180916-16-9

Usage

Uses

Used in Pharmaceutical Industry:
Lasofoxifene is used as a therapeutic agent for treating disorders associated with increased bone turnover and osteopenia. Its selective estrogen receptor modulating properties help in managing these conditions effectively.
Additionally, due to its estrogen receptor modulating capabilities, Lasofoxifene may also have potential applications in other areas such as treating osteoporosis or certain types of cancer. However, further research and clinical trials would be necessary to confirm these potential uses.

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 academic research and scientific papers

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.

Total synthesis of lasofoxifene and nafoxidine

An intramolecular reductive coupling process of diketone with low-valent titanium species to form a dihydronapthalene skeleton was an important step in the synthesis of nafoxidine (1) and lasofoxifene (2). Diketone 6 was prepared in a convenient, three-st

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

Pharmaceutical composition having uniform drug distribution and potency

Pharmaceutical compositions having uniform drug distribution and potency utilizing laxofoxifene as an active ingredient and containing a silicon dioxide to reduce loss of the active ingredient during the manufacturing process and methods for manufacturing such compositions are disclosed.

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.

Enzyme-catalyzed asymmetric deacylation for the preparation of Lasofoxifene (CP-336156), a selective estrogen receptor modulator

(Matrix presented) A potent and selective estrogen receptor modulator (SERM), Lasofoxifene (CP-336156), was prepared by an enzyme-catalyzed asymmetric deacylation with high optical purity and excellent yield even though the hydrolytic site is remote from