CN113943340A - 4-aza steroid compound and preparation method and application thereof - Google Patents
4-aza steroid compound and preparation method and application thereof Download PDFInfo
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- CN113943340A CN113943340A CN202111346354.8A CN202111346354A CN113943340A CN 113943340 A CN113943340 A CN 113943340A CN 202111346354 A CN202111346354 A CN 202111346354A CN 113943340 A CN113943340 A CN 113943340A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
- C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
- C07J73/005—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by nitrogen as hetero atom
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
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Abstract
The invention provides a 4-aza steroid compound, a preparation method and application thereof, wherein the structural formula is as follows:
the compound is obtained by taking finasteride as a raw material and carrying out an epoxy reaction under an oxidant and an alkaline environment; can be used as an impurity standard substance or a reference substance to be applied to the detection and analysis of finasteride bulk drugs or preparations, and has important effects on the quality control and the process optimization of finasteride.
Description
Technical Field
The invention relates to the field of compound synthesis, in particular to a 4-azasteroid compound and a preparation method and application thereof.
Background
The chemical name of Finasteride is N-tert-butyl-3-oxo-4-aza-5 alpha-androst-1-ene-17 β -formamide of formula C23H36N2O2Is a 4-azasteroid compound, and the structural formula is as follows:
finasteride as competitive intracellular enzyme-II type 5 a-reductase inhibitor can effectively reduce dihydrotestosterone in blood and prostate, and has reliable treatment effect on benign prostatic hyperplasia and androgen alopecia, and good safety and tolerance.
With the improvement of the scientific research level and the policy of encouraging the innovation of the medicine, the number of the innovative medicine in China is in a remarkable trend, but compared with the research of the innovative medicine in developed countries, the research level of the innovative medicine impurities in China still has a certain gap.
The Chinese pharmacopoeia defines impurities as any substance affecting the purity of the medicine, and the impurities in the medicine quality standard refer to impurities introduced by raw and auxiliary materials or production processes of the medicine produced according to the specified raw and auxiliary materials and the specified processes, or degradation products generated in the storage process and confirmed by stability tests.
The research of innovative drug impurities is of great significance, and firstly, the research of impurities is the need of ensuring the safety of drugs. Safety is the most important research content in the whole research stage of innovative drugs. Second, impurity studies involve the entire process of study. The factors brought by impurities have great influence on the selection of dosage forms, the composition of prescriptions, the determination of processes, the research of analytical methods, the storage of medicines and the like. Therefore, the impurities are the key points of the quality research, quality control and safety research of the innovative medicaments. The research on impurities directly reflects the research level of innovative medicines.
Therefore, innovative drug research is an important aspect of drug research, and impurity research is carried out throughout the entire drug research. Whether the impurities in the medicine can be reasonably and effectively controlled is directly related to the quality controllability and the safety of the medicine.
Disclosure of Invention
In view of this, it is an object of the present invention to provide a 4-azasteroid compound identified as having the formula:
the second object of the present invention is to provide a process for producing the above 4-azasteroid compound, which comprises the steps of:
under the alkaline condition, finasteride is subjected to an epoxy reaction under the action of an oxidant to obtain the 4-aza steroid compound.
In some embodiments, the oxidizing agent is a peroxide. Specifically, the oxidizing agent comprises a first oxidizing agent and/or a second oxidizing agent, and the first oxidizing agent comprises m-chloroperoxybenzoic acid; the second oxidant comprises hydrogen peroxide and/or peroxyacetic acid. As a preferable scheme, the first oxidant and the second oxidant are selected and mixed and are used simultaneously, so that the conversion rate and the yield of the product can be improved, and the high-purity product can be obtained without column chromatography purification. More preferably, when the first oxidant and the second oxidant are used simultaneously, the first oxidant is added for reaction for a first period of time, and the second oxidant is added for reaction for a second period of time; specifically, the first oxidant is added for reaction for 0.5-1.5 h, and then the second oxidant is added for reaction for 10-12 h.
In some embodiments, the solvent in the reaction system is at least one of tetrahydrofuran, DMF and DMSO, and the alkaline condition is that carbonate and/or bicarbonate is added in the reaction system; the carbonate includes but is not limited to at least one of sodium carbonate and potassium carbonate; the bicarbonate includes but is not limited to at least one of sodium bicarbonate and potassium bicarbonate.
In some embodiments, the reaction temperature is 20 to 60 ℃.
The method also comprises a step of purifying the product, which specifically comprises the following steps: after the reaction was completed, extraction was performed with dichloromethane, and then the 4-azasteroid was crystallized using acetone.
In some embodiments, the process for preparing the 4-azasteroid comprises the steps of:
dissolving the finasteride compound in a solvent, adding alkali to make a system solution alkaline, adding an oxidant, carrying out heat preservation reaction, adding water to quench the reaction after the reaction is finished, extracting with dichloromethane, washing with water, distilling to nearly dry to remove the dichloromethane, and adding acetone to crystallize to obtain the 4-azasteroid compound.
The invention also aims to provide the application of the 4-azasteroid serving as an impurity standard substance or a reference substance in the detection and analysis of finasteride. Specifically, the application is as follows: and (3) detecting and analyzing finasteride by using a high performance liquid chromatography analysis method by taking the 4-azasteroid compound as a reference substance or a standard substance.
Compared with the prior art, the invention has the beneficial effects that:
the invention is based on a newly discovered 4-aza steroid compound, which has a structure similar to finasteride and also contains a genetic toxicity warning structure-epoxy structure, and the product can be used as an impurity standard substance or a reference substance, is used for detecting, analyzing and controlling the quality of a finasteride raw material drug or a preparation product, and has an important role in the quality control and process optimization of finasteride.
The invention also provides a preparation method of the 4-aza steroid compound, which has the advantages of simple process, easily obtained raw materials and high reaction conversion rate. The invention further provides an optimized process of the method, a high-purity product can be obtained without column separation, the conversion rate of raw materials is high, and the product yield is high.
Drawings
FIG. 1 is a liquid phase spectrogram of a finasteride crude drug (self-made according to the iodination and deiodination route);
FIG. 2 is a liquid phase spectrum of finasteride tablets (formerly ground tablets, merck);
FIG. 3 is a mass spectrum of 1, 2-epoxyfinasteride prepared in example 1;
FIG. 4 is a chart showing the hydrogen spectrum of 1, 2-epoxyfinasteride obtained in example 1;
FIG. 5 is a carbon spectrum of 1, 2-epoxyfinasteride prepared in example 1;
FIG. 6 is an IR spectrum of 1, 2-epoxyfinasteride obtained in example 1;
FIG. 7 is a diagram of an adaptive solution HPLC of the system of example 4;
FIG. 8 is a graph of a localization HPLC of finasteride impurity A (Chinese pharmacopoeia impurity I or EP pharmacopoeia impurity A) in example 4;
FIG. 9 is a chart of 1, 2-epoxy impurity localization HPLC in example 4
FIG. 10 is an HPLC plot of finasteride drug substance (homemade synthesis process batch 21040801-02) from example 5;
FIG. 11 is an HPLC chart of finasteride tablets (reference formulation: Baolizhi, batch No. T027138 batch) in example 5.
Detailed Description
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein, but rather should be construed as broadly as the present invention is capable of modification in various respects, all without departing from the spirit and scope of the present invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
In the process development of the bulk drug of finasteride drugs, a synthetic route using a bisamide compound as a starting material is adopted, and the specific route is as follows (the following formula shows two steps of iodination and deiodination):
yet another synthetic route employs the dehydrogenation of DDQ to finasteride, as follows:
the finasteride bulk drug synthesized by the two routes has various impurities, which brings challenges to the quality control of the bulk drug.
The inventor of the present application discovered that, accidentally during the research, whether the finasteride drug substance product obtained by dehydrogenating DDQ, the finasteride drug substance product obtained by deiodination, or the original finasteride drug substance (original tablet, merck) has an unknown impurity with very similar polarity to finasteride by liquid chromatography (see fig. 1 and fig. 2). By analyzing the reaction process, we suspected that the impurity is finasteride, the double bond at the 1,2 position is oxidized to form 1, 2-epoxy finasteride. Meanwhile, the impurity tends to increase when peroxide is added into a finasteride solution, so that the inventor directionally synthesizes 1, 2-epoxy finasteride (the structure of a compound is identified by mass spectrum, nuclear magnetic hydrogen spectrum, carbon spectrum and infrared spectrum), determines that the unknown impurity existing in a bulk drug and a tablet is 1, 2-epoxy finasteride, determines the chemical structure of the unknown impurity and determines that the impurity (the structure is:
name it: 1, 2-epoxyfinasteride; chemical name: n-tert-butyl-1, 2-epoxy-3-oxo-4-aza-5 alpha-androst-1-ene-17 beta-carboxamide. Also referred to herein as "epoxy impurities" or "1, 2-epoxy impurities".
As shown in formula I, the impurity has an epoxy structure and is a byproduct generated in the process of deiodination or DDQ dehydrogenation in the synthesis process of finasteride. The impurity contains a genetic toxicity warning structure, namely an epoxy structure, and is an impurity which needs to be focused in the quality research of finasteride.
1, 2-epoxy finasteride is very similar to finasteride, and a pure reference substance is difficult to obtain by a conventional method for separating and purifying impurities from raw materials. For example, the column separation is difficult due to the small difference in polarity.
Based on this, the inventors prepared 1, 2-epoxyfinasteride by a directed synthesis method. The inventor takes finasteride compound as raw material, and under alkaline condition, the finasteride compound reacts under the action of oxidant to generate 1, 2-epoxy finasteride, and the preparation route is as follows:
the method comprises the following specific steps:
dissolving the finasteride compound in a solvent, adding alkali to make a system solution alkaline, slowly adding an oxidant, carrying out heat preservation reaction, after the reaction is finished, adding a large amount of water, extracting with dichloromethane, washing with water to be neutral, carrying out reduced pressure distillation to remove dichloromethane, adding acetone for crystallization, filtering, leaching with a small amount of acetone, and drying to obtain the 4-azasteroid compound.
In the scheme, at least one of m-chloroperoxybenzoic acid, hydrogen peroxide and peracetic acid is selected as an oxidant, preferably a mixture of m-chloroperoxybenzoic acid and hydrogen peroxide, or a mixture of m-chloroperoxybenzoic acid and peracetic acid, or a mixture of the m-chloroperoxybenzoic acid and the peracetic acid is selected as the oxidant, so that the conversion rate of raw materials and the yield of products can be improved, and high-purity products can be obtained without silica gel column treatment. The method is characterized in that a weaker oxidant such as m-chloroperoxybenzoic acid and the like is used independently, the reaction speed is slow, the conversion rate is low, a strong oxidant such as hydrogen peroxide, peroxyacetic acid and the like is used singly, the oxidability is too strong, the reaction product is relatively complex, and when the two oxidants are used in combination, the reaction efficiency can be improved, and the generation of byproducts can be inhibited at the same time.
The solvent is at least one of tetrahydrofuran, DMF and DMSO, the alkaline condition is that alkaline substances are added into a reaction system, carbonate and/or bicarbonate are added in the scheme, and specifically at least one of sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate is added; the reaction temperature is 20-60 ℃.
The preferred concentration of the base in the system is: 5-30% of water solution
Preferably, in the process of adding the oxidant, when the m-chloroperoxybenzoic acid and the hydrogen peroxide are simultaneously used, or the m-chloroperoxybenzoic acid and the peracetic acid are simultaneously used, or the m-chloroperoxybenzoic acid, the hydrogen peroxide and the peracetic acid are simultaneously used, the m-chloroperoxybenzoic acid is firstly added for reaction for 0.5 to 1.5 hours, and then the hydrogen peroxide and/or the peracetic acid are added for 10 to 12 hours, so that the yield and the purity of the product can be further improved.
Preferably, the addition amounts of the m-chloroperoxybenzoic acid, the hydrogen peroxide and the peracetic acid are respectively as follows: the dosage of the m-chloroperoxybenzoic acid is as follows: 1.0-1.5 molar equivalent, and 30% of hydrogen peroxide is as follows: 0.7-1.3 volume ratio, and the dosage of the peroxyacetic acid is 0.7-1.3 volume ratio.
In order to make the aforementioned objects, features and advantages of the present invention more comprehensible and to show the utility of the compounds of the present invention, the following scheme of the present invention is further described with reference to specific examples.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
Example 1
A preparation method of a 4-azasteroid compound comprises the following steps:
dissolving 5g of finasteride compound in 50mL of tetrahydrofuran, adding 20mL of 20% sodium carbonate aqueous solution, preserving heat to 20-30 ℃, stirring, slowly adding 2.5g of m-chloroperoxybenzoic acid for three times, preserving heat, stirring for 1 hour, adding 5mL of 30% hydrogen peroxide, continuing preserving heat, reacting for 10-12 hours, adding 200mL of water, quenching, extracting twice with 100mL of 2-dichloromethane, combining organic phases, washing once with 100mL of water, distilling under reduced pressure to be nearly dry, adding 8mL of acetone, stirring for 1 hour, filtering, leaching a filter cake with a small amount of acetone, and drying by air blowing at 50 ℃ to obtain a compound I; the yield thereof was found to be 91.2%. And identifying the obtained compound I by mass spectrum, nuclear magnetic hydrogen spectrum, carbon spectrum and infrared spectrogram, wherein the identification result is shown in figures 3-6 and table 1, and the compound I is determined to be 1, 2-epoxy finasteride.
TABLE 1 analysis results of Compound I by Mass Spectrometry, Nuclear magnetic Hydrogen Spectrometry, and carbon Spectroscopy
Example 2
Dissolving 5g of finasteride compound in 50mL of tetrahydrofuran, adding 20mL of 20% sodium carbonate aqueous solution, keeping the temperature to 20-30 ℃, stirring, slowly adding 2.5g of m-chloroperoxybenzoic acid for three times, keeping the temperature, stirring for 1 hour, adding 5mL of peracetic acid, continuing to keep the temperature, reacting for 10-12 hours, adding 200mL of water, quenching, extracting twice with 100mL of 2-dichloromethane, combining organic phases, washing once with 100mL of water, distilling under reduced pressure to be nearly dry, adding 8mL of acetone, stirring for 1 hour, filtering, leaching a filter cake with a small amount of acetone, and drying by air blowing at 50 ℃ to obtain 1, 2-epoxy finasteride, wherein the yield is 98.7%.
Example 3
Dissolving 5g of finasteride compound in 50mL of tetrahydrofuran, adding 20mL of 20% sodium carbonate aqueous solution, preserving heat to 20-30 ℃, stirring, slowly adding 2.5g of m-chloroperoxybenzoic acid for three times, preserving heat for reaction for 10-12 hours, adding 200mL of water, quenching for reaction, extracting twice with 100mL of 2 dichloromethane, combining organic phases, washing once with 100mL of water, carrying out reduced pressure distillation for near drying, and carrying out column separation to obtain 1, 2-epoxy finasteride with the yield of 17.3%.
From the above examples, it can be seen that the method for synthesizing 1, 2-epoxyfinasteride of the present invention uses a single oxidant, compared with the use of a composite oxidant, and has the advantages of low conversion rate, low yield, and the product requires column separation.
The method is characterized in that a weaker oxidant such as m-chloroperoxybenzoic acid and the like is used independently, the reaction speed is slow, the conversion rate is low, a strong oxidant such as hydrogen peroxide, peroxyacetic acid and the like is used singly, the oxidability is too strong, the reaction product is relatively complex, and when the two oxidants are used in combination, the reaction efficiency can be improved, and the generation of byproducts can be inhibited at the same time.
Example 4
The method for detecting whether the separation degrees of finasteride epoxy impurities, 1, 2-epoxy impurities and finasteride and Chinese pharmacopoeia impurities meet the detection requirements by adopting a high performance liquid chromatography analysis method comprises the following specific steps:
preparing a test solution: precisely weighing about 25mg (+ -0.5 mg) of finasteride, placing into a 25mL measuring flask, adding a diluent to dissolve and dilute to scale, and shaking up to obtain the final product.
Preparing an impurity stock solution: taking finasteride impurity A (namely Chinese pharmacopoeia impurity I or EP pharmacopoeia impurity A, abbreviated as CKA001-A) and 1, 2-epoxy impurity (prepared in example 1, finasteride impurity I, abbreviated as CKA001-I) which are respectively about 12.5mg (+/-0.5 mg), accurately weighing, respectively placing into 50mL measuring bottles, adding a proper amount of diluent to dissolve and dilute to scale, shaking up, and taking the obtained product as impurity stock solution and respectively serving as positioning solution of finasteride impurity A and 1, 2-epoxy impurity;
preparing a system applicability solution: precisely weighing about 25mg (+ -0.5 mg) of finasteride, placing into a 25mL measuring flask, adding appropriate amount of diluent to dissolve, precisely adding 0.1mL of the impurity stock solution, diluting to scale with diluent, and shaking to obtain the final product (the concentration of finasteride as main component is 1mg/mL, and the concentration of impurity is 1 μ g/mL).
All the above solutions were prepared using acetonitrile-water (V/V ═ 50: 50) as diluent
Chromatographic conditions are as follows: octadecylsilane chemically bonded silica is used as a filling agent (Phenomenex Luna Omega C18, 250 x 4.6mm, 5 mu m), acetonitrile-water (38: 62; V/V) is used as a mobile phase, the flow rate is 1.0mL/min, the column temperature is 55-60 ℃, and the detection wavelength is 210 nm. Elution was performed according to isocratic procedure.
The determination method comprises the following steps: and precisely measuring 10 mu L of each system applicability solution and each impurity positioning solution, respectively injecting the solutions into a liquid chromatograph, and recording a chromatogram. The HPLC profile of the system adapted solution is shown in fig. 7; the positioning HPLC chart of CKA001-A (Chinese pharmacopoeia impurity I or EP pharmacopoeia impurity A) is shown in figure 8; the location HPLC profile of CKA001-I (1, 2-epoxy impurity) is shown in FIG. 9.
And (4) analyzing results: as can be seen from the HPLC chart of the system applicability solution and the impurity positioning, the epoxy impurities (CKA001-I, RRT 0.88-0.89) and the impurities A (CKA001-A) are completely separated from finasteride by the method, the separation degree meets the regulation, and the quantitative analysis of the epoxy impurities in finasteride can be met.
It should be noted that the purpose of this example is to examine whether the separation degree of 1, 2-epoxyfinasteride as epoxy impurity and finasteride or finasteride impurity a (chinese pharmacopoeia impurity I or EP pharmacopoeia impurity a) in the high performance liquid chromatography analysis method meets the specification, and it is verified that the 1, 2-epoxyfinasteride of the present invention can be used as epoxy impurity for quantifying or determining the epoxy impurity in finasteride.
Example 5
The detection of the epoxy impurities in the relevant substances of finasteride bulk drugs (self-made synthesis process batch 21040801-02 batch) and finasteride tablets (reference preparation: Baoezhi, batch number T027138 batch) is carried out by the following specific steps:
preparing a test solution:
preparing a solution of a sample to be tested of a self-prepared finasteride raw material medicament: taking 25mg of a self-made raw material, precisely weighing, placing in a 25mL measuring flask, adding a diluent (50% acetonitrile water) to dissolve and dilute to a scale, and shaking up to obtain the product; filtering to obtain the subsequent filtrate.
Preparing a solution of a finasteride tablet sample to be detected: taking the tablets (equivalent to 25mg of finasteride), precisely weighing, putting the tablets into a 25mL measuring flask, adding a diluent (50% acetonitrile water), dissolving and diluting to a scale, and shaking up to obtain the finished product; filtering to obtain the subsequent filtrate.
Chromatographic conditions are as follows: octadecylsilane chemically bonded silica was used as a filler (Phenomenex Luna Omega C18, 250X 4.6mm, 5 μm), acetonitrile-water (38: 62; V/V) was used as a mobile phase, the flow rate was 1.0mL/min, the column temperature was 60 ℃, and the detection wavelength was 210 nm. Elution was performed according to isocratic procedure.
The determination method comprises the following steps: and precisely measuring 10 mu L of each sample solution to be measured, respectively injecting the solution into a liquid chromatograph, and recording the chromatogram.
The HPLC chart of finasteride bulk drug (homemade synthesis process batch 21040801-02 batch) is shown in FIG. 10;
the HPLC profile of finasteride tablets (reference formulation: Baoenz, batch No. T027138 batch) is shown in FIG. 11;
and (4) analyzing results: as can be seen from HPLC charts of finasteride tablets (reference preparation: Baolizhi) and home-made batches of finasteride bulk drugs, epoxy impurities (CKA 001-I; RRT:0.89) are detected in the finasteride tablets and the home-made bulk drugs, and a proper detection method needs to be developed to detect the content of the epoxy impurities so as to control the limit of the impurities.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (10)
1. A 4-azasteroid compound having the structure:
2. a process for the preparation of a 4-azasteroid compound as claimed in claim 1, comprising the steps of:
under alkaline conditions, enabling the finasteride compound to perform an epoxy reaction under the action of an oxidant to obtain the 4-azasteroid compound.
3. A process for the preparation of a 4-azasteroid compound according to claim 2, wherein the oxidizing agent is a peroxide.
4. A process for the preparation of a 4-azasteroid compound according to claim 3, wherein the oxidizing agent comprises a first oxidizing agent and/or a second oxidizing agent, the first oxidizing agent comprising m-chloroperoxybenzoic acid; the second oxidant comprises hydrogen peroxide and/or peroxyacetic acid.
5. A process according to claim 4, wherein said oxidizing agent is added by: the first oxidant is added for reaction for a first period of time, and then the second oxidant is added for reaction for a second period of time.
6. A process according to claim 5, wherein the first period of time is from 0.5 to 1.5 hours and the second period of time is from 10 to 12 hours.
7. The process for producing a 4-azasteroid compound according to claim 2, wherein the basic condition is the addition of a carbonate and/or a bicarbonate to the reaction system.
8. The method for preparing 4-azasteroid compound according to claim 2, wherein the solvent in the reaction system comprises one or any combination of tetrahydrofuran, DMF, and DMSO; and/or the reaction temperature is 20-60 ℃.
9. A process for the preparation of a 4-azasteroid compound according to any one of claims 2 to 8, further comprising a purification step, in particular: after the reaction was completed, extraction was performed with dichloromethane, and then the 4-azasteroid was crystallized using acetone.
10. Use of a 4-azasteroid compound according to claim 1 as an impurity standard or control in the detection of a finasteride drug substance or formulation.
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| CN202111346354.8A CN113943340A (en) | 2021-11-15 | 2021-11-15 | 4-aza steroid compound and preparation method and application thereof |
| PCT/CN2021/134288 WO2023082368A1 (en) | 2021-11-15 | 2021-11-30 | 4-azasteroid compound, and preparation method therefor and use thereof |
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| US2737518A (en) * | 1955-01-19 | 1956-03-06 | Schering Corp | 1-hydroxycortisone, 1-hydroxyhydrocortisone and esters thereof |
| US3084158A (en) * | 1960-07-08 | 1963-04-02 | Roussel Uclaf | 11beta, 18-oxido-18zata-methyl-progesterone |
| JPS3822142B1 (en) * | 1960-08-31 | 1963-10-19 |
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- 2021-11-15 CN CN202111346354.8A patent/CN113943340A/en active Pending
- 2021-11-30 WO PCT/CN2021/134288 patent/WO2023082368A1/en unknown
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| US20060084671A1 (en) * | 2004-10-18 | 2006-04-20 | Ramesh Dandala | Process for the preparation of pure finasteride |
| CN101486753A (en) * | 2009-03-02 | 2009-07-22 | 浙江仙居君业药业有限公司 | Novel method for synthesizing finasteroid |
| CN105399790A (en) * | 2015-10-28 | 2016-03-16 | 湖南科瑞生物制药股份有限公司 | Synthesis method of 3-ketone-4-androstene-17 beta carboxylic acid |
| CN105646641A (en) * | 2016-02-26 | 2016-06-08 | 赵建华 | Method for forming double bonds between 1-position and 2-position during synthesis of finasteride and dutasteride |
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