180916-16-9

Basic information

• Product Name: Lasofoxifene
• Synonyms: CP-336,156;(5R,6S)-6-phenyl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl]tetralin-2-ol;(5R,6S)-5,6,7,8-Tetrahydro-6-phenyl-5-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-2-naphthalenol;(5R-cis)-5,6,7,8-Tetrahydro-6-phenyl-5-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-2-naphthalenol;Lasofoxifene;(5R,6S)-;Lasofoxifene Base
• CAS NO: 180916-16-9
• Molecular Formula: C₂₈H₃₁NO₂
• Molecular Weight: 413.55
• Product Categories: Aromatics;Chiral Reagents;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 180916-16-9.mol
• Article Data: 7

Chemical Properties

• Melting Point: 110-113°C
• Boiling Point: 572.4 °C at 760 mmHg
• Flash Point: 300 °C
• Appearance: /
• Density: 1.15 g/cm³
• Vapor Pressure: 1.05E-13mmHg at 25°C
• Refractive Index: 1.613
• Storage Temp.: Refrigerator
• Solubility: Chloroform (Slightly), Methanol (Slightly)
• PKA: 10.31±0.60(Predicted)
• CAS DataBase Reference: Lasofoxifene(CAS DataBase Reference)
• NIST Chemistry Reference: Lasofoxifene(180916-16-9)
• EPA Substance Registry System: Lasofoxifene(180916-16-9)

Safety Data

• Hazardous Substances Data: 180916-16-9(Hazardous Substances Data)

Usage

Chemical Properties

Off-White Solid

Uses

A next-generation selective estrogen receptor modulator for treating disorders associated with increased bone turnover and osteopenia.

Clinical Use

Lasofoxifene is a very potent second-generation SERM currently in phase III clinical trials for the treatment and prevention of osteoporosis in postmenopausal women.

InChI:InChI=1/C28H31NO2/c30-24-11-15-27-23(20-24)10-14-26(21-6-2-1-3-7-21)28(27)22-8-12-25(13-9-22)31-19-18-29-16-4-5-17-29/h1-3,6-9,11-13,15,20,26,28,30H,4-5,10,14,16-19H2/t26-,28+/m1/s1

Synthetic route

1-{2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-phenoxy]-ethyl}-pyrrolidine (5879-98-1) → lasofoxifene (180916-16-9)

Conditions	Yield
With boron tribromide In dichloromethane at -50 - 0℃; for 3h;	80%
With boron tribromide In dichloromethane	74%
With boron tribromide In dichloromethane	74%

7-methoxylasofoxifene → lasofoxifene (180916-16-9)

Conditions	Yield
Stage #1: 7-methoxylasofoxifene With boron tribromide In dichloromethane at -78 - 0℃; for 2h; Stage #2: With water; sodium hydrogencarbonate In dichloromethane	76%

1-[2-(4-bromophenoxy)ethyl]pyrrolidine (1081-73-8) + n-BuU + 6-methoxy-3,4-dihydro-1(2H)-naphthalenone (1078-19-9) → lasofoxifene (180916-16-9)

Conditions	Yield
CeCl3 In tetrahydrofuran; hydrogenchloride; diethyl ether	57%
CeCl3 In tetrahydrofuran; hydrogenchloride; diethyl ether	57%

lasofoxifene → lasofoxifene (180916-16-9)

Butyric acid (5S,6R)-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalen-2-yl ester → (5S,6R)-6-Phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalen-2-ol + lasofoxifene (180916-16-9) + Butyric acid (5R,6S)-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalen-2-yl ester

Conditions	Yield
With Lipase (Mucor Miehei) In phosphate buffer at 20℃; pH=7; Hydrolysis; enzymatic resolution;

lasofoxifene + AcX → lasofoxifene (180916-16-9)

Conditions	Yield
Multi-step reaction with 2 steps 2: Lipase (Mucor Miehei) / aq. phosphate buffer / 20 °C / pH 7 View Scheme

nafoxidine (1845-11-0) → lasofoxifene (180916-16-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: H2 / Pd(OH)2/C 2: BBr3 View Scheme

(1RS,2SR)-1-(4-[2-pyrrolidinoethoxy]phenyl)-2-phenyl-6-methoxy-1,2,3,4-tetrahydronaphthalene → lasofoxifene (180916-16-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: BBr3 View Scheme

6-benzyloxy-1-[4-(2-(pyrrolidin-1-yl)ethoxy)phenyl]-3,4-dihydronaphthalen-2(1H) -one → lasofoxifene (180916-16-9)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: cerium(III) chloride / tetrahydrofuran / 1.5 h / -10 - 0 °C / Inert atmosphere 1.2: 2 h / -10 - -5 °C 2.1: methanol 3.1: hydrogen; 5%-palladium/activated carbon / methanol; ethanol / 10 h / 50 °C / 7600.51 Torr / Autoclave View Scheme

6-benzyloxy-2-phenyl-1-{4-[2-(pyrrolin-1-yl)ethoxy]phenyl}-3,4-dihydronaphthalene → lasofoxifene (180916-16-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: methanol 2: hydrogen; 5%-palladium/activated carbon / methanol; ethanol / 10 h / 50 °C / 7600.51 Torr / Autoclave View Scheme

C35H35NO2*C4H6O6 → lasofoxifene (180916-16-9)

Conditions	Yield
With 5%-palladium/activated carbon; hydrogen In methanol; ethanol at 50℃; under 7600.51 Torr; for 10h; Autoclave;

1-[2-(4-bromophenoxy)ethyl]pyrrolidine (1081-73-8) → lasofoxifene (180916-16-9)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: magnesium / tetrahydrofuran / 20 - 30 °C / Inert atmosphere 1.2: 1 h / Reflux 2.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 2 h / 0 - 5 °C 3.1: cerium(III) chloride / tetrahydrofuran / 1.5 h / -10 - 0 °C / Inert atmosphere 3.2: 2 h / -10 - -5 °C 4.1: methanol 5.1: hydrogen; 5%-palladium/activated carbon / methanol; ethanol / 10 h / 50 °C / 7600.51 Torr / Autoclave View Scheme

6-benzyloxy-1-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}-3,4-dihydronaphthalene → lasofoxifene (180916-16-9)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 2 h / 0 - 5 °C 2.1: cerium(III) chloride / tetrahydrofuran / 1.5 h / -10 - 0 °C / Inert atmosphere 2.2: 2 h / -10 - -5 °C 3.1: methanol 4.1: hydrogen; 5%-palladium/activated carbon / methanol; ethanol / 10 h / 50 °C / 7600.51 Torr / Autoclave View Scheme

D-tartaric acid (147-71-7) + lasofoxifene (180916-16-9) → Lasofoxifene tartrate (190791-29-8)

Conditions	Yield
In ethanol for 0.0833333h; Reflux;	50%

1-{2-[4-(6-methoxy-2-phenyl-3,4-dihydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine hydrochloride (1847-63-8) + lasofoxifene (180916-16-9) → 1-{2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-phenoxy]-ethyl}-pyrrolidine (5879-98-1)

Conditions	Yield
palladium dihydroxide In ethanol	863 mg (93%)
palladium dihydroxide In ethanol	863 mg (93%)

lasofoxifene (180916-16-9) → C34H42BNO3

Conditions	Yield
Multi-step reaction with 2 steps 1: pyridine / dichloromethane / 1 h / 0 - 20 °C 2: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 1 h / 120 °C / Microwave irradiation View Scheme

trifluoromethylsulfonic anhydride (358-23-6) + lasofoxifene (180916-16-9) → C29H30F3NO4S

Conditions	Yield
With pyridine In dichloromethane at 0 - 20℃; for 1h;	0.15 g

Upstream product

• 1081-73-8 1-[2-(4-bromophenoxy)ethyl]pyrrolidine 
• 5879-98-1 1-{2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-phenoxy]-ethyl}-pyrrolidine 
• 1078-19-9 6-methoxy-3,4-dihydro-1(2H)-naphthalenone 
• 1845-11-0 nafoxidine 
• 180915-78-0 lasofoxifene 

Downstream Products

• 5879-98-1 1-{2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-phenoxy]-ethyl}-pyrrolidine 
• 190791-29-8 Lasofoxifene tartrate 

Relevant articles and documents

LASOFOXIFENE MODULATION OF MEMBRANE-INITIATED ESTROGEN SIGNALS AND METHODS FOR TUMOR TREATMENT

The present invention found that lasofoxifene is an antagonist of ER-α36. It not only inhibits the growth of ER-α36 positive lung, colon and gastric cancers, and also it can inhibit the growth of acquired or de novo tamoxifen-resistant MCF-7 cells. Our finding also provides methods and compositions for treating cancer comprising lasofoxifene alone or in combination with at least one other agent selected from the group consisting of gefitinib and/or trastuzumab or functional equivalent thereof, and an inhibitor in hormonal or epidermal growth factor signal transduction pathways.

PROCESS FOR PRODUCTION OF LASOFOXIFENE OR ANALOGUE THEREOF

Disclosed is a novel process for production of lasofoxifene, nafoxidine or an analogue thereof, which comprises reduced number of reaction steps, has a high efficiency, and is practically advantageous. For the production of lasofoxifene or an analogue the

Method for manufacturing a low dose pharmaceutical composition having uniform drug distribution and potency

A method for manufacturing a pharmaceutical composition having uniform drug distribution and potency is described which utilizes silicon dioxide to reduce the loss of active ingredient during the manufacturing process. The method is particularly useful for the manufacture of low dosage tablet compositions.