl) Ethoxy] Phenyl]methanone.HCL;RALOXAFINE;[6-Hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone;[6-hydroxy-2-(4-hydroxyphenyl)benzothiophen-3-yl]-[4-[2-(1-piperidyl)ethoxy]phenyl]methanone hydrochloride;[6-Hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-y1][4-[2-(1-piperidinyl)ethoxy]phenyl]methamone;Evista;Methanone, [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]-;[6-Hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl] ketone
• CAS NO: 84449-90-1
• Molecular Formula: C₂₈H₂₇NO₄S
• Molecular Weight: 473.58
• EINECS: 1806241-263-5
• Product Categories: Raloxifene;Intermediates & Fine Chemicals;Pharmaceuticals;Pharmaceutical intermediate
• Mol File: 84449-90-1.mol

Chemical Properties

• Melting Point: 250-253°C
• Boiling Point: 728.2 °C at 760 mmHg
• Flash Point: 394.2 °C
• Appearance: light yellow/solid
• Density: 1.289 g/cm³
• Storage Temp.: Desiccate at +4°C
• Solubility: DMSO: 28 mg/mL, soluble
• PKA: 8.83±0.15(Predicted)
• Water Solubility: 560μg/L at 25℃
• CAS DataBase Reference: Raloxifene(CAS DataBase Reference)
• NIST Chemistry Reference: Raloxifene(84449-90-1)
• EPA Substance Registry System: Raloxifene(84449-90-1)

Safety Data

• WGK Germany: 3
• Hazardous Substances Data: 84449-90-1(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Raloxifene is used as an antiosteoporotic agent for the prevention and treatment of osteoporosis in postmenopausal women. Its agonist properties on bone help to increase bone mineral density and reduce the risk of fractures.
Used in Oncology:
Raloxifene is used as a breast cancer prevention agent, particularly in postmenopausal women at high risk of developing the disease. It has been compared with tamoxifen and has shown similar effectiveness in preventing breast cancer, but with a more favorable side effect profile.
Used in Research:
Raloxifene is used in research for studying the effects of selective estrogen receptor modulators on various tissues and diseases. Its unique structure and properties allow for a better understanding of the mechanisms of action of SERMs and their potential applications in the treatment and prevention of various conditions, including cardiovascular diseases and osteoporosis.

Application in Particular Diseases

In Osteoporosis: Raloxifene is an estrogen agonist on bone but an antagonist on the breast and uterus. It is approved for prevention and treatment of postmenopausal osteoporosis. Other estrogen agonists/antagonists may be approved soon (e.g., bazedoxifene, lasofoxifene). Raloxifene decreases vertebral fractures and increases spine and hip BMD, but to a lesser extent than bisphosphonates. After discontinuation, the beneficial effect is lost and bone loss returns to age- or disease-related rates. Raloxifene (like tamoxifen) is associated with decreased breast cancer risk. Raloxifene is associated with decreases in total and low-density lipoprotein cholesterol, neutral effects on high-density lipoprotein cholesterol, but slight increases in triglycerides; no beneficial cardiovascular effects have yet been demonstrated. Raloxifene is well tolerated overall. Hot flushes occur more frequently in women recently finishing menopause or discontinuing estrogen therapy (ET). Endometrial bleeding occurs rarely. Raloxifene is contraindicated in women with an active or past history of venous thromboembolism. Therapy should be stopped if a patient anticipates extended immobility.

Indications

Raloxifene (Evista) is a new SERM approved for use in the treatment and prevention of osteoporosis because it has estrogenic activity in bone. Raloxifene is an estrogen antagonist in both breast and endometrial tissues. The estrogenlike properties of raloxifene result in the maintenance of a favorable serum lipid profile (decreased low-density lipoprotein levels with no change in either high-density lipoproteins or triglycerides). Raloxifene is 95% bound to plasma proteins. Absorption of raloxifene is impaired by cholestyramine.

Biological Activity

Selective estrogen receptor modulator (SERM) that binds to ER α and ER β , and tissue-dependently activates or blocks estrogen-induced transcription. Acts as an antiestrogen in breast and uterine tissue, but displays estrogen agonist activity in bone. In D12 rat hypothalamic cells, inhibits progesterone receptor induction by estrogen with an IC 50 of 1 nM.

Clinical Use

Raloxifene, the first SERM approved for the prevention of osteoporosis in postmenopausal women, acts as an estrogen agonist on receptors in osteoblasts and osteoclasts but as an antagonist at breast and uterine estrogen receptors.

InChI:InChI=1/C28H27NO4S/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/h4-13,18,30-31H,1-3,14-17H2

Synthetic route

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

Conditions	Yield
Stage #1: raloxifene hydrochloride With sodium hydroxide In water; acetone at 20℃; Stage #2: With acetic acid In water; acetone at 16 - 20℃; for 1.75h; pH=8;	100%
Stage #1: raloxifene hydrochloride With sodium hydroxide In water; acetone at 20℃; Stage #2: With acetic acid In water; acetone at 16 - 18℃; for 0.75h; pH=8;	100%
With sodium hydroxide; water; isopropyl alcohol at 20℃; for 5h; pH=9;
With sodium hydroxide In methanol; water at 15 - 30℃; for 12.5h; pH=8 - 8.5;	180 g

1-(2-(4-[6-Hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophene-3-carbonyl]-phenoxy)-ethyl)-piperidinium bromide (1293408-87-3) → Raloxifen (84449-90-1)

Conditions	Yield
Stage #1: 1-(2-(4-[6-Hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophene-3-carbonyl]-phenoxy)-ethyl)-piperidinium bromide With sodium hydroxide In water; acetone at 20℃; Stage #2: With acetic acid In water; acetone at 12℃; for 1h; pH=8 - 9;	100%
Stage #1: 1-(2-(4-[6-Hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophene-3-carbonyl]-phenoxy)-ethyl)-piperidinium bromide With sodium hydroxide In 1,4-dioxane; water at 16 - 20℃; Stage #2: With acetic acid In 1,4-dioxane; water for 0.166667h; pH=8; Product distribution / selectivity;	85.8%

[6-Methoxy-2-(4-Methoxyphenyl)benzo[b]thien-3-yl]-[4-[2-(1-Piperidinyl)ethoxy]phenyl] Methanone (84541-38-8) → Raloxifen (84449-90-1)

Conditions	Yield
With aluminum (III) chloride In dichloromethane at 50℃;	90%
With aluminium trichloride; ethanethiol demethylation;	78%
In dichloromethane for 6h; Ionic liquid; Reflux;	61%

1-piperidinoethanol (3040-44-6) + [2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thien-3-yl] [4-fluorophenyl]methanone (202336-25-2) → Raloxifen (84449-90-1)

Conditions	Yield
With sodium hydride In N,N-dimethyl-formamide at 50℃; for 5h;	86%

<6-<(methylsulfonyl)oxy>-2-<4-<(methylsulfonyl)oxy>phenyl>benzothien-3-yl><4-<2-(1-pyrrolidinyl)ethoxy>phenyl>methanone hydrochloride (84449-85-4) → Raloxifen (84449-90-1)

Conditions	Yield
Stage #1: <6-<(methylsulfonyl)oxy>-2-<4-<(methylsulfonyl)oxy>phenyl>benzothien-3-yl><4-<2-(1-pyrrolidinyl)ethoxy>phenyl>methanone hydrochloride With potassium hydroxide; water In dimethyl sulfoxide at 60 - 62℃; for 4h; Stage #2: With acetic acid In water; dimethyl sulfoxide at 20℃; Stage #3: With ammonia In water; dimethyl sulfoxide at 20℃; Product distribution / selectivity;	70.5%
Stage #1: <6-<(methylsulfonyl)oxy>-2-<4-<(methylsulfonyl)oxy>phenyl>benzothien-3-yl><4-<2-(1-pyrrolidinyl)ethoxy>phenyl>methanone hydrochloride With potassium hydroxide; water In dimethyl sulfoxide at 60 - 62℃; for 4h; Stage #2: With hydrogenchloride In water; dimethyl sulfoxide at 20℃; for 1h; Stage #3: With ammonia In water; dimethyl sulfoxide at 20℃; Product distribution / selectivity;	66.33%
With sodium hydroxide In ethanol for 1.5h; Heating;	42%

6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)-3-[4-(2-piperidinoethoxy)-benzoyl]benzo[b]thiophene → Raloxifen (84449-90-1)

Conditions	Yield
With potassium hydroxide In dimethyl sulfoxide Inert atmosphere;	67%
Stage #1: 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)-3-[4-(2-piperidinoethoxy)-benzoyl]benzo[b]thiophene With sodium hydroxide; ethanol; water for 1.5h; Stage #2: In water Acidic aqueous solution; Stage #3: With sodium hydrogencarbonate In water Product distribution / selectivity;	42.2%
With sodium hydroxide In tetrahydrofuran; methanol; chloroform
With sodium hydroxide In tetrahydrofuran; methanol; chloroform
With sodium hydroxide In tetrahydrofuran; methanol; chloroform

1-piperidinoethanol (3040-44-6) → Raloxifen (84449-90-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: 90 percent / NaH / dimethylformamide / 0.5 h / 20 °C 2: 78 percent / AlCl3; ethanethiol View Scheme
Multi-step reaction with 3 steps 1: 97 percent / NaH / dimethylformamide / 0.25 h / 20 °C 2: 90 percent / tetrahydrofuran / 2 h / 5 - 23 °C 3: 78 percent / AlCl3; ethanethiol View Scheme

4-fluorobenzoyl chloride (403-43-0) → Raloxifen (84449-90-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: 70 percent / chlorobenzene / 20 °C 2: 97 percent / NaH / dimethylformamide / 0.25 h / 20 °C 3: 90 percent / tetrahydrofuran / 2 h / 5 - 23 °C 4: 78 percent / AlCl3; ethanethiol View Scheme
Multi-step reaction with 4 steps 1: 70 percent / chlorobenzene / 20 °C 2: 83 percent / tetrahydrofuran / 1 h / 5 - 23 °C 3: 90 percent / NaH / dimethylformamide / 0.5 h / 20 °C 4: 78 percent / AlCl3; ethanethiol View Scheme
Multi-step reaction with 4 steps 1: 70 percent / chlorobenzene / 20 °C 2: 97 percent / dimethylformamide / 0.25 h / 20 °C 3: 90 percent / tetrahydrofuran / 2 h / 5 - 23 °C 4: 78 percent / AlCl3; ethanethiol View Scheme
Multi-step reaction with 3 steps 1: 74 percent / AlCl3 / CH2Cl2 2: 81 percent / BBr3 / CH2Cl2 / 3 h / 5 °C 3: 86 percent / NaH / dimethylformamide / 5 h / 50 °C View Scheme

6-methoxy-N,N-dimethylbenzo[b]thiophen-2-amine (111359-29-6) → Raloxifen (84449-90-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: 70 percent / chlorobenzene / 20 °C 2: 97 percent / NaH / dimethylformamide / 0.25 h / 20 °C 3: 90 percent / tetrahydrofuran / 2 h / 5 - 23 °C 4: 78 percent / AlCl3; ethanethiol View Scheme
Multi-step reaction with 4 steps 1: 70 percent / chlorobenzene / 20 °C 2: 83 percent / tetrahydrofuran / 1 h / 5 - 23 °C 3: 90 percent / NaH / dimethylformamide / 0.5 h / 20 °C 4: 78 percent / AlCl3; ethanethiol View Scheme
Multi-step reaction with 4 steps 1: 70 percent / chlorobenzene / 20 °C 2: 97 percent / dimethylformamide / 0.25 h / 20 °C 3: 90 percent / tetrahydrofuran / 2 h / 5 - 23 °C 4: 78 percent / AlCl3; ethanethiol View Scheme

[2-dimethylamino-6-methoxybenzothien-3-yl] [4-[2-(1-piperidinyl)ethoxy]phenyl]-methanone (165742-76-7) → Raloxifen (84449-90-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: 90 percent / tetrahydrofuran / 2 h / 5 - 23 °C 2: 78 percent / AlCl3; ethanethiol View Scheme

6-methoxy-2-(4-methoxyphenyl)-3-(4-fluorobenzoyl)benzo[b]thiophene (206434-77-7) → Raloxifen (84449-90-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: 90 percent / NaH / dimethylformamide / 0.5 h / 20 °C 2: 78 percent / AlCl3; ethanethiol View Scheme
Multi-step reaction with 2 steps 1: 81 percent / BBr3 / CH2Cl2 / 3 h / 5 °C 2: 86 percent / NaH / dimethylformamide / 5 h / 50 °C View Scheme

(2-dimethylamino-6-methoxy-benzo[b]thiophen-3-yl)-(4-fluoro-phenyl)-methanone (243845-88-7) → Raloxifen (84449-90-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: 97 percent / NaH / dimethylformamide / 0.25 h / 20 °C 2: 90 percent / tetrahydrofuran / 2 h / 5 - 23 °C 3: 78 percent / AlCl3; ethanethiol View Scheme
Multi-step reaction with 3 steps 1: 83 percent / tetrahydrofuran / 1 h / 5 - 23 °C 2: 90 percent / NaH / dimethylformamide / 0.5 h / 20 °C 3: 78 percent / AlCl3; ethanethiol View Scheme
Multi-step reaction with 3 steps 1: 97 percent / dimethylformamide / 0.25 h / 20 °C 2: 90 percent / tetrahydrofuran / 2 h / 5 - 23 °C 3: 78 percent / AlCl3; ethanethiol View Scheme

2-(4'-methoxyphenyl)-6-methoxybenzothiophene (63675-74-1) → Raloxifen (84449-90-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: 74 percent / AlCl3 / CH2Cl2 2: 81 percent / BBr3 / CH2Cl2 / 3 h / 5 °C 3: 86 percent / NaH / dimethylformamide / 5 h / 50 °C View Scheme
Multi-step reaction with 4 steps 1: 71 percent / pyridine hydrochloride / 6 h / 220 °C 2: 99 percent / 4-(dimethylamino)pyridine, pyridine / Ambient temperature 3: 93 percent / trifluoromethanesulfonic acid / 1,2-dichloro-ethane / Heating 4: 42 percent / 5 N aq. NaOH / ethanol / 1.5 h / Heating View Scheme

3-methoxybenzenethiol (15570-12-4) → Raloxifen (84449-90-1)

Conditions

Yield

Multi-step reaction with 6 steps 1: 80.4 percent / KOH / ethanol; H2O; ethyl acetate / Ambient temperature 2: 69 percent / PPA / 1 h / 85 - 90 °C 3: 71 percent / pyridine hydrochloride / 6 h / 220 °C 4: 99 percent / 4-(dimethylamino)pyridine, pyridine / Ambient temperature 5: 93 percent / trifluoromethanesulfonic acid / 1,2-dichloro-ethane / Heating 6: 42 percent / 5 N aq. NaOH / ethanol / 1.5 h / Heating View Scheme

6-hydroxy-2-(4-hydroxyphenyl)benzo[B]-thiophene (63676-22-2) → Raloxifen (84449-90-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: 99 percent / 4-(dimethylamino)pyridine, pyridine / Ambient temperature 2: 93 percent / trifluoromethanesulfonic acid / 1,2-dichloro-ethane / Heating 3: 42 percent / 5 N aq. NaOH / ethanol / 1.5 h / Heating View Scheme

4-(2-(piperidin-1-yl)ethoxy)benzoyl chloride (166975-76-4) → Raloxifen (84449-90-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: 93 percent / trifluoromethanesulfonic acid / 1,2-dichloro-ethane / Heating 2: 42 percent / 5 N aq. NaOH / ethanol / 1.5 h / Heating View Scheme

α-(3-methoxyphenyl-thio)-4-methoxyacetophenone (63675-73-0) → Raloxifen (84449-90-1)

Conditions	Yield
Multi-step reaction with 5 steps 1: 69 percent / PPA / 1 h / 85 - 90 °C 2: 71 percent / pyridine hydrochloride / 6 h / 220 °C 3: 99 percent / 4-(dimethylamino)pyridine, pyridine / Ambient temperature 4: 93 percent / trifluoromethanesulfonic acid / 1,2-dichloro-ethane / Heating 5: 42 percent / 5 N aq. NaOH / ethanol / 1.5 h / Heating View Scheme

6-<(methylsulfonyl)oxy>-2-<4-<(methylsulfonyl)oxy>phenyl>benzothiophene (84449-65-0) → Raloxifen (84449-90-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: 93 percent / trifluoromethanesulfonic acid / 1,2-dichloro-ethane / Heating 2: 42 percent / 5 N aq. NaOH / ethanol / 1.5 h / Heating View Scheme
Multi-step reaction with 3 steps 1: aluminum (III) chloride / 1,2-dichloro-ethane / 20.5 h / 20 °C / Inert atmosphere 2: sodium t-butanolate / acetonitrile / 16 h / 80 °C / Inert atmosphere 3: potassium hydroxide / dimethyl sulfoxide / Inert atmosphere View Scheme

4-(2-piperidin-1-ylethoxy)benzoic acid hydrochloride (84449-80-9) → Raloxifen (84449-90-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: SOCl2, DMF / toluene 2: 93 percent / trifluoromethanesulfonic acid / 1,2-dichloro-ethane / Heating 3: 42 percent / 5 N aq. NaOH / ethanol / 1.5 h / Heating View Scheme

2-Bromo-4'-methoxyacetophenone (2632-13-5) → Raloxifen (84449-90-1)

Conditions

Yield

Multi-step reaction with 6 steps 1: 80.4 percent / KOH / ethanol; H2O; ethyl acetate / Ambient temperature 2: 69 percent / PPA / 1 h / 85 - 90 °C 3: 71 percent / pyridine hydrochloride / 6 h / 220 °C 4: 99 percent / 4-(dimethylamino)pyridine, pyridine / Ambient temperature 5: 93 percent / trifluoromethanesulfonic acid / 1,2-dichloro-ethane / Heating 6: 42 percent / 5 N aq. NaOH / ethanol / 1.5 h / Heating View Scheme

6-acetoxy-2-(4-acetoxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene, hydrochloride (84449-82-1) → Raloxifen (84449-90-1)

Conditions	Yield
With sodium hydroxide In methanol; chloroform; water
With sodium hydroxide In methanol; chloroform; water

6-benzoyloxy-2-(4-benzoyloxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene, hydrochloride (84449-83-2) → Raloxifen (84449-90-1)

Conditions	Yield
With methanesulfonic acid In ethanol; water

6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)-3-[4-(2-piperidinoethoxy)-benzoyl]benzo[b]thiophene → C29H29NO6S2 (1100049-65-7) + C29H29NO6S2 (1100049-66-8) + Raloxifen (84449-90-1)

Conditions	Yield
Stage #1: 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)-3-[4-(2-piperidinoethoxy)-benzoyl]benzo[b]thiophene With sodium hydroxide; water In N,N-dimethyl-formamide at 80 - 90℃; for 3h; Stage #2: With hydrogenchloride In water; N,N-dimethyl-formamide at 20℃; for 1h; Stage #3: With ammonia In water; N,N-dimethyl-formamide Product distribution / selectivity;
Stage #1: 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)-3-[4-(2-piperidinoethoxy)-benzoyl]benzo[b]thiophene With sodium hydroxide; water In tetrahydrofuran at 60 - 62℃; for 14h; Stage #2: With acetic acid In tetrahydrofuran; water at 20℃; for 0.333333h; Stage #3: With ammonia In tetrahydrofuran; water Product distribution / selectivity;

C24H20O10S4 (1390631-69-2) → Raloxifen (84449-90-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium t-butanolate / acetonitrile / 16 h / 80 °C / Inert atmosphere 2: potassium hydroxide / dimethyl sulfoxide / Inert atmosphere View Scheme

methanesulfonic acid 4-chlorocarbonyl-phenyl ester (89938-63-6) → Raloxifen (84449-90-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: aluminum (III) chloride / 1,2-dichloro-ethane / 20.5 h / 20 °C / Inert atmosphere 2: sodium t-butanolate / acetonitrile / 16 h / 80 °C / Inert atmosphere 3: potassium hydroxide / dimethyl sulfoxide / Inert atmosphere View Scheme

methyl 4-hydroxylbenzoate (99-76-3) → Raloxifen (84449-90-1)

Conditions	Yield
Multi-step reaction with 6 steps 1: potassium carbonate / acetone / Reflux 2: hydrogenchloride; water / tetrahydrofuran 3: thionyl chloride / dichloromethane 4: aluminum (III) chloride / dichloromethane / 12 h / 50 °C / Inert atmosphere 5: neat liquid / 12 h / Inert atmosphere; Reflux 6: aluminum (III) chloride / dichloromethane / 50 °C View Scheme

4-(2-Chloroethoxy)benzoic acid methyl ester (38567-00-9) → Raloxifen (84449-90-1)

Conditions	Yield
Multi-step reaction with 5 steps 1: hydrogenchloride; water / tetrahydrofuran 2: thionyl chloride / dichloromethane 3: aluminum (III) chloride / dichloromethane / 12 h / 50 °C / Inert atmosphere 4: neat liquid / 12 h / Inert atmosphere; Reflux 5: aluminum (III) chloride / dichloromethane / 50 °C View Scheme

4-(2-chloroethoxy)benzoic acid (65136-51-8) → Raloxifen (84449-90-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: thionyl chloride / dichloromethane 2: aluminum (III) chloride / dichloromethane / 12 h / 50 °C / Inert atmosphere 3: neat liquid / 12 h / Inert atmosphere; Reflux 4: aluminum (III) chloride / dichloromethane / 50 °C View Scheme

4-(2-chloro-ethoxy)-benzoyl chloride (65136-50-7) → Raloxifen (84449-90-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: aluminum (III) chloride / dichloromethane / 12 h / 50 °C / Inert atmosphere 2: neat liquid / 12 h / Inert atmosphere; Reflux 3: aluminum (III) chloride / dichloromethane / 50 °C View Scheme

Raloxifen (84449-90-1) → [6-hydroxy-2-(4-hydroxyphenyl)-benzothiophene-3-yl]-[4-[2-(1-piperidyl)ethoxy]phenyl]methanone sulfamate (1326716-58-8)

Conditions	Yield
With aminosulfonic acid In water; acetonitrile at 80℃; Product distribution / selectivity;	96.4%

Raloxifen (84449-90-1) → [2-(4-Hydroxyphenyl)-6-hydroxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanol (174731-13-6)

Conditions	Yield
With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 6h;	91%

Raloxifen (84449-90-1) → 1-(2-(4-[6-Hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophene-3-carbonyl]-phenoxy)-ethyl)-piperidinium bromide (1293408-87-3)

Conditions	Yield
With hydrogen bromide In methanol; water at 1 - 35℃; pH=1.5; Reflux;	87.4%
With hydrogen bromide In methanol; water at 35℃; pH=1.5; Reflux;	87.4%

trifluoromethylsulfonic anhydride (358-23-6) + Raloxifen (84449-90-1) → Trifluoro-methanesulfonic acid 3-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-2-(4-trifluoromethanesulfonyloxy-phenyl)-benzo[b]thiophen-6-yl ester

Conditions	Yield
With triethylamine In 1,2-dichloro-ethane	51%
With pyridine In dichloromethane at 0 - 20℃; for 1h;	0.16 g

benzyl chloride (100-44-7) + Raloxifen (84449-90-1) → [6-Benzyloxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (189940-64-5) + [2-(4-Benzyloxy-phenyl)-6-hydroxy-benzo[b]thiophen-3-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone + 6-benzyloxy-2-(4-benzyloxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene

Conditions	Yield
With sodium hydride In N,N-dimethyl-formamide	A 20% B 20% C 20%

Raloxifen (84449-90-1) + tert-butyldimethylsilyl chloride (18162-48-6) → (6-((tert-butyldimethylsilyl)oxy)-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)(4-(2-(piperidin-1-yl)ethoxy)phenyl)methanone (174264-47-2) + 2-[4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]phenyl]-6-hydroxybenzo[b]thiophen-3-yl 4-[2-(1-piperidinyl)ethoxy]phenyl ketone (174264-46-1) + {6-(tert-Butyl-dimethyl-silanyloxy)-2-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-benzo[b]thiophen-3-yl}-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone

Conditions	Yield
With dmap In tetrahydrofuran; N,N-dimethyl-formamide	A 20% B 20% C 20%

benzoyl chloride (98-88-4) + Raloxifen (84449-90-1) → 4-(6-hydroxy-3-(4-(2-(piperidin-1-yl)ethoxy)phenylcarbonyl)benzo[b]thiophen-2-yl)phenyl benzoate (1248544-66-2)

Conditions	Yield
Stage #1: Raloxifen With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.0833333h; Stage #2: benzoyl chloride In N,N-dimethyl-formamide at 20℃; for 0.25h;	7.8%

Raloxifen (84449-90-1) + tert-butyldimethylsilyl chloride (18162-48-6) → (6-((tert-butyldimethylsilyl)oxy)-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)(4-(2-(piperidin-1-yl)ethoxy)phenyl)methanone (174264-47-2) + 2-[4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]phenyl]-6-hydroxybenzo[b]thiophen-3-yl 4-[2-(1-piperidinyl)ethoxy]phenyl ketone (174264-46-1)

Conditions	Yield
With dmap 1.) THF, DMF, RT, 1 h, 2.) THF, DMF, RT, 72 h; Yield given. Multistep reaction. Yields of byproduct given;
With dmap In tetrahydrofuran; N,N-dimethyl-formamide

Raloxifen (84449-90-1) → [2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane (166975-45-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: 91 percent / LiAlH4 / tetrahydrofuran / 6 h / 0 °C 2: 72 percent / Et3SiH, CF3CO2H / CH2Cl2 / 16 h / 0 °C View Scheme

Raloxifen (84449-90-1) → [6-Hydroxy-2-(4-vinyl-phenyl)-benzo[b]thiophen-3-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone

Conditions	Yield
Multi-step reaction with 3 steps 1: 20 percent / DMAP / tetrahydrofuran; dimethylformamide 2: 85 percent / Et3N / CH2Cl2 3: 1.) Pd(OAc)2, bis-diphenylphosphinopropane, Et3N, 2.) TBAF / 1) DMF; 2) CH2Cl2 View Scheme
Multi-step reaction with 4 steps 1: 1.) DMAP / 1.) THF, DMF, RT, 1 h, 2.) THF, DMF, RT, 72 h 2: 88 percent / Et3N / 1,2-dichloro-ethane / Ambient temperature 3: Et3N, Pd(OAc)2, 1,3-bis(diphenylphosphino)propane / dimethylformamide / 4 h / 100 °C 4: tetra-N-butylammoium fluoride / tetrahydrofuran / 3 h View Scheme

Raloxifen (84449-90-1) → [2-(4-Ethynyl-phenyl)-6-hydroxy-benzo[b]thiophen-3-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone

Conditions	Yield
Multi-step reaction with 3 steps 1: 20 percent / DMAP / tetrahydrofuran; dimethylformamide 2: 85 percent / Et3N / CH2Cl2 3: 1.) Pd(OAc)2, bis-diphenylphosphinopropane, Et3N, 2.) TBAF / 1) DMF; 2) CH2Cl2 View Scheme
Multi-step reaction with 4 steps 1: 1.) DMAP / 1.) THF, DMF, RT, 1 h, 2.) THF, DMF, RT, 72 h 2: 88 percent / Et3N / 1,2-dichloro-ethane / Ambient temperature 3: Et3N, Pd(OAc)2, 1,3-bis(diphenylphosphino)propane / dimethylformamide / 10 h / 75 °C 4: tetra-N-butylammonium fluoride / tetrahydrofuran View Scheme

Raloxifen (84449-90-1) → 1-(4-{6-Hydroxy-3-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-benzo[b]thiophen-2-yl}-phenyl)-ethanone

Conditions	Yield
Multi-step reaction with 3 steps 1: 20 percent / DMAP / tetrahydrofuran; dimethylformamide 2: 85 percent / Et3N / CH2Cl2 3: 1.) Pd(OAc)2, bis-diphenylphosphinopropane, Et3N, 2.) TBAF / 1) DMF; 2) CH2Cl2 View Scheme
Multi-step reaction with 4 steps 1: 1.) DMAP / 1.) THF, DMF, RT, 1 h, 2.) THF, DMF, RT, 72 h 2: 88 percent / Et3N / 1,2-dichloro-ethane / Ambient temperature 3: Et3N, Pd(OAc)2, 1,3-bis(diphenylphosphino)propane / dimethylformamide / 19 h / 80 °C 4: tetra-N-butylammonium fluoride / tetrahydrofuran / 3 h View Scheme

Raloxifen (84449-90-1) → 4-{6-Hydroxy-3-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-benzo[b]thiophen-2-yl}-benzamide

Conditions	Yield
Multi-step reaction with 4 steps 1: 20 percent / DMAP / tetrahydrofuran; dimethylformamide 2: 85 percent / Et3N / CH2Cl2 3: 1.) Pd(OAc)2, bis-diphenylphosphinopropane, Et3N, 2.) TBAF / 1) DMF; 2) CH2Cl2 4: NH3 / methanol View Scheme
Multi-step reaction with 5 steps 1: 1.) DMAP / 1.) THF, DMF, RT, 1 h, 2.) THF, DMF, RT, 72 h 2: 88 percent / Et3N / 1,2-dichloro-ethane / Ambient temperature 3: 54 percent / Et3N, Pd(OAc)2, 1,3-bis(diphenylphosphino)propane / dimethylformamide / 4.5 h / 70 °C 4: MeAl(Cl)NH2 / toluene / Ambient temperature 5: 1N aq. HCl / tetrahydrofuran / 5 h / Heating View Scheme

Raloxifen (84449-90-1) → 4-{6-Hydroxy-3-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-benzo[b]thiophen-2-yl}-benzoic acid methyl ester (185416-94-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: 20 percent / DMAP / tetrahydrofuran; dimethylformamide 2: 85 percent / Et3N / CH2Cl2 3: 1.) Pd(OAc)2, bis-diphenylphosphinopropane, Et3N, 2.) TBAF / 1) DMF; 2) CH2Cl2 View Scheme
Multi-step reaction with 3 steps 1: 1.) DMAP / 1.) THF, DMF, RT, 1 h, 2.) THF, DMF, RT, 72 h 2: 88 percent / Et3N / 1,2-dichloro-ethane / Ambient temperature 3: 27 percent / Et3N, Pd(OAc)2, 1,3-bis(diphenylphosphino)propane / dimethylformamide / 4.5 h / 70 °C View Scheme
Multi-step reaction with 4 steps 1: 1.) DMAP / 1.) THF, DMF, RT, 1 h, 2.) THF, DMF, RT, 72 h 2: 88 percent / Et3N / 1,2-dichloro-ethane / Ambient temperature 3: 54 percent / Et3N, Pd(OAc)2, 1,3-bis(diphenylphosphino)propane / dimethylformamide / 4.5 h / 70 °C 4: tetra-n-butylammonium fluoride / tetrahydrofuran View Scheme

Raloxifen (84449-90-1) → 4-{6-Hydroxy-3-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-benzo[b]thiophen-2-yl}-N,N-dimethyl-benzamide

Conditions	Yield
Multi-step reaction with 4 steps 1: 20 percent / DMAP / tetrahydrofuran; dimethylformamide 2: 85 percent / Et3N / CH2Cl2 3: 1.) Pd(OAc)2, bis-diphenylphosphinopropane, Et3N, 2.) TBAF / 1) DMF; 2) CH2Cl2 4: Me3Al / toluene View Scheme
Multi-step reaction with 5 steps 1: 1.) DMAP / 1.) THF, DMF, RT, 1 h, 2.) THF, DMF, RT, 72 h 2: 88 percent / Et3N / 1,2-dichloro-ethane / Ambient temperature 3: 54 percent / Et3N, Pd(OAc)2, 1,3-bis(diphenylphosphino)propane / dimethylformamide / 4.5 h / 70 °C 4: Me3Al / toluene / 21 h / 50 °C 5: tetra-N-butylammonium fluoride / tetrahydrofuran / 3 h View Scheme

Raloxifen (84449-90-1) → 4-{6-Hydroxy-3-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-benzo[b]thiophen-2-yl}-benzoic acid ethyl ester

Conditions	Yield
Multi-step reaction with 3 steps 1: 20 percent / DMAP / tetrahydrofuran; dimethylformamide 2: 85 percent / Et3N / CH2Cl2 3: 1.) Pd(OAc)2, bis-diphenylphosphinopropane, Et3N, 2.) TBAF / 1) DMF; 2) CH2Cl2 View Scheme
Multi-step reaction with 4 steps 1: 1.) DMAP / 1.) THF, DMF, RT, 1 h, 2.) THF, DMF, RT, 72 h 2: 88 percent / Et3N / 1,2-dichloro-ethane / Ambient temperature 3: Et3N, Pd(OAc)2, 1,3-bis(diphenylphosphino)propane / dimethylformamide / 4.5 h / 70 °C 4: tetra-N-butylammonium fluoride / tetrahydrofuran / 3 h View Scheme

Raloxifen (84449-90-1) → (4-{6-Hydroxy-3-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-benzo[b]thiophen-2-yl}-phenyl)-phosphonic acid diethyl ester

Conditions	Yield
Multi-step reaction with 3 steps 1: 20 percent / DMAP / tetrahydrofuran; dimethylformamide 2: 85 percent / Et3N / CH2Cl2 3: 1.) Pd(PPh3)4, 2.) TBAF / 1) MeCN; 2) CH2Cl2 View Scheme
Multi-step reaction with 4 steps 1: 1.) DMAP / 1.) THF, DMF, RT, 1 h, 2.) THF, DMF, RT, 72 h 2: 88 percent / Et3N / 1,2-dichloro-ethane / Ambient temperature 3: Pd(PPh3)4, 2,6-lutidine / acetonitrile / 16 h / 70 °C 4: tetra-N-butylammonium fluoride / tetrahydrofuran / 3 h View Scheme

Upstream product

• 84449-85-4 <6-<(methylsulfonyl)oxy>-2-<4-<(methylsulfonyl)oxy>phenyl>benzothien-3-yl><4-<2-(1-pyrrolidinyl)ethoxy>phenyl>methanone hydrochloride 
• 3040-44-6 1-piperidinoethanol 
• 202336-25-2 [2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thien-3-yl] [4-fluorophenyl]methanone 
• 84541-38-8 [6-Methoxy-2-(4-Methoxyphenyl)benzo[b]thien-3-yl]-[4-[2-(1-Piperidinyl)ethoxy]phenyl] Methanone 
• 403-43-0 4-fluorobenzoyl chloride 
• 206434-77-7 6-methoxy-2-(4-methoxyphenyl)-3-(4-fluorobenzoyl)benzo[b]thiophene 
• 63675-74-1 2-(4'-methoxyphenyl)-6-methoxybenzothiophene 
• 15570-12-4 3-methoxybenzenethiol 
• 63675-73-0 α-(3-methoxyphenyl-thio)-4-methoxyacetophenone 
• 84449-65-0 6-<(methylsulfonyl)oxy>-2-<4-<(methylsulfonyl)oxy>phenyl>benzothiophene 
• 84449-80-9 4-(2-piperidin-1-ylethoxy)benzoic acid hydrochloride 
• 2632-13-5 2-Bromo-4'-methoxyacetophenone 
• 82640-04-8 raloxifene hydrochloride 
• 1293408-87-3 1-(2-(4-[6-Hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophene-3-carbonyl]-phenoxy)-ethyl)-piperidinium bromide 

Downstream Products

• 174264-47-2 (6-((tert-butyldimethylsilyl)oxy)-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)(4-(2-(piperidin-1-yl)ethoxy)phenyl)methanone 
• 174264-46-1 2-[4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]phenyl]-6-hydroxybenzo[b]thiophen-3-yl 4-[2-(1-piperidinyl)ethoxy]phenyl ketone 
• 189940-64-5 [6-Benzyloxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone 
• 174731-13-6 [6-HYDROXY-2-(4-HYDROXYPHENYL)BENZO[B]THIEN-3-YL][4-[2-(1-PIPERIDINYL)ETHOXY]PHENYL]METHANOL 
• 185416-94-8 4-{6-Hydroxy-3-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-benzo[b]thiophen-2-yl}-benzoic acid methyl ester 
• 185416-87-9 Trifluoro-methanesulfonic acid 4-{6-(tert-butyl-dimethyl-silanyloxy)-3-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-benzo[b]thiophen-2-yl}-phenyl ester 
• 1025925-22-7 [6-(tert-Butyl-dimethyl-silanyloxy)-2-(4-vinyl-phenyl)-benzo[b]thiophen-3-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone 
• 1026314-83-9 1-(4-{6-(tert-Butyl-dimethyl-silanyloxy)-3-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-benzo[b]thiophen-2-yl}-phenyl)-ethanone 
• 1025845-03-7 4-{6-(tert-Butyl-dimethyl-silanyloxy)-3-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-benzo[b]thiophen-2-yl}-N,N-dimethyl-benzamide 
• 1027485-30-8 (4-{6-(tert-Butyl-dimethyl-silanyloxy)-3-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-benzo[b]thiophen-2-yl}-phenyl)-phosphonic acid diethyl ester 
• 185417-15-6 4-{6-(tert-Butyl-dimethyl-silanyloxy)-3-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-benzo[b]thiophen-2-yl}-N-methyl-benzamide 
• 185416-95-9 4-{6-(tert-Butyl-dimethyl-silanyloxy)-3-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-benzo[b]thiophen-2-yl}-benzoic acid methyl ester 

Relevant articles and documents

Efficient synthesis of 3-benzoyl Benzo[b]thiophenes and raloxifene via Mercury(II)-Catalyzed cyclization of 2-alkynylphenyl alkyl sulfoxides

The unique selective estrogen receptor modulator, Raloxifene (1), and antitubulin agent 2 were synthesized through the key intermediate, 4-methoxybenzyl 2-bromo-4-methoxyphenyl sulfoxide (6), respectively. It was found that compared with the o-sulfanyl aryl bromides, the sulfinyl group at ortho position accelerated the Sonogashira coupling reaction of aryl bromides. Thus, compound 6 was coupled with 3,4,5-trimethoxyphenyl acetylene, followed by mercury-catalyzed cyclization reaction afford compound 2 in 79% overall yield. Raloxifene (1) was prepared from compound 6 in four steps and 33% overall yield via coupling reaction with 1-trimethylsily-2-(4-tert-butyldimethylsiloxy)phenylethyne, mercury-catalyzed cyclization reaction, alkylation and demethylation.

Sulfoxide compound and method of producing benzothiophene derivatives using the same

A sulfoxide compound and method of producing benzothiophene derivatives using the same are provided. The sulfoxide compound is represented by formula (I), wherein R1 and R2 are individually and independently benzoyl group; alkyl, acyl or silyl group of C1-C6 straight chain or branched chain; or alkenyl group of C3-C6 straight chain or branched chain; and X is halogen atom. The sulfoxide compound reacts with alkynyl compound, and then the synthesis efficiency of benzothiophene derivatives can be effectively increased.

Methods for Determining the Oncogenic Condition of Cell, Uses Thereof, and Methods for Treating Cancer

The invention relates to methods for detecting the oncogenic condition of cells, including step where the amount of the OCDO compound in said cells is measured, and to the uses thereof. The invention further relates to OCDO inhibitors for use in methods for treating cancer.

Piperidine nucleophilic substitution without solvent: An efficient synthesis of raloxifene

Mild and high-yielding synthesis is described for raloxifene via piperdine nucleophilic substitution of a new raloxifene intermediate 3-aroyl-2-aryl-substituted benzo[b]thiophenes, which is obtained by acylation of para-substituted benzoyl chlorides and 2-arylbenzo[b]thiophenes. The key step is solvent free and offers valuable advantages, such as low cost, and is suitable for industrial production.

OXALIC ACID ADDITION SALTS AND/OR SOLVATES OF A SELECTIVE ESTROGEN RECEPTOR MODULATOR

The present invention provides raloxifene oxalate, including derivatives thereof. In particular, the present invention provides solvates and/or hydrates of raloxifene oxalate, and polymorphs thereof. The present invention also provides processes for preparing the novel compounds, pharmaceutical compositions including the novel compounds and medical uses of the novel compounds.

Synthesis of aryl ethers via a sulfonyl transfer reaction

A general synthesis of aryl ethers from primary and secondary alcohols and aryl mesylates is presented. The reaction proceeds via a sulfonyl-transfer mechanism. In this paper, we compare the sulfonyl transfer reaction to Mitsunobu ether formation. The reaction can be employed in a multistep synthesis where the aryl mesylate is used as a phenol protecting group and then as an activating group for ether formation. This protecting/activating group strategy is demonstrated using raloxifene as the target.

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 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.

An efficient synthesis of raloxifene in ionic liquid: A Green Approach

An efficient and green procedure for the synthesis of raloxifene has been developed by using Suzuki couplings, Friedel-Crafts acylation, and copper catalyzed coupling reactions in an ionic liquid.