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Enclomiphene powder, CAS number: 15690-57-0, molecular formula: C26H28ClNO, white to off white crystalline powder, odorless and tasteless. Easy to dissolve in chloroform, slightly soluble in ethanol, almost insoluble in water, stable at room temperature and pressure, needs to be stored away from light, sealed, and kept away from strong oxidants, strong acids, and strong bases. Can bind to estrogen receptors, prevent endogenous estradiol from binding to its receptors, indirectly inhibit the synthesis and release of GnRH in the hypothalamus, thereby downregulating the secretion of FSH and LH in the pituitary gland, reducing the production of ovarian androgens, and lowering estrogen levels. It is the trans isomer of the selective estrogen receptor modulator clomiphene, which is anti estrogenic (AE). It is mainly used to treat female infertility caused by anovulation, luteal insufficiency, male infertility caused by oligospermia, etc. It can also be used to treat infertility caused by low estrogen levels in postmenopausal women. However, it should be noted that this product is only for scientific research use!
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Enclomiphene powder, as a non steroidal estrogen receptor modulator, belongs to the class of tristyrene compounds. Its powder form is widely used in pharmaceutical research and clinical treatment due to its ease of storage, transportation, and formulation processing.
1. Treatment of anovulatory infertility
Enclomiphene competitively binds to hypothalamic estrogen receptors, blocking the negative feedback of endogenous estrogen and promoting the secretion of follicle stimulating hormone (FSH) and luteinizing hormone (LH) in the anterior pituitary gland, thereby stimulating ovarian follicle development and ovulation. Clinical studies have shown that about 70% -80% of women will resume ovulation after using enrofloxacin, with 30% -40% achieving successful pregnancy. Its typical usage is oral administration starting from the 5th day of the menstrual cycle, 50mg per day for 5 consecutive days; If ovulation has not occurred, the dose can be gradually increased to 100mg or 150mg per day, but the maximum dose for a single course of treatment should not exceed 150mg.
In assisted reproductive technologies such as in vitro fertilization embryo transfer (IVF-ET), enrofloxacin can induce synchronous development of multiple follicles, improve egg quality and quantity, and thus increase the chances of pregnancy. Its mechanism of action is similar to natural cycle ovulation induction, but strict monitoring of follicle development is necessary to avoid the occurrence of ovarian hyperstimulation syndrome (OHSS).
3. Treating luteal insufficiency
Insufficient luteal function can lead to menstrual disorders, recurrent miscarriages, and other issues. Enclomiphene powder can indirectly improve luteal function, enhance endometrial receptivity, and provide a favorable environment for embryo implantation by promoting follicular development and ovulation. The commonly used clinical dosage is 25-75mg per day, administered orally, and adjusted according to individual reactions.
4. Regulate menstrual cycle
For women with irregular menstrual cycles, enrofloxacin can regulate the secretion of estrogen and progesterone by affecting the function of the hypothalamic pituitary ovarian axis, thereby restoring a normal menstrual cycle. Its usage is to take it orally at a fixed time every day, continuously for several days to several weeks, and the specific treatment course needs to be formulated according to the patient's condition.
1. Treatment of male hypogonadism
Enclomiphene can stimulate the secretion of gonadotropins in the anterior pituitary gland, thereby promoting the secretion of testosterone by testicular interstitial cells and increasing male serum testosterone levels. Clinical studies have shown that enrofloxacin can significantly improve testosterone levels, sperm concentration, and motility in male patients with hypogonadism. Its efficacy is comparable to exogenous testosterone supplementation therapy, but it avoids the potential inhibition of sperm production caused by testosterone replacement therapy.
2. Treatment of male oligospermia
For patients with oligospermia, enrofloxacin can promote sperm production, improve sperm quantity and quality. Its mechanism of action is closely related to the increase in testosterone levels, as testosterone is a key hormone for sperm production. The commonly used dosage in clinical practice is 25-50mg per day, administered orally, and the course of treatment is generally 3-6 months.
3. Detecting dysfunction of the hypothalamic pituitary gonadal axis in males
Enclomiphene can be used as a diagnostic tool to evaluate the functional status of the male hypothalamic pituitary gonadal axis by observing changes in serum testosterone and gonadotropin levels after medication. If testosterone levels significantly increase after medication, it indicates normal hypothalamic or pituitary function; If the response is slow, there may be abnormal axis function.
Enclomiphene powder (CAS number 15690-57-0) is a selective estrogen receptor modulator widely used in the treatment of female anovulatory infertility and male oligospermia. Its chemical essence is a derivative of trans tristyrene, with a molecular formula of C26H28ClNO, a molecular weight of 405.96, and a melting point of 149.0-150.5 ° C. The core challenge in synthesizing enrofloxacin is to control the ratio and purity of the cis trans isomer, as the trans configuration (enrofloxacin) has pharmacological activity, while the cis configuration (Zhuclomiphene) has lower activity. The following systematically elaborates on its synthesis method from three aspects: classical synthesis route, key reaction steps, and process optimization.
Classic synthesis route: two-step method leading industrial production
The industrial synthesis of enrofloxacin generally adopts a two-step method of "preparation of cis trans isomer mixture+chiral separation". This route uses N, N-diethyl-2- [4- (1,2-diphenylvinyl) phenoxy] ethylamine hydrochloride as the starting material, generates a cis trans isomer mixture through chlorination reaction, and then separates it with chiral reagents to obtain high-purity trans products.
Reaction mechanism: The starting material undergoes α - carbochlorination under the action of N-chlorosuccinimide (NCS), resulting in a mixture of chlorinated products containing cis (Z) and trans (E) configurations. The reaction needs to be refluxed under dark conditions to prevent photo induced isomerization.
Typical process: Dissolve 59.8g of starting material (purity 92%) in 730mL of dichloromethane, add 20.35g of NCS, and heat to reflux for 6 hours. HPLC monitoring showed that the cis peak area accounted for 24.50% and the trans peak area accounted for 61.26% of the reaction solution. The post-treatment includes alkaline washing (2% sodium hydroxide solution), water washing, saturated salt water washing, and anhydrous sodium sulfate drying. After concentration, 50.0g of crude product (purity 85.76%, yield 78.2%) is obtained.
Optimization of reaction conditions:
Solvent selection:
Dichloromethane is advantageous for high-temperature reflux reaction and subsequent concentration due to its low boiling point (39.6 ° C) and inertness.
Dosage of Chlorination Reagent:
The molar ratio of NCS to raw materials needs to be precisely controlled (about 1.2:1), as excessive amounts can lead to the formation of by-products (such as dichloro compounds).
Temperature control:
Reflux temperature (about 40 ° C) can balance reaction rate and isomerization risk, while low temperature (<25 ° C) will significantly reduce yield.
Principle of Separation: Using 1,1 '- BINOL phosphate to form a stable complex with the trans configuration, chiral separation is achieved through crystal separation.
Typical process:
Step 1 splitting: Dissolve 5.0g of cis trans mixture (68.3% cis, 29.8% trans) in n-propyl ether/methanol (30mL/40mL), heat to reflux, and add 4.5g BINOL phosphate in batches. Cool naturally to 25-30 ° C and stir for 8 hours. Cool in an ice bath to 0 ° C for crystallization, and filter to obtain 2.1g of crude composite (purity 96.1%, separation yield 72.8%).
Step 2 refining: Dissolve the crude composite in water/ethanol (13mL/16mL), reflux and beat for 5 hours, cool naturally, then precipitate in an ice bath, filter and dry to obtain 1.7g of refined enrofloxacin (purity 99.5%).
Split efficiency optimization:
Solvent system:
A mixed solvent of n-propyl ether and methanol can adjust the solubility of the complex, and a high proportion of methanol can lead to co precipitation of the cis configuration.
Crystallization temperature:
Low temperature of 0 ° C can improve the crystallization purity of the composite, while room temperature crystallization will introduce 10% -15% cis impurities.
Chiral reagent recovery:
BINOL phosphate can be regenerated through acidification, with a recovery rate of over 85%, reducing production costs.
Alternative synthetic route: multi-step construction of trans configuration
In addition to the two-step method, researchers have developed a route for directly constructing trans configurations through multi-step reactions to reduce the number of splitting steps. Typical methods include:
4-iodophenol route
Reaction steps:
Iodization: 4-iodophenol reacts with sulfonyl chloride to produce 4-iodobenzene chloride.
Etherification: Williamson etherification occurs with N, N-diethylethanolamine under alkaline conditions (K ₂ CO3/DMF) to produce intermediate A.
Coupling: Intermediate A undergoes cross coupling with benzophenone under nickel catalysis to construct a styrene framework.
Isomerization control: By adjusting the ratio of catalyst (such as Pd (PPh3) ₄) to ligand, selective trans configuration is generated.
Advantages: It can avoid the formation of cis trans isomer mixtures, but the steps are lengthy (requiring 4-5 steps) and the overall yield is low (about 40%).
Route of 2-diethylaminochloroethane hydrochloride
Reaction steps:
Preparation of Grignard reagent: 2-diethylaminochloroethane hydrochloride reacts with magnesium shavings to form Grignard reagent.
Carbonyl addition: Reacts with 4-fluorobenzophenone in anhydrous THF to form a tertiary alcohol intermediate.
Dehydration elimination: Dehydration under acidic conditions (H ₂ SO ₄/toluene) to form double bonds.
Chlorination shaping: Selective chlorination of trans sites using NCS to generate enrofloxacin.
Challenge: The dehydration step can easily lead to cis trans isomerization, requiring strict control of reaction temperature (<50 ° C) and time (<3 hours).
Process optimization and quality control
Refinement of reaction conditions
Chlorination reaction: The amount of NCS used should be precise to a molar ratio of 1.05:1. Excessive use can lead to the formation of dichloro by-products (such as 1,1-dichloros), which can affect purity.
Splitting crystallization: The amount of BINOL phosphate used should be 1.2 times the theoretical amount. Insufficient amount will result in incomplete splitting, while excessive amount will increase the difficulty of post-processing.
Solvent recovery: solvents such as dichloromethane and n-propyl ether can be recovered through distillation, with a recovery rate of over 90%, reducing environmental costs.
Quality control system
Purity testing: HPLC (C18 column, methanol/water=70:30 as mobile phase) is used to monitor the ratio of cis trans isomers, and the purity of enrofloxacin should be ≥ 99.0%.
Structural confirmation: The structure was confirmed by ¹ H NMR (with δ 7.2-7.8ppm as aromatic protons and δ 3.5-4.0ppm as ethoxy protons) and ESI-MS (m/z 406.2 [M+H] ⁺).
Impurity control: Focus on monitoring dichlorides (≤ 0.5%), cis configurations (≤ 1.0%), and solvent residues (dichloromethane ≤ 500ppm).
Industrial production case
The enclomiphene powder production line jointly developed by Shanghai Dude Pharmaceutical Technology Co., Ltd. and Zhengda Tianqing Pharmaceutical Group adopts a two-step process with an annual production capacity of 500kg. Its key optimization points include:
Continuous chlorination reaction:
Rapid mixing of NCS and raw materials is achieved through a tubular reactor, reducing reaction time to 4 hours and increasing yield to 82%.
Crystallization process improvement:
Gradient cooling crystallization was adopted (from 30 ° C to 0 ° C, at a rate of 0.5 ° C/min), resulting in a composite purity of 98.5% and a separation yield of 75%.
Wastewater treatment:
Alkali washed wastewater is acidified and precipitated (pH=2) to recover sodium chloride, and the supernatant is treated by activated carbon adsorption, with a COD removal rate of 90%.
Future research directions
Enzymatic Resolution:
Explore the selective hydrolysis of cis trans isomers by lipases or esterases to achieve green resolution.
Flow chemistry:
Continuous synthesis of cis trans mixtures through microreactors, reducing reaction time and improving safety.
Computational chemistry assistance:
using DFT calculations to predict reaction pathways and optimize the selection of chlorination reagents and catalysts.
The synthesis of enrofloxacin requires a balance between yield, purity, and cost, and the two-step method is still the mainstream process. In the future, through technological innovations such as enzyme catalysis and flow chemistry, it is expected to achieve more efficient and environmentally friendly production.
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