CN105566432A - Ulipristal acetate impurities and preparation and detection method thereof - Google Patents
Ulipristal acetate impurities and preparation and detection method thereof Download PDFInfo
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Abstract
The invention provides ulipristal acetate impurity compounds and a preparation method thereof, and particularly provides novel compound impurities including A (a compound A), G (a compound G), H (a compound H) and J (a compound J). The invention further provides a detection method of the impurities and application of the impurities on quality analysis of an ulipristal acetate bulk drug and a preparation thereof.
Description
Technical field
The invention provides a kind of impurity compound and preparation and determination methods method thereof of CDB-2914, described impurity compound is applied to the mass analysis of CDB-2914 bulk drug and preparation thereof.Belong to analytical chemistry field, particularly relate to pharmaceutical analysis chemical field.
Background technology
CDB-2914 (UlipristalAcetate; As shown in the formula compounds X, chemical name: 17 α-acetoxyl group-11 β-[4-(N, N-dimethylamino) phenyl]-19-norpregna-4,9-diene-3,20-diketone) be a kind of potent antiprogestin and Antiglucocorticoid drug.Structural formula is as follows:
CDB-2914 in Europe and U.S.'s approval listing, for unshielded sexual life or known or suspect and use in 5 days after contraceptive failure, is a kind of effective and emergency contraception of safety as emergency contraception.Emergency contraception is defined as the methods for the treatment of of the pregnancy preventing the behavior of unprotect measure from causing, and is a kind of important method of the unplanned pregnancy preventing the sexual behaviour of unprotect measure from causing.It is a measure for subsequent use as using time accidental, urgent.
CDB-2914 ratifies listing in Europe, for preoperative therapy women of child-bearing age moderate severe hysteromyoma as hysteromyoma curative.Hysteromyoma (also known as leiomyoma of uterus) is optimum, monoclonal, the uterine smooth muscle tumors of hormone-sensitive.It is that most kinds of tumor is progenesised in women's menopause, it is reported that Women of childbearing age 20-40% suffers from this tumour.Hysteromyoma is often asymptomatic, but when there is symptom, initial symptom is serious uterine hemorrhage, anaemia, belly pressurized, abdominal pain, and frequent micturition increases the weight of with sterile.Especially, serious is the symptom of modal hysteromyoma through oligohemia.
Prior art CN102516345B discloses can the method for suitability for industrialized production CDB-2914, be easy to get 3, 3-(ethylenedioxy-19-norpregna-5 (10), 9 (11)-diene-3, 17-diketone (Compound II per) and cyanylation agent addition reaction obtain compound III, then by 17 Alpha-hydroxy protections, obtain formula IV compound, then formula V compound is obtained through acid hydrolysis after reacting with lithium methide or methyl grignard reagent, 3 are obtained again through the catalysis such as tosic acid and glycol reaction, the two ketal compound VI of 20-, then epoxidation reaction obtains epoxy material VII, then compound VI II is obtained with grignard reagent react, Compound I X is obtained again through hydrolyzed under acidic conditions, obtain CDB-2914 (compounds X) (Scheme1) finally by acetoxylation.The method synthetic route is short, totally 8 step reactions, and reaction conditions is gentle, and more easily carry out, total recovery is about about 25-27%, and operation is easier, is suitable for industrialization.
Any material affecting pharmaceutical purity is referred to as impurity.Assorted Quality Research is an important content of drug research and development, and it comprises selects suitable analytical procedure, differentiates exactly and measures the content of impurity and the reasonable limit of the result determination impurity of comprehensive pharmacy, toxicity and clinical study.This research is through the whole process of drug research and development.Impurity in medicine is generally divided three classes by its physico-chemical property: organic impurity, inorganic impurity and residual solvent.According to its source, the impurity etc. that impurity can be divided into process contaminants (comprising unreacted reactant and reagent, intermediate, by product etc. completely in synthesis), degraded product, be mixed into from reactant and reagent.According to its toxicity category, impurity can be divided into toxic impurities and common impurities etc. again.Impurity also can by its classification of chemical structure, as steroidal, alkaloid, geometrical isomer, optical isomer and polymkeric substance etc.Organic impurity comprises the impurity and degraded product etc. introduced in technique, may be known or the unknown, volatile or non-volatility.Chemical structure due to this kind of impurity is general and activeconstituents is similar or tool original relationship, therefore usually can be referred to as related substance again.The selection of analytical procedure is directly connected to specificity and the accuracy of impurity determination result, and therefore, when carrying out impurity research, matter of utmost importance selects suitable impurity analysis method.
Impurity of the drug Inspection and analysis method should be sensitive, exclusive.By suitable analytical technology, the impurity of different structure is carried out being separated, detecting, thus reach the effective control to impurity.Along with being separated, the development of detection technique and renewal, efficiently, fast isolation technique combine with detection means that is sensitive, stable, accurate, that be suitable for, nearly all organic impurity all can obtain well separation and detection under suitable conditions.In quality standard, the method for detecting impurities generally adopted at present is mainly high performance liquid chromatography (HighPerformanceLiquidChromatography; HPLC), tlc (ThinLayerChromatography; TLC), vapor-phase chromatography (GasChromatography; And capillary electrophoresis (CapillaryElectrophoresis GC); CE).In recent years, mass-spectrometric technique is applied increasingly extensive in impurity of the drug analysis, and gas-chromatography coupling technology, liquid chromatography coupling technique have become the important means that impurity of the drug is analyzed.
Summary of the invention
In order to control the drug quality of CDB-2914 bulk drug and preparation thereof better, the present invention studies the impurity in bulk drug, obtains related impurities compound, and provides its preparation method and detection method.Impurity compound prepared by the present invention, as impurity reference substance, can be used for the mass analysis of this CDB-2914 bulk drug and preparation thereof, also can provide reference for the selection of processing condition simultaneously, be conducive to the control of production process Quality Evaluation of Chinese Medicinal amount.
Technical solution of the present invention is as follows:
The invention provides a kind of compound or its salt, the structure of described compound is as shown in the formula shown in compd A, compound G, compound H, Compound I or compound J:
Compd A:
Compound G:
Compound H:
Compound I:
Compound J:
Compound or its salt described above, wherein said salt is inorganic acid salt or organic acid salt.
As another object of the present invention, a kind of preparation method of compound or its salt described above is also provided, it comprises and preparing in the reaction product of CDB-2914 through being separated the step preparing described compd A, compound G, compound H, Compound I or compound J from by the two ketal (intermediate VI) of 3,20-.Preferably, the described reaction process preparing CDB-2914 by the two ketal (intermediate VI) of 3,20-is as follows:
Preparation method described above, wherein:
Described epoxidation reaction is:
Such as, compound VI is dissolved in methylene dichloride, under alkaline condition, reacts under adding oxygenant and perhalogeno acetone room temperature.Alkali is selected from pyridine, dipotassium hydrogen phosphate, potassium primary phosphate, Sodium phosphate dibasic, SODIUM PHOSPHATE, MONOBASIC etc.; Oxygenant is selected from hydrogen peroxide, metachloroperbenzoic acid etc., preferred hydrogen peroxide; Temperature of reaction-10-10 DEG C.
Described Grignard reagent reaction is:
Such as, at THF, under cuprous chloride catalysis, carry out addition with 4-(N, N mono-dimethylamino) phenyl-magnesium-bromide Grignard reagent; Preferably, reaction raw materials and Grignard reagent mol ratio 1: 1.5-5, temperature of reaction-10-40 DEG C, reaction times 2-8h.
Described hydrolysis reaction is:
Such as, be hydrolyzed under stirring in methylene dichloride and diluted acid reaction; Preferably, described acid is selected from the mineral acids such as hydrochloric acid, sulfuric acid, sodium pyrosulfate, is preferably 0.2-4NHCl solution; Preferably, temperature of reaction-10-50 DEG C, reaction times 1-5h.
Described acetylization reaction is:
Such as, by acylation reaction under any one or two or more acylating agents in Glacial acetic acid, perchloric acid or aceticanhydride; Glacial acetic acid is added in preferred perchloric acid and aceticanhydride; Preferably, temperature of reaction-40-25 DEG C, preferably-10-25 DEG C; Preferably, the 1-50%V/V of the acetylation reagent volume that the amount of Glacial acetic acid accounts for Glacial acetic acid, perchloric acid, aceticanhydride are formed, preferred 10-15%V/V.
As another embodiment of the present invention, the preparation method of another kind of compound or its salt described above is also provided, it comprises and preparing in the reaction product of CDB-2914 through being separated the step preparing described compd A, compound G, compound H, Compound I or compound J from by the two ketal (intermediate VI) of 3,20-.The two ketal (intermediate VI) of 3,20-prepares the reaction of CDB-2914, such as can see can the method for suitability for industrialized production CDB-2914 disclosed in prior art CN102516345B.
Preparation method described above, wherein said separation is prepared as preparation high pressure liquid chromatography and is separated; Preferably, described preparation high pressure liquid chromatography condition is: stationary phase is C18 reverse phase filler, and moving phase is triethylamine phosphoric acid solution-acetonihile gradient elution, and determined wavelength is 258nm.
Preferably, preparation method described above, is preferably separated and prepares described compd A, compound G, compound H, Compound I or compound J from the recrystallization mother liquor that CDB-2914 recrystallization obtains.
As another object of the present invention, also provide a kind of detection method of compound or its salt described above, wherein said method is HPLC method or HPLC-MS method;
Preferably, the testing conditions of described HPLC method is: stationary phase take octadecylsilane chemically bonded silica as weighting agent, and moving phase is triethylamine phosphoric acid solution-acetonihile gradient elution, and determined wavelength is 258nm; Preferably, moving phase is the triethylamine phosphoric acid solution-acetonitrile of pH2.5 ~ 3.5, and volume ratio is 30: 70 ~ 50: 50; More preferably, moving phase is the triethylamine phosphoric acid solution-acetonitrile of pH3.0, and volume ratio is 40: 60;
Preferably, the testing conditions of described HPLC-MS method is: the chromatographic condition of HPLC is stationary phase take octadecylsilane chemically bonded silica as weighting agent, moving phase is acetonitrile: the condition of 0.1% formic acid water=50: 50, MS is for adopting selectivity HPLC-ION, detection compound A parent ion [M+H]
+m/z397.1, compound G parent ion [M+H]
+m/z476.2, compound H parent ion [M+H]
+m/z441.2, Compound I parent ion [M+H]
+m/z516.2 or compound J parent ion [M+H]
+m/z474.2.
As another object of the present invention, also provide compound or its salt described above purposes as impurity reference substance in the related substance of CDB-2914 bulk drug or preparation detects.
As another object of the present invention, the quality determining method of a kind of CDB-2914 bulk drug or preparation is also provided, it comprises the step measuring wherein related substance, described related substance is selected from compd A described above, compound G, compound H, Compound I or compound J, it is characterized in that described mensuration adopts HPLC method or HPLC-MS method to detect; Preferably, described HPLC method or HPLC-MS method as described above; More preferably, described detection adopts HPLC method to detect; More preferably, the testing conditions of described HPLC method is: stationary phase is octadecylsilane chemically bonded silica, triethylamine phosphoric acid solution-the acetonitrile of moving phase to be volume ratio be pH2.5 ~ 3.5 of 30: 70 ~ 50: 50, determined wavelength is DAD (diode-array detector) 258nm, and number of theoretical plate calculates should be not less than 2000 by CDB-2914 peak; More preferably, during described related substance detects, if any impurity peaks in the color atlas of need testing solution, with calculated by peak area, the peak corresponding with each impurity phase respectively must not be greater than 0.15 times (namely foreign matter content is no more than 0.15%) of impurity reference substance solution.
Purposes described above, wherein said detection adopts HPLC method or HPLC-MS method to detect; Preferably, described detection adopts HPLC method to detect; More preferably, described HPLC method testing conditions is: stationary phase is octadecylsilane chemically bonded silica, triethylamine phosphoric acid solution-the acetonitrile of moving phase to be volume ratio be pH2.5 ~ 3.5 of 30: 70 ~ 50: 50, more preferably moving phase is 0.2% triethylamine (phosphoric acid adjusts pH3.0) damping fluid: acetonitrile=40: 60, determined wavelength is DAD (diode-array detector) 258nm, and number of theoretical plate calculates should be not less than 2000 by CDB-2914 peak; More preferably, during described related substance detects, if any impurity peaks in the color atlas of need testing solution, with calculated by peak area, the peak corresponding with each impurity phase respectively must not be greater than 0.15 times (namely foreign matter content is no more than 0.15%) of impurity reference substance solution.Total impurities content must not more than 1.0%.
As the present invention's embodiment, impurity compound A described above, compound G, compound H, Compound I or compound J specifically prepare by following methods.
1, the preparation process of CDB-2914
By two for 3,20-ketal (compound VI 1mol), methylene dichloride, pyridine, three water Perfluoroacetones, be cooled to-10-0 DEG C, drip 50% hydrogen peroxide, in-5-5 DEG C of reaction 2-3h, separate organic phase, aqueous phase dichloromethane extraction twice merging, with 10% sodium thiosulfate solution washing, organic phase washing twice, anhydrous magnesium sulfate drying, filters, is evaporated to constant weight.
By Mg (1.6mol), 1, 2 one ethylene dibromides and THF add there-necked flask, drip the bromo-N of 4-, accelerine and THF, after adding thermal booster reaction, backflow drips, finish, Grignard reagent is obtained in 50-60 DEG C of stirring reaction 3h, be cooled to 25 DEG C, add cuprous chloride, 25 DEG C are stirred after 30 minutes, the lower dichloromethane solution dripping above-mentioned epoxide of cooling, keep temperature 10-20 DEG C, finish insulated and stirred 2h, pour in the saturated NH4Cl aqueous solution of ice, stir 10 minutes, separate organic phase, aqueous phase dichloromethane extraction, organic phase merges, add 2NHCl solution.2h is stirred at 25 DEG C, separate organic phase, aqueous phase dichloromethane extraction, merge, use saturated sodium bicarbonate aqueous solution successively, water is respectively washed once, anhydrous magnesium sulfate drying, filter, filtrate proceeds in reaction flask, add Glacial acetic acid (1.25mol), be cooled to-10-0 DEG C, add 70% perchloric acid (1.18mol), then aceticanhydride (5.96mol) is dripped in-10-0 DEG C under stirring, insulated and stirred is after 30 minutes, aqueous phase dichloromethane extraction, merge, use saturated sodium bicarbonate aqueous solution successively, water is respectively washed once, anhydrous magnesium sulfate drying, filter, be evaporated to dry about 110g, through with 10 times amount Virahols: ethanol (95: 5) recrystallization obtains Light yellow crystals 244.8g, recrystallization mother liquor is concentrated does to obtain solid, stand-by.Product uses Virahol again: ethanol (95: 5) recrystallization, and 60 DEG C of oven dry obtain the product of Light yellow crystals, and recrystallization mother liquor is concentrated does to obtain solid, stand-by.
The CDB-2914 of above-mentioned gained is analyzed through LC-MS, containing multiple impurity, comprising impurity A (i.e. compd A), impurity G (i.e. compound G), impurity H (i.e. compound H), impurity I (i.e. Compound I) or impurity J (i.e. compound J), MS detected result is: impurity A: [M+H]
+397.1, impurity B: [M+H]
+415.1, impurity C:[M+H]
+373.1, impurity D:[M+H]
+462.2, impurity E: [M+H]
+434.0, impurity F: [M+H]
+518.2, impurity G:[M+H]
+476.2, impurity H:[M+H]
+441.2, impurity I:[M+H]
+516.2, impurity J:[M+H]
+474.2, impurity K:[M+H]
+492.3.
LC-MS condition used is:
HPLC: moving phase is Yi Jing ︰ 0.1% formic acid water=50 ︰ 50
Column temperature 25 ~ 35 DEG C
Flow velocity 0.3ml/min
Determined wavelength 258nm
Chromatographic column: AgilentPoroshe11120EC-C182.7um4.6X50mm
MS: condition
ESI，fg＝25，MS2scan。
2, the preparation process of impurity A, G, H, I, J
Analyze through HPLC, the content of CDB-2914 lmpurities is lower than 0.1%, but through analyzing the mother liquor in building-up process, wherein the content of impurity is higher, therefore adopts preparative separation impurity in the mother liquor processed from building-up process.
Be concentrated into by gained recrystallization mother liquor in the preparation process of CDB-2914 and dryly obtain solid, containing higher proportion impurity in this solid, this solid is prepared liquid phase purifying through high pressure, process can obtain high-purity impurity reference substance, concrete operations are as follows:
Purification condition:
Gradient elution ratio:
| Time (dividing) | A％ | B％ |
| 0 | 90 | 10 |
| 30 | 40 | 60 |
| 60 | 40 | 60 |
Concrete operation step:
Mother liquor concentrations is obtained solid to dry, gets about 1g, dissolve by 40% acetonitrile/water, upper prop, gradient elution, according to going out peak situation, Fractional Collections elutriant, after each purifying completes, purification column, with after 5% acetonitrile solution rebalancing, can repeat sample introduction purifying.The elutriant containing each component purity >98% obtained by multiple batches of purifying merges respectively.The most of acetonitrile of concentrated removing, aqueous layer with ethyl acetate extracts, and concentrated ethyl acetate, to dry, obtains impurity solid respectively.Every Batch purification can obtain impurity A and be about 5mg, and impurity B is about 10mg, and impurity C is about 5mg, and impurity D is about 15mg, impurity E is about 5mg, and impurity F is about 5mg, and impurity G is about 5mg, and impurity H is about 15mg, impurity I is about 5mg, and impurity J is about 10mg, and impurity K is about 5mg.
Analyzing and testing condition in above-mentioned purge process is:
Moving phase is pH3.0 triethylamine phosphoric acid buffer: acetonitrile=40: 60
Determined wavelength 258nm
Column temperature: 30 DEG C
Flow velocity 1.0mL/min
As the present invention's embodiment, additionally provide above-claimed cpd A, compound G, compound H, Compound I or the compound J purposes as impurity reference substance in CDB-2914 raw material and formulation products quality determining method thereof.Preferably use HPLC and/or HPLC-MS checked for impurities compd A, compound G, compound H, Compound I or compound J and content thereof.
More preferably, the condition that described HPLC adopts is,
Moving phase: the triethylamine phosphoric acid solution-acetonitrile of pH2.5 ~ 3.5, volume ratio is 30: 70 ~ 50: 50; Wherein the triethylamine phosphoric acid solution of pH2.5 ~ 3.5 is by triethylamine-phosphoric acid buffer to forming, and 1000 parts of water add 1 ~ 3 part of triethylamine and obtain triethylamine solution, with phosphorus acid for adjusting pH for 2.5 ~ 3.5;
Flow velocity: 0.8 ~ 1.2mL/min (preferable flow rate 1.0mL/min);
Column temperature: 25 ~ 35 degrees Celsius, preferably 30 DEG C;
Determined wavelength: adopt multi-wavelength detection, select the maximum absorption wavelength of each impurity to carry out related substance detection, checking respectively.CDB-2914: 303nm; Impurity A: 259nm; Impurity B: 234nm; Impurity C:241nm; Impurity D:303nm; Impurity E: 304nm; Impurity F: 328nm; Impurity G:253nm; Impurity H:262nm; Impurity I:256nm; Impurity J:261nm; Impurity K:299nm.
Stationary phase: take octadecylsilane chemically bonded silica as weighting agent
More a step is preferred, and the condition that described HPLC-MS adopts is:
Chromatographic condition is: moving phase: 0.05% ~ 0.5%HAc/ water: acetonitrile=(75 ~ 80): (25 ~ 20); Preferred 0.1%HAc/ water, with acetonitrile ratio preferably 78: 22
Flow velocity: 0.1 ~ 0.5ml/min, preferred 0.3ml/min; Column temperature: 20 ~ 40 DEG C, preferably 30 DEG C
Mass Spectrometry Conditions is: adopt selected ion monitoring ((SIM) method
Dry gas temperature: 300 ~ 400 DEG C, preferably 350 DEG C
Flow rate of carrier gas: 8 ~ 12L/min, preferred 10L/min
Atomization gas pressure: 30 ~ 50psi, preferred 40psi
Capillary voltage: 4000V
As a preferred embodiment of the invention, provide above-mentioned impurity compound A, compound G, compound H, Compound I or compound J as the application of impurity reference substance in the mass analysis of the Related substances separation of CDB-2914 and preparation thereof, wherein said CDB-2914 and the detection method of impurity thereof are preferably HPLC method, and HPLC testing conditions is as follows:
Stationary phase: take octadecylsilane chemically bonded silica as weighting agent
Triethylamine phosphoric acid solution-the acetonitrile of moving phase: pH3.0, volume ratio is 40: 60; Wherein the triethylamine phosphoric acid solution of pH3.0 is by triethylamine-phosphoric acid buffer to forming, and 1000 parts of water add 2 parts of triethylamines, with phosphorus acid for adjusting pH for 3.0;
Flow velocity: 0.8 ~ 1.2mL/min (preferable flow rate 1.0mL/min);
Column temperature: 25 ~ 35 degrees Celsius, preferably 30 DEG C;
Determined wavelength: preferably 258nm.
Number of theoretical plate calculates should be not less than 2000 by CDB-2914 peak
Determined wavelength: UV scanning show, each impurity and principal constituent maximum absorption wavelength as follows:
CDB-2914: 303nm; Impurity A: 259nm; Impurity B: 234nm; Impurity C:241nm; Impurity D:303nm; Impurity E: 304nm; Impurity F: 328nm; Impurity G:253nm; Impurity H:262nm; Impurity I:256nm; Impurity J:261nm; Impurity K:299nm, considers, and adopts multi-wavelength detection, selects the maximum absorption wavelength of each impurity to carry out related substance detection, checking respectively.
Experimental implementation:
Take CDB-2914 reference substance and impurity A respectively, B, C, D, E, F, G, H, I, J, K reference substance is in right amount each, add moving phase to dissolve and dilute and to make in every 1ml respectively containing the mixing solutions of each about 20ug of CDB-2914, impurity A, B, C, D, E, F, G, H, I, J, K, as system suitability solution.Precision measures system suitability solution 10ul injection liquid chromatography, record color atlas, and CDB-2914 and the mutual resolution of each impurity peaks should meet the requirements, and number of theoretical plate calculates should be not less than 2000 by CDB-2914 peak.
Assay method
Precision takes this product 10mg, puts in 20ml measuring bottle, dissolves, and is diluted to scale, shake up, as need testing solution by moving phase.Precision measures need testing solution 1ml and puts in 100ml measuring bottle, is diluted to scale by moving phase, shakes up, in contrast solution.Measure contrast solution 10 μ l, injection liquid chromatography, regulate detection sensitivity to make the peak height of principal constituent chromatographic peak be the 10-20% of full range.Precision measures need testing solution 10 μ l again, injection liquid chromatography, and record color atlas is to 3 times of principal constituent peak retention time.
Each impurity primary study determined wavelength:
| Wavelength | Impurity 9--> |
| 302nm | Impurity D, E, F, K |
| 237nm | Impurity B, C |
| 258nm | Impurity A, G, H, I, J |
If any impurity peaks in the color atlas of need testing solution, with calculated by peak area, the peak corresponding with each impurity phase respectively must not be greater than 0.15 times (namely foreign matter content is no more than 0.15%) of contrast solution; Other arbitrary single impurity peaks all must not be greater than 0.15 times (namely foreign matter content is no more than 0.15%) of contrast solution, total impurities must not more than 1.0 (i.e. total impurities content must not more than 1.0%), ignore in the peak being less than contrast solution main peak area 0.05 times (namely content is less than 0.05%).
The advantage of the method for the detection of above-mentioned CDB-2914 related substance provided by the invention be measurement result accurately and reliably, specificity is strong, and practical, each impurity can effectively detect, and all reach good separation between CDB-2914 and each impurity, adopt this system to detect plurality of impurities.
Aforesaid method is suitable for the Related substance of CDB-2914 preparation equally.
Accompanying drawing illustrates:
Fig. 1: CDB-2914 and magazins' layout degree collection of illustrative plates
Fig. 2: CDB-2914 detects collection of illustrative plates
Fig. 3: the HPLC of impurity A measures linear relationship chart
The HPLC of Fig. 4: impurity G measures linear relationship chart
The HPLC of Fig. 5: impurity H measures linear relationship chart
The HPLC of Fig. 6: impurity I measures linear relationship chart
The HPLC of Fig. 7: impurity J measures linear relationship chart
Embodiment
Embodiment 1: the preparation of CDB-2914
By 3, two ketal (the 100g of 20-, 0.25mol), methylene dichloride (1L), pyridine (5ml), three water Perfluoroacetones (20ml, 143mmol), be cooled to-10-0 DEG C, drip 50% hydrogen peroxide (70ml, 1.44mol), after-5-5 DEG C of reaction 2-3h raw material disappears, organic phase is separated, aqueous phase dichloromethane extraction twice merging, wash once with 10% sodium thiosulfate solution (10ml), organic phase washing twice (50ml*2), anhydrous magnesium sulfate drying, filter, be evaporated to constant weight and be about 200ml.
By Mg (9.6g, 0.4mol), 1, 2-ethylene dibromide (1ml) and THF (50ml) add there-necked flask, drip the bromo-N of 4-, accelerine (71g, 0.35mol) with THF (200ml) solution, the lower dropping of backflow is kept after adding thermal booster reaction, finish, Grignard reagent is obtained in 50-60 DEG C of stirring reaction 3h, be cooled to 25 DEG C, add cuprous chloride (3g, 30mmol), 25 DEG C are stirred after 30 minutes, the lower dichloromethane solution dripping above-mentioned epoxide of cooling, keep temperature 10-20 DEG C, finish insulated and stirred 2h, pour the NH that the 500ml of ice is saturated into
4in the Cl aqueous solution, stir 10 minutes, separate organic phase, aqueous phase dichloromethane extraction 400ml*5 time, organic phase merges, and adds 1000ml2NHCl solution.2h is stirred at 25 DEG C, separate organic phase, aqueous phase dichloromethane extraction 200ml*3, merge organic phase, use saturated sodium bicarbonate aqueous solution successively, water is respectively washed once, anhydrous magnesium sulfate drying, filter, filtrate proceeds in reaction flask, add Glacial acetic acid (18ml, 315mmol), be cooled to-10 ~ 0 DEG C, add 70% perchloric acid (24ml, 295mmol), then aceticanhydride (140ml is dripped in-10 ~ 0 DEG C under stirring, l.49mol), insulated and stirred is after 30 minutes, aqueous phase dichloromethane extraction twice 200ml*3, merge, use saturated sodium bicarbonate aqueous solution successively, water is respectively washed once, anhydrous magnesium sulfate drying, filter, be evaporated to dry about 110g, through with 10 times amount Virahols: ethanol (95: 5) recrystallization obtains Light yellow crystals 61.2g, recrystallization mother liquor is concentrated does to obtain solid, stand-by.Product uses Virahol again: ethanol (95: 5) recrystallization, and 60 DEG C of oven dry obtain the product of Light yellow crystals, and recrystallization mother liquor is concentrated does to obtain solid, stand-by.
Embodiment 2: the preparation of impurity compound
Gained recrystallization mother liquor in the preparation process of CDB-2914 is concentrated into and dryly obtains solid, containing higher proportion impurity in this solid, this solid is prepared liquid phase purifying through high pressure, process can obtain high-purity impurity reference substance,
Concrete operations are as follows:
Purification condition:
Gradient elution ratio:
| Time (dividing) | A％ | B％ |
| 0 | 90 | 10 |
| 30 | 40 | 60 |
| 60 | 40 | 60 |
Concrete operation step:
Mother liquor concentrations is obtained solid to dry, gets about 1g, dissolve by 40% acetonitrile/water, upper prop, gradient elution, according to going out peak situation, Fractional Collections elutriant, after each purifying completes, purification column, with after 5% acetonitrile solution rebalancing, can repeat sample introduction purifying.The elutriant containing each component purity >98% obtained by multiple batches of purifying merges respectively.The most of acetonitrile of concentrated removing, aqueous layer with ethyl acetate extracts, and concentrated ethyl acetate, to dry, obtains impurity solid respectively.Every Batch purification can obtain impurity A and be about 5mg, and impurity B is about 10mg, and impurity C is about 5mg, and impurity D is about 15mg, impurity E is about 5mg, and impurity F is about 5mg, and impurity G is about 5mg, and impurity H is about 15mg, impurity I is about 5mg, and impurity J is about 10mg, and impurity K is about 5mg.Wherein impurity D and E is known compound.Wherein, the structure of gained new compound A (i.e. impurity A), compound G (i.e. impurity G), compound H (i.e. impurity H), Compound I (i.e. impurity I) or compound J (i.e. impurity J) is respectively:
Impurity A:
Impurity G:
Impurity H:
Impurity I:
Impurity J:
Described impurity A, molecular formula: C
24h
28o
5
Molecular weight: 396.48
Chemical name: 3,17 α-diacetoxy-19-norpregna-2,4,10,9 (11)-tetraene-20-ketone
MS：397.16[M+H]+，419.13[M+Na]+，435.11[M+K]+
INSTRUMENT MODEL: BRUKERBV-500 type nuclear magnetic resonance analyser
It is as shown in the table that the 1H-NMR spectrum of impurity A, 13C-NMR spectrum, DEPT compose, COSY spectrum, hsqc spectrum and HMBC compose ownership
Described impurity G, molecular formula: C
30h
37nO
4
Molecular weight: 475.62
Chemical name: 17 α-acetoxyl group-10-(4-N, N-dimethylaminophenyl)-19-norpregna-4,9 (11)-diene-3,20-diketone
MS：476.23[M+H]+
INSTRUMENT MODEL: BRUKERBV-500 type nuclear magnetic resonance analyser
It is as shown in the table that the 1H-NMR spectrum of impurity G, 13C-NMR spectrum, DEPT compose, COSY spectrum, hsqc spectrum and HMBC compose ownership
Described impurity H, molecular formula: C
26h
32o
6
Molecular weight: 440.53
Chemical name: 3-acetoxyethoxy-17 α-acetoxyl group-19-norpregna-2,4,10,9 (11)-tetraene-20-ketone
MS：441.20[M+H]+，463.19[M+Na]+，479.14[M+K]+
INSTRUMENT MODEL: BRUKERBV-500 type nuclear magnetic resonance analyser
It is as shown in the table that the 1H-NMR spectrum of impurity H, 13C-NMR spectrum, DEPT compose, COSY spectrum, hsqc spectrum and HMBC compose ownership
Described impurity I, molecular formula: C
32h
37nO
5
Molecular weight: 515.64
Chemical name: 3,17 α-diacetoxy-11 β-(4-N, N-dimethylaminophenyl)-19-norpregna-2,4,10,9 (11)-tetraene-20-ketone
MS：516.26[M+H]+
INSTRUMENT MODEL: BRUKERAV-500 type nuclear magnetic resonance analyser
It is as shown in the table that the 1H-NMR spectrum of impurity I, 13C-NMR spectrum, DEPT compose, COSY spectrum, hsqc spectrum and HMBC compose ownership
Described impurity J, molecular formula: C
30h
35nO
4
Molecular weight: 473.60
Chemical name: 17 α-acetoxyl group-11 β-(4-N, N-dimethylaminophenyl)-19-norpregna-4,8 (14), 9 (11)-triolefin-3,20-diketone
MS：474.29[M+H]+，496.27[M+Na]+
INSTRUMENT MODEL: BRUKERAV-500 type nuclear magnetic resonance analyser
It is as shown in the table that the 1H-NMR spectrum of impurity J, 13C-NMR spectrum, DEPT compose, COSY spectrum, hsqc spectrum and HMBC compose ownership
Embodiment 3: the detection method of CDB-2914 and impurity thereof
The method of the detection of CDB-2914 related substance adopts liquid chromatographic detection, and HPLC testing conditions is as follows:
Stationary phase: take octadecylsilane chemically bonded silica as weighting agent
Moving phase: 0.2% triethylamine (phosphoric acid adjusts pH3.0) damping fluid: acetonitrile=40: 60
Determined wavelength: DAD302nm, 258nm, 237nm
Flow velocity: 1.0ml/min;
Column temperature: 25 DEG C
Experimental implementation:
Take CDB-2914 reference substance respectively and each impurity reference substance is in right amount each, add moving phase and dissolve and dilute and make respectively containing the mixing solutions of CDB-2914, each about 20ug of each impurity in every 1ml, as system suitability solution.Precision measures system suitability solution 10ul injection liquid chromatography, record color atlas (as shown in Figure 1), CDB-2914 and the mutual resolution of each impurity peaks should meet the requirements, and number of theoretical plate calculates should be not less than 2000 by CDB-2914 peak.
Assay method:
Precision takes CDB-2914 10mg, puts in 20ml measuring bottle, dissolves, and is diluted to scale, shake up, as need testing solution by moving phase.Precision measures need testing solution 1ml and puts in 100ml measuring bottle, is diluted to scale by moving phase, shakes up, in contrast solution.Measure contrast solution 10 μ l, injection liquid chromatography, regulate detection sensitivity to make the peak height of principal constituent chromatographic peak be the 10-20% of full range.Precision measures need testing solution 10 μ l again, injection liquid chromatography, and record color atlas is to 3 times of principal constituent peak retention time, and color atlas as shown in Figure 2.
Each impurity primary study determined wavelength:
| Wavelength | Impurity |
| 302nm | Impurity D, E, F, K |
| 237nm | Impurity B, C |
| 258nm | Impurity A, G, H, I, J |
If any impurity peaks in the color atlas of need testing solution, with calculated by peak area, the peak corresponding with each impurity phase respectively must not be greater than 0.15 times (namely foreign matter content is no more than 0.15%) of contrast solution; Other arbitrary single impurity peaks all must not be greater than 0.15 times (namely foreign matter content is no more than 0.15%) of contrast solution, total impurities must not more than 1.0 times (namely total impurities content is no more than 1.0%), ignore in the peak being less than contrast solution main peak area 0.05 times (namely content is less than 0.05%).
Method validation:
Impurity determination Method validation result is as follows:
Claims (10)
1. a compound or its salt, the structure of described compound is as shown in the formula shown in compd A, compound G, compound H, Compound I or compound J:
Compd A:
Compound G:
Compound H:
Compound I:
Compound J:
2. compound or its salt according to claim 1, wherein said salt is inorganic acid salt or organic acid salt.
3. the preparation method of compound or its salt described in claim 1-2, it comprises and preparing in the reaction product of CDB-2914 through being separated the step preparing described compd A, compound G, compound H, Compound I or compound J from by the two ketal (intermediate VI) of 3,20-.
4. method according to claim 3, the reaction wherein preparing CDB-2914 by the two ketal (intermediate VI) of 3,20-is:
5. method according to claim 4, wherein:
Described epoxidation reaction is in methylene dichloride, under alkaline condition, reacts under adding oxygenant and perhalogeno acetone room temperature;
Described grignard reaction is in tetrahydrofuran (THF), reacts under cuprous chloride catalysis with 4-(N, N mono-dimethylamino) phenyl-magnesium-bromide Grignard reagent;
Described hydrolysis reaction reacts under stirring in methylene dichloride and diluted acid;
Described acetylization reaction reacts under any one or two or more acylating agents with in Glacial acetic acid, perchloric acid or aceticanhydride.
6. preparation method according to claim 5, is characterized in that described separation is prepared as preparation high pressure liquid chromatography and is separated; Preferably, described preparation high pressure liquid chromatography condition is: stationary phase is octadecylsilane chemically bonded silica (C18) reverse phase filler, and moving phase is triethylamine phosphoric acid solution-acetonihile gradient elution, and determined wavelength is 258nm.
7. the preparation method according to claim 3-6, is characterized in that, is separated and prepares described compd A, compound G, compound H, Compound I or compound J from the recrystallization mother liquor that CDB-2914 recrystallization obtains.
8. the detection method of compound or its salt described in claim 1 or 2, is characterized in that described method is HPLC method or HPLC-MS method; Preferably, the testing conditions of described HPLC method is: stationary phase take octadecylsilane chemically bonded silica as weighting agent, and moving phase is triethylamine phosphoric acid solution-acetonihile gradient elution, and determined wavelength is 258nm; Preferably, moving phase is the triethylamine phosphoric acid solution-acetonitrile of pH2.5 ~ 3.5, and volume ratio is 30: 70 ~ 50: 50; More preferably, moving phase is the triethylamine phosphoric acid solution-acetonitrile of pH3.0, and volume ratio is 40: 60; Preferably, the testing conditions of described HPLC-MS method is: the chromatographic condition of HPLC is stationary phase take octadecylsilane chemically bonded silica as weighting agent, moving phase is acetonitrile: the condition of 0.1% formic acid water=50:50, MS is for adopting selectivity HPLC-ION, detection compound A parent ion [M+H]
+m/z397.1, compound G parent ion [M+H]
+m/z476.2, compound H parent ion [M+H]
+m/z441.2, Compound I parent ion [M+H]
+m/z516.2 or compound J parent ion [M+H]
+m/z474.2.
9. compound or its salt described in claim 1 or 2 in the related substance of CDB-2914 bulk drug or preparation detects as the purposes of impurity reference substance.
10. the quality determining method of a CDB-2914 bulk drug or preparation, it comprises the step measuring wherein related substance, described related substance is selected from the compound or its salt described in claim 1 or 2, it is characterized in that described mensuration adopts HPLC method or HPLC-MS method to detect; Preferably, described detection adopts HPLC method to detect; More preferably, the testing conditions of described HPLC method is: stationary phase is octadecylsilane chemically bonded silica, triethylamine phosphoric acid solution-the acetonitrile of moving phase to be volume ratio be pH2.5 ~ 3.5 of 30: 70 ~ 50: 50, determined wavelength is DAD (diode-array detector) 258nm, and number of theoretical plate calculates should be not less than 2000 by CDB-2914 peak; More preferably, during described related substance detects, if any impurity peaks in the color atlas of need testing solution, with calculated by peak area, the peak corresponding with each impurity phase respectively must not be greater than 0.15 times (namely foreign matter content is no more than 0.15%) of impurity reference substance solution.
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| CN112461957A (en) * | 2020-11-12 | 2021-03-09 | 湖南新合新生物医药有限公司 | Method for detecting impurity content in ulipristal acetate intermediate II |
| CN112578037A (en) * | 2020-11-12 | 2021-03-30 | 湖南新合新生物医药有限公司 | Method for detecting content of hexaketal in ulipristal acetate intermediate I |
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