911-45-5

Usage

Uses

Used in Infertility Treatment:
Clomifene is used as an antiestrogen for the treatment of infertility in men attempting to conceive. It is believed to increase sperm parameters, thereby improving the chances of conception.
Used in Women's Infertility Treatment:
Clomifene is used as an oral agent for the treatment of infertility in women who desire pregnancy. It is particularly effective for women with oligoovulatory cycles, helping to increase their reproductive properties and promote normal monthly ovulation.
Used in Liver Function Monitoring:
While Clomifene is generally considered safe, it has been linked to a low rate of transient serum aminotransferase elevations during therapy. In rare instances, it can also cause clinically apparent liver injury, which can be severe and even fatal. Therefore, monitoring liver function is an important aspect of Clomifene usage.

Hormonal modulation

CLOMIPHENE exerts its effects centrally with a result of increased LH and FSH secretion and increased testicular testosterone production. Many studies have described significant increases in serum testosterone, LH, and FSH with CLOMIPHENE treatment. Studies have revealed comparable increases in serum testosterone levels in hypogonadal men treated with CLOMIPHENE compared with TRT. CLOMIPHENE has also been compared with aromatase inhibitors, such as anastrozole, and CLOMIPHENE has proven to be more effective in increasing testosterone levels.

Indications

Clomifene acts by enhancing follicular growth caused by ovulation. The primary indication for using clomifene is induction of ovulation in non-ovulating women who still have some estrogen production.

Synthesis

Clomifene, 2-[p-(2-chloro-1,2-diphenylvinyl)phenoxy]triethylamine (28.2.4), is synthesized from 4-hydroxybenzophenone by reacting it with 2-diethylaminoethylchloride in the presence of an alkali, which gives 4-(2-diethylaminoethoxy)benzophenone (28.2.1). This is reacted with benzylmagnesium chloride in a Grignard reaction, forming as a result the corresponding carbinol (28.2.2). Dehydrating this with hydrogen chloride gives 2-[p-(1,2-diphenylvinyl) phenoxy]triethylamine (28.2.4), the vinylic hydrogen atom of which is replaced with a chlorine atom using N-chlorosuccinimide, giving clomifene (28.2.4) .

InChI:InChI=1/C26H28ClNO/c1-3-28(4-2)19-20-29-24-17-15-22(16-18-24)25(21-11-7-5-8-12-21)26(27)23-13-9-6-10-14-23/h5-18H,3-4,19-20H2,1-2H3/b26-25-

Synthetic route

Dimethyl 1-Chloro-1-phenylmethanephosphonate (16965-75-6) + 4-[2-(N,N-diethylamino)ethoxy]benzophenone (796-77-0) → clomiphene (911-45-5)

Conditions	Yield
With tert.-butyl lithium 1.) THF/pentane, -78 deg C, 30 min; 2.) THF, reflux; Yield given. Multistep reaction;

cis-1,2-Diphenyl-1-<4-(2-diethylaminoethoxy)phenyl>ethylene hydrochloride (97813-50-8) → clomiphene (911-45-5)

Conditions	Yield
With N-chloro-succinimide In chloroform for 18h; Heating;

dimethyl benzylphosphonate (773-47-7) → clomiphene (911-45-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: 96 percent / chlorination 2: 1.) tert-butyllithium / 1.) THF/pentane, -78 deg C, 30 min; 2.) THF, reflux View Scheme

benzyl chloride (100-44-7) → clomiphene (911-45-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: 72 percent / 20 h / Heating 2: 96 percent / chlorination 3: 1.) tert-butyllithium / 1.) THF/pentane, -78 deg C, 30 min; 2.) THF, reflux View Scheme

1-{4-[2-(diethylamino)ethoxy]phenyl}-1,2-diphenylethanol (73404-00-9) → clomiphene (911-45-5)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sulfuric acid / dichloromethane / 1 h / 0 - 20 °C 2.1: N-chloro-succinimide / dichloromethane / 32 h / 20 °C 2.2: 0.5 h / 20 °C / pH 8 - 9 View Scheme

2-{4-[(Z)-1,2-diphenylvinyl]phenoxy}-N,N-diethylethanaminium hydrogen sulfate → clomiphene (911-45-5)

Conditions	Yield
Stage #1: 2-{4-[(Z)-1,2-diphenylvinyl]phenoxy}-N,N-diethylethanaminium hydrogen sulfate With N-chloro-succinimide In dichloromethane at 20℃; for 32h; Stage #2: With sodium hydrogencarbonate In dichloromethane; water at 20℃; for 0.5h; pH=8 - 9;	6.86 g

N,N-diethyl-2-[4-(1,2-diphenylvinyl)phenoxy]ethylamine hydrochloride → clomiphene (911-45-5)

Conditions	Yield
With N-chloro-succinimide In dichloromethane for 6h; Reflux; Darkness;

clomiphene (911-45-5) → clomiphene citrate (7599-79-3)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: methanol / 2 h / 20 °C 2.1: ammonia / ethyl acetate 2.2: 1 h / 20 °C View Scheme

1,1'-binaphthyl-2,2'-diyl hydrogenphosphate (35193-63-6, 35193-64-7, 39648-67-4, 50574-52-2) + clomiphene (911-45-5) → ethanamine, 2-[4-[(1E)-2-chloro-1,2-diphenyl ethenyl]phenoxy]-N,N-diethyl-, (±)-1,1‘-binaphthyl-2,2’-diylhydrogenphosphate

Conditions	Yield
In methanol at 20℃; for 2h;

clomiphene (911-45-5) + citric acid (77-92-9) → clomifene citrate (50-41-9)

Conditions	Yield
In ethanol for 0.0833333h; Reflux;	30.8 g

Upstream product

• 81233-91-2 4-<2-(diethylamino)ethoxy>iodobenzene 
• 27435-08-1 (E)-bis(trimethylstannyl)stilbene 
• 73404-00-9 1-{4-[2-(diethylamino)ethoxy]phenyl}-1,2-diphenylethanol 
• 74056-26-1 2-{4-[(Z)-1,2-diphenylvinyl]phenoxy}-N,N-diethylethanaminium hydrochloride 
• 536-74-3 phenylacetylene 
• 98-80-6 phenylboronic acid 
• 5720-07-0 4-methoxyphenylboronic acid 
• 72474-40-9 cis-1-Chloro-2-(4-hydroxyphenyl)-1,2-diphenylethylene 
• 869-24-9 2-chloro-N,N-diethylethylamine hydrochloride 
• 140868-82-2 (E)-(2-bromo-1-chloro-2-iodovinyl)benzene 
• 72474-42-1 (Z)-(1-chloro-2-(4-methoxyphenyl)ethene-1,2-diyl)dibenzene 
• 97813-50-8 cis-1,2-Diphenyl-1-<4-(2-diethylaminoethoxy)phenyl>ethylene hydrochloride 
• 932-87-6 1-Bromo-2-phenylacetylene 
• 74056-26-1 N,N-diethyl-2-[4-(1,2-diphenylvinyl)phenoxy]ethylamine hydrochloride 

Downstream Products

• 133157-86-5 (Z)-1-<4-(2-diethylaminoethoxy)phenyl>-1,2-diphenyl-1-penten-5-ol 
• 133157-93-4 (E)-1-<4-(2-diethylaminoethoxy)phenyl>-1,2-diphenyl-1-penten-5-ol 
• 7619-53-6 cis-clomiphene citrate 
• 7599-79-3 clomiphene citrate 
• 50-41-9 clomifene citrate 

Relevant academic research and scientific papers

Stereoselective Nickel(II)-Catalyzed Addition of Aryl Grignards to Diphenylacetylene in the Synthesis of Zuclomiphene

Stereoselective synthesis of zuclomiphene was developed using nickel-catalyzed addition of 4-fluorophenylmagnesium bromide to 1,2-diphenylacetylene, followed by quenching with a chlorinating reagent. Since the aryl fluoride addition and chlorination reactions occur consecutively in one pot, the cis orientation of the two phenyl groups of 1,2-diphenylacetylene is conserved, leading to the highly selective synthesis of zuclomiphene. The use of the Grignard reagent resulted in the presence of bromide ions in the reaction mixture, which led to the formation of the bromo-analog of zuclomiphene. Alternative routes were then explored to overcome this issue to yield high-purity zuclomiphene.

Salts of Zuclomiphene

The present invention provides salts of zuclomiphene and crystalline forms thereof. Specific salts of zuclomiphene provided by the present invention include sulphate, phosphate, succinate, L-tartrate, tosylate, L-malate, maleate, malonate, fumarate, glycolate, and hemi-citrate. Also provided are pharmaceutical compositions including the zuclomiphene salts and crystalline forms thereof and the use of these salts in the treatment of a disorder selected from the group including osteoporosis, bone fractures, loss of bone mineral density (BMD) and hot flashes in a subject suffering therefrom.

TEMPO-Regulated Regio- and Stereoselective Cross-Dihalogenation with Dual Electrophilic X+ Reagents

A TEMPO catalyzed cross-dihalogenation reaction was established via redox-regulation of the otherwise complex system of dual electrophilic X+ reagents. Formally, the ICl, BrCl, I2 and Br2 were generated in-situ, which enabled high regio- or stereoselective access to a myriad of iodochlorination, bromochlorination and homo-dihalogenation products with a wide spectrum of functionalities. With its mild conditions and operational simplicity, this method could enable wide applications in organic synthesis, which was exemplified by divergent synthesis of two pharmaceuticals. Detailed mechanistic investigations via radical clock reaction, pinacol ring expansion and Hammett experiments were conducted, which confirmed the intermediacy of halonium ion. In addition, a dynamic catalytic model based on the versatile catalytic role of TEMPO was proposed to explain the selective outcomes.

Processes for the Preparation of Zuclomiphene and Intermediates Thereof

The present invention provides processes for the preparation of zuclomiphene, as well as intermediates useful in the preparation thereof. In particular, processes are provided for the carbometallation of diphenylacetylene with a compound of Formula (3) to afford either zuclomiphene or an intermediate which is converted to zuclomiphene.

COMPOSITION FOR CROSS TALK BETWEEN ESTROGEN RECEPTORS AND CANNABIONOID RECEPTORS

A composition for cross talk between estrogen receptors and cannabinoid receptors including a chelator and a receptor ligand is provided. A method of synthesizing the composition is also provided, and the composition may be further prepared in pharmaceutical formulations or kits for therapy or molecular imaging.

Preparation method of enclomiphene

The invention relates to a preparation method of enclomiphene. The preparation method comprises steps as follows: (1) clomiphene or salt thereof and racemic 1,1'-binaphthyl-2,2'-diyl hydrogenphosphate are subjected to a reaction in alcohol solvents containing ether solvents, and an enclomiphene and 1,1'-binaphthyl-2,2'-diyl hydrogenphosphate compound in a solid form is obtained; (2) the enclomiphene and 1,1'-binaphthyl-2,2'-diyl hydrogenphosphate compound in a solid form is subjected to a free reaction, and enclomiphene is prepared. With the alcohol solvents containing the ether solvents as splitting solvents, enclomiphene and the splitting solvents can form a solid compound which is directly separated out from the splitting solvents, the flowability of a reaction system is improved, and the enclomiphene preparation method with better industrial application prospects is provided, and by means of the preparation method, the splitting yield is high, the purity of a split product is high, the cost is low and environmental pollution is low.

CLOMIPHENE SYNTHESIS USING A SINGLE SOLVENT

The present invention provides a one-pot method for synthesizing clomiphene (a mixture of the isomers cis-clomiphene and trans-clomiphene) utilizing a single solvent. In a preferred embodiment, the single solvent is dichloromethane (DCM, also known as methylene chloride). The present invention provides an improved method for synthesizing clomiphene and purifying clomiphene isomers.

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.

Stereospecific synthesis of clomiphene and tamoxifen via stannylcupration of diphenylacetylene

Stereospecific trans-stannylcupration of diphenylacetylene affords a 1,2-dimetallostilbene which may be elaborated into either Clomiphene or Tamoxifen through palladium-catalyzed coupling with an aryl iodide.

Synthesis of Clomid Using Palladium-Catalysed Cross-Coupling

Two methods of choice for the synthesis of clomid, a tetrasubstituted olefin with antiestrogenic activity, are described.The key reaction is hydroalumination of diphenylacetylene followed by C-C cross-coupling using catalytic amount of Pd0.