CN109369766A - Uliprista acetate relevant chiral impurity and its synthesis preparation method - Google Patents
Uliprista acetate relevant chiral impurity and its synthesis preparation method Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J21/005—Ketals
- C07J21/006—Ketals at position 3
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- C07—ORGANIC CHEMISTRY
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- C07J1/0051—Estrane derivatives
- C07J1/0081—Substituted in position 17 alfa and 17 beta
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- C—CHEMISTRY; METALLURGY
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- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
- C07J71/001—Oxiranes
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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Abstract
The invention discloses uliprista acetate relevant chiral impurity and its synthesis preparation methods, uliprista acetate relevant chiral impurity disclosed by the invention can be using 3- ketal as starting material, addition reaction obtains intermediate II, deprotection obtains intermediate III in acid condition again, it acts on obtaining intermediate compound IV by hydrolysis oxidation, upper blocking group and etc. obtain part chiral impurity, or with 3, the bis- ketal oxidation products of 20- are through obtaining part chiral impurity etc. by grignard reaction etc., the structure of all impurity compounds of the present invention is through nucleus magnetic hydrogen spectrum, high resolution mass spectrum and high performance liquid chromatography confirmation, the purity of uliprista acetate relevant chiral impurity compound is 95% or more obtained by this method, reference substance be can be used as quality research.
Description
Technical field
The invention belongs to organic chemistry filed more particularly to pharmaceutical synthesis chemical fields.The present invention provides acetic acid Wu Lisi
His relevant chiral impurity and its synthesis preparation method, the chiral impurity compound be applied to uliprista acetate bulk pharmaceutical chemicals and
The quality analysis of its preparation.
Background technique
Uliprista acetate (Ulipristal Acetate；Compound XI；Chemical name: -11 β of 17 α-acetoxyl group-[4-
(N, N- dimethylamino) phenyl] -19- norpregna -4,9- diene -3,20- diketone) it is a kind of potent antiprogestin and anti-
Glucocorticoid medicine.Its structural formula is as follows:
Uliprista acetate has listed in Europe and U.S.'s approval as emergency contraception, for unshielded sexual life or
It is used in 5 days after knowing or suspecting contraceptive failure, is a kind of effective and safe emergency contraception.Emergency contraception is defined as preventing
The treatment method being pregnant caused by unprotect measure sexual behaviour is surprisingly cherished caused by a kind of sexual behaviour for preventing unprotect measure
Pregnant important method.It is as it is accidental, urgent when a spare measure using.
Uliprista acetate, in Europe approval listing, is used in the preoperative therapy women of child-bearing age as fibroid medicine
Spend severe fibroid.Fibroid (also known as leiomyoma of uterus) be it is benign, monoclonal, the uterus of hormone-sensitive is flat
Sliding Muscle neoplasms.It is the most common tumour of the premenopausal genital tract of women, it was reported that Women of childbearing age 20-40% suffers from this tumour.Son
Palace myomata is often asymptomatic, but when there is symptom, and initial symptom is serious uterine hemorrhage, anaemia, abdomen compression, abdomen
Pain, frequent micturition aggravates and infertility.In particular, serious blood volume reduction is the symptom of the most common fibroid.
Prior art CN102516345B disclose can industrialized production uliprista acetate method, be be easy to get 3,
3- (ethylenedioxy -19- norpregna -5 (10), 9 (11)-diene -3,17- diketone (compound 1) and cyanylation agent addition
Reaction obtains compound 2, then protects 17 Alpha-hydroxies, obtains 3 compound of formula, then anti-with lithium methide or methyl grignard reagent
Should after through sour water solution obtain 4 compound of formula, then obtain compound 5 through the catalysis such as p-methyl benzenesulfonic acid and glycol reaction, then ring
Oxidation reaction obtains epoxy material 6, then reacts to obtain compound 7 with Grignard Reagent, then obtain chemical combination through hydrolyzed under acidic conditions
Object 8 most obtains uliprista acetate (compound XI) (Scheme 1) through acetoxylation afterwards.This method synthetic route is short, and totally 8 steps are anti-
It answers, and reaction condition is mild, it is easier to carry out, total recovery about 25-27% or so, and operation is easier, is suitable for industrialization.
The substance of any influence pharmaceutical purity is referred to as impurity.Miscellaneous Quality Research is an important content of drug research and development,
It includes selecting suitable analysis method, is accurately differentiated and the content of measurement impurity and comprehensive pharmacy, toxicity and clinical research
Result determine the reasonable limit of impurity.Whole process of this research through drug research and development.Impurity in drug is by its reason
Change property and be generally divided into three classes: organic impurities, inorganic impurity and residual solvent.According to its source, it is miscellaneous that impurity can be divided into technique
Matter (including synthesis in the complete reactant of unreacted and reagent, intermediate, by-product etc.), catabolite, from reactant and examination
Mixed impurity etc. in agent.According to its toxicity category, impurity can be divided into toxic impurities and common impurities etc. again.Impurity can also be by it
Classification of chemical structure, such as steroidal, alkaloid, geometric isomer, optical isomer and polymer.Organic impurities includes in technique
Impurity and catabolite of introducing etc., it may be possible to known or unknown, volatile or fixedness.Due to this kind of impurity
Chemical structure is generally similar with active constituent or tool original relationship, therefore usually can be referred to as related substance again.In these impurity
Research process in, in relation to substance, chiral impurity and genetoxic impurity be in development process pay close attention to and study emphasis.Vinegar
Chiral centre of the sour Ulipristal due to synthesizing introducing containing there are two, so in the exploitation and research in later period, chiral impurity
Research becomes the key influenced in its research and development process.
It is completely the same with its imaging plane shape possessed by the object of three-dimensional structure, but in three dimensions cannot be complete
The property of overlapping, it is referred to as chiral, there is chiral drug to be known as chiral drug.And it is produced because chiral centre conformation is different
Raw isomer impurities are then known as chiral impurity, all exist in chirality due to there is many marketed drug at present and grinding drug
The heart, so research chiral impurity is a highly important scientific research mission.Although the only difference of chiral centre configuration, has
It is influenced brought by chiral impurity and consequence is then that catastrophic such as most notable reaction stops event.Due to falling for technology
Property afterwards did not recognized that the importance of clear chiral configuration at that time, also without detect chiral centre configuration effective means and
Lead to the generation of this tragedy.The Thalidomide of S type is not only acted on without anti-pregnancy reaction, can also bring serious fetus teratogenesis
Consequence, contain so the lesson of history teaches that the configuration of clear chiral drug and the relationship of curative effect and controls chiral impurity
The research and development for measuring chiral drug play a crucial role.
There are mainly four types of the synthetic methods of chipal compounds, first is that using chiral substrate: this method generally compares office
Limit, is all applied to substantially there are in the natural products substrate of chiral centre, using original chiral centre, by steric effect or
Person's conformational effect etc. introduces the configuration of new chiral centre and fixation.Second is that using chiral auxiliary: chiral auxiliary is exactly to help
Reaction is helped to construct the reagent that the configuration of chiral centre removes again, such as many metallic catalysts and chiral sulphoxide reagent
Deng later shape is complexed by having the atoms such as chiral nitrogen or oxygen in the metal ion and substrate in chiral auxiliary in many reactions
At fixed chiral configuration, target product can be obtained in this way.Third is that using chiral reagent: this method is by using certain
Optically pure reagent is planted to induce the generation of stereoselective reaction, the relatively more extensive for example chiral borane reagent of application, chiral negative hydrogen
Reagent and Chiral stationary phase.Fourth is that using asymmetric catalyst: catalysis asymmetric syntheses is optimal chipal compounds
Synthetic method because being obtained with a large amount of chiral product by using a small amount of asymmetric catalyst, but and opportunity
And the challenge deposited is transition metal and chiral ligand is expensive is unable to satisfy large-scale production, so screening at present is high living
Property, highly-solid selectively and cheap asymmetric catalysis agent is also one of popular research field.With science and technology into
Step, biocatalysis asymmetric syntheses are also in the stage of a fast development, it is believed that in the near future, chipal compounds
Synthesis will not become the problem for influencing chiral drug development.
The separation method of chiral impurity is varied, laboratory be easier realize there are mainly three types of, the first side
Method is crystallisation, and this is most convenient, the method for simplest separating chiral compound, at the same product purity obtained also compared with
It is high, it is easy to accomplish industrialized production.Have also been developed for example mechanical resolving racemic mixtures of many new methods, preferential crystallization and
Priority enrichment etc., but be suitble to and not all compound is suitable for this method, so while easy to operate but there is also substrates
Not applicable limitation.Second method is thin-layered chromatography, using enantiomter polarity or the difference of adsorption capacity, is led to
It crosses thin-layered chromatography and enantiomter is realized into fractionation, compare and be suitble to laboratory operation, but most of enantiomerism volume propertys
Very similar, polarity or adsorption capacity are also quite similar, and common thin-layer chromatography can not separate, so can only pass through solvent
Type and a large amount of of proportion grope to attempt to achieve the purpose that separation.The third is by chiral chromatogram post separation, this side
Method advantage is efficient and can obtain the higher product of purity, but disadvantage is also fairly obvious, can not largely prepare target
Compound is only suitable for laboratory lab scale and prepares a small amount of target compound.
The identification of chipal compounds it is total be divided into two classes, direct method and indirect method.Direct method refers to through single method
The configuration of chipal compounds, such as single crystal method of X-ray diffractometry (Single-crystal X-ray can be confirmed
Diffraction, SXRD).And indirect method refers to that the chiral compound of dependence is analyzed, and comprehensive various other data,
It can determine that the configuration of the chipal compounds.Such as specific rotation (Specific Rotation), chiral chromatogram (Chiral
Chromatography), nuclear magnetic resonance (NMR) and optical rotational activity spectrum (Optical Rotatory Dispersion, ORD), circle
The analysis methods such as two chromatographies (Circular Dichroism, CD) belong to indirect method.
Summary of the invention
In order to preferably control the drug quality of uliprista acetate bulk pharmaceutical chemicals and its preparation, the present invention is in bulk pharmaceutical chemicals
Impurity is studied, and obtains relevant chiral impurity compound, and provide preparation method.Chiral impurity prepared by the present invention
Compound can be used for the quality analysis of the uliprista acetate bulk pharmaceutical chemicals and its preparation as impurity reference substance, while can also be with
Reference is provided for the selection of process conditions, is conducive to the control of production process Quality Evaluation of Chinese Medicinal amount.
Technical solution of the present invention is as follows:
The present invention provides the relevant chiral impurity compound or its salt of uliprista acetate, and the compound is selected from structure
As shown in following formula: compound A-M:
Compound or its salt of the present invention, wherein the salt can be inorganic acid salt or acylate, inorganic acid packet
Include but be not limited to hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid and perchloric acid etc., organic acid includes but unlimited
In acetic acid, trifluoroacetic acid, propionic acid, acrylic acid, caproic acid, pentamethylene propionic acid, glycolic acid, pyruvic acid, oxalic acid, (D) or (L) apple
Acid, fumaric acid, maleic acid, benzoic acid, hydroxybenzoic acid, gamma-hydroxybutyric acid, methoxy benzoic acid, phthalic acid, methylsulphur
Acid, ethanesulfonic acid, naphthalene -1- sulfonic acid, naphthalene-2-sulfonic acid, p-methyl benzenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, cinnamic acid, ten
Dialkyl group sulfuric acid, gluconic acid, glutamic acid, aspartic acid, stearic acid, mandelic acid, succinic acid or malonic acid etc..
As another object of the present invention, the preparation method of compound or its salt described above is also provided comprising following
(1), (2) or (3):
(1) with 3- ketal (intermediate compound I) for starting material, addition reaction obtains intermediate II, then takes off in acid condition
Protection obtains intermediate III, acts on obtaining intermediate compound IV by hydrolysis oxidation, and finally upper blocking group obtains impurity compound A,
Impurity compound B and impurity compound C are obtained through peroxidization, obtains impurity compound D after carrying out grignard reaction respectively
With impurity compound E, deprotection group obtains impurity compound G and impurity compound H in acid condition, finally passes through second
Acylation reaction step obtains impurity compound J and impurity compound K, and reaction equation is as follows:
It (2) include being obtained for reaction starting material by grignard reaction with the bis- ketal oxidation products (intermediate V) of 3,20-
Impurity compound F, then deprotection group obtains impurity compound I in acid condition, finally walks by acetylization reaction
Suddenly impurity compound L is obtained, reaction equation is as follows:
It (3) include being obtained for reaction starting material by grignard reaction with the bis- ketal oxidation products (intermediate VI) of 3,20-
Intermediate VII, deprotection group obtains intermediate VIII under acid condition, obtains intermediate compound I X by nitration reaction, passes through
Acetylization reaction obtains intermediate X, finally obtains impurity compound M by reduction reaction, reaction equation is as follows:
Further, in one embodiment, preparation method described above, in which:
(1) addition reaction described in:
In a specific embodiment, for example, compound I is dissolved in solvent, acetylene gas room is passed through under alkaline condition
Temperature reaction；The solvent be selected from tetrahydrofuran, acetonitrile, acetone, one of dioxane or a variety of, but not limited to this；Alkali choosing
From lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium ethoxide, sodium methoxide, potassium tert-butoxide, lithium diisopropylamine or n-BuLi
Deng, but not limited to this, preferred potassium tert-butoxide；0-25 DEG C of reaction temperature, preferably 5-15 DEG C, further preferred 10 DEG C.
(1) reaction of intermediate II deprotection base in are as follows:
In a specific embodiment, for example, compound II carries out the reaction of deprotection base under conditions of diluted acid,
Diluted acid is selected from formic acid, acetic acid, hydrochloric acid, perchloric acid, sulfuric acid or nitric acid etc., but not limited to this, preferred acetic acid；Reaction temperature is 0-25
DEG C, preferably 5-15 DEG C, further preferred 10 DEG C, reaction time 1-4h.
(1) hydrolysis oxidation of the intermediate III in reacts are as follows:
In a specific embodiment, for example, compound III is dissolved in solvent, catalyst is added under acid condition；Its
In, it is preferred that solvent is tetrahydrofuran, acetonitrile, methanol, ethyl alcohol, acetone, one of methylene chloride or a variety of；Acid is selected from first
Acid, acetic acid, hydrochloric acid, sulfuric acid, nitric acid or perchloric acid etc., preferably dilute sulfuric acid；The catalyst is mercuric sulfate or mercury oxide；Reaction
Temperature is 30-60 DEG C, reaction time 2-5h.
(1) blocking group can be under lewis acid effect in intermediate compound IV in, reaction are as follows:
In a specific embodiment, for example, compound IV is dissolved in solvent, Louis acid catalysis is added；Preferably,
Selected solvent is methylene chloride, tetrahydrofuran, acetonitrile, one of dioxane or a variety of；Lewis acid is selected from alchlor,
Ferric trichloride, titanium tetrachloride, boron trifluoride, antimony pentafluoride, indium trichloride, but not limited to this, preferred indium trichloride；Preferably,
Reaction temperature is 30-80 DEG C, reaction time 2-6h.
(1) oxidation reaction of impurity compound A in are as follows:
In a specific embodiment, for example, compound A is dissolved in solvent, under alkaline condition, oxidant is added and urges
Agent is reacted at room temperature.Preferably, solvent is methylene chloride, tetrahydrofuran, acetone, one of acetonitrile or a variety of；Alkali is selected from
Pyridine, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate or sodium dihydrogen phosphate etc., but not limited to this；Oxidant is selected from dioxygen
Water or metachloroperbenzoic acid etc., preferably hydrogen peroxide；Catalyst is selected from hexachloroacetone or Hexafluoro acetone etc.；Reaction temperature -10-10
℃。
(1) reaction equation that the grignard reaction in~(3) is related to is as follows:
In a specific embodiment, for example, reaction raw materials be under solvent, catalyst with 4- (mono- diformazan of N, N
Base amino) phenyl-magnesium-bromide Grignard Reagent or phenyl-magnesium-bromide Grignard Reagent carry out addition；Preferably, catalyst is protochloride
Iron, ferrous bromide, zinc chloride, zinc bromide, stannous chloride, cuprous bromide, but not limited to this；Selected solvent be methylene chloride, four
Hydrogen furans, acetonitrile, one of acetone or a variety of；Reaction raw materials and Grignard Reagent molar ratio are preferably 1:1.5-5, reaction temperature
Preferably -10-40 DEG C, the reaction time is preferably 2-8h.
(1) reaction equation that the group of deprotection in acid condition in~(3) is related to is as follows:
In a specific embodiment, for example, reaction raw materials are that reaction is hydrolyzed under stirring in water and diluted acid；It is excellent
Selection of land, the acid are selected from inorganic acid, such as hydrochloric acid, sulfuric acid, sodium bisulfate etc., preferably 0.2-4N HCl solution；Preferably,
- 10-50 DEG C of reaction temperature, reaction time 1-5h.
(1) reaction equation that the acetylization reaction in~(3) is related to is as follows:
In a specific embodiment, for example, be with any in glacial acetic acid, chloroacetic chloride, perchloric acid or acetic anhydride or
Person is two or more as acylating agent progress acylation reaction；It is preferred that glacial acetic acid is added in perchloric acid and acetic anhydride；Preferably, reaction temperature
- 40-25 DEG C of degree, preferably -10-25 DEG C；Preferably, the amount of glacial acetic acid accounts for the acetylation examination that glacial acetic acid, perchloric acid, acetic anhydride are constituted
The 1-50%V/V of agent volume total amount, preferably 10-15%V/V；Acylation reaction solvent for use is preferably methylene chloride, tetrahydrofuran,
Acetone, one of acetonitrile or a variety of.
(3) nitration reaction described in are as follows:
In a specific embodiment, preferably dense for example, carrying out nitration reaction under conditions of nitron and sulfuric acid
Sulfuric acid, reaction temperature are preferably -15-10 DEG C, and the reaction time is preferably 1-5h, and the nitrating agent is preferably concentrated nitric acid, hair
Cigarette nitric acid or potassium nitrate etc..
(3) reduction reaction described in are as follows:
In a specific embodiment, for example, compound X is dissolved in solvent, catalyst is added and carries out reduction reaction；It is excellent
Choosing, selected solvent is methylene chloride, tetrahydrofuran, methanol, ethyl alcohol, acetonitrile, one of dioxane or a variety of；It is described to urge
Agent includes but is not limited to palladium carbon, iron powder, Raney's nickel, zinc powder etc., preferably palladium carbon；Reducing agent includes but is not limited to hydrogen, dilute salt
Acid, acetic acid or dilute sulfuric acid etc. are preferred, and reaction temperature is 25-40 DEG C, reaction time 6-12h.
The relevant chiral impurity compound or its salt of the above-mentioned uliprista acetate also provided in the present invention are according to acetic acid crow
Application in the detection of the Li Sita quality of the pharmaceutical preparations as impurity reference substance.
Unless otherwise noted, noun used is described as follows in the present invention:
" diluted acid " refers to that concentration is the acid of 2N-4N.
" dilute sulfuric acid " refers to the sulfuric acid solution that Solute mass fraction is less than or equal to 70%.
" dilute hydrochloric acid " refers to the hydrochloric acid solution that Solute mass fraction is lower than 20%.
" concentrated sulfuric acid " refers to the sulfuric acid solution that Solute mass fraction is greater than 70%.
" concentrated nitric acid " refers to nitric acid solution of the Solute mass fraction 68%~95%.
" fuming nitric aicd " refers to the nitric acid solution that Solute mass fraction is greater than 95%.
The invention has the following advantages that
Present invention firstly discloses the relevant chiral impurity compound of above-mentioned uliprista acetate or its salt, compensate at present
The vacancy of the impurity method is prepared, and the method is easy to operate, post-processing is simple, the related hand for the uliprista acetate prepared
Property impurity purity is high, high income.
Detailed description of the invention
Fig. 1: uliprista acetate high-efficient liquid phase chromatogram；
Fig. 2: impurity compound K liquid chromatogram；
Fig. 3: impurity compound K nucleus magnetic hydrogen spectrum figure；
Fig. 4: impurity compound L nucleus magnetic hydrogen spectrum figure；
Fig. 5: impurity compound G single crystal diffraction figure；
Fig. 6: impurity compound J single crystal diffraction figure.
Specific embodiment
Embodiment below facilitates a better understanding of the present invention, but does not limit the present invention.Experiment in following embodiments
Method is unless otherwise specified conventional method.Test material as used in the following examples is unless otherwise specified certainly
What routine biochemistry reagent shop was commercially available.
Embodiment 1: the preparation of intermediate II
Potassium tert-butoxide 75g (668.39mmol) is weighed, is put into the three-necked bottle of 1000mL, the anhydrous of 500mL is added
THF is continually fed into acetylene gas, is cooled to 0 DEG C after 1 hour is stirred at room temperature, is added raw material I 100g (318.28mmol), control
Temperature processed is lower than 0 DEG C, keeps being passed through for acetylene gas, and saturated ammonium chloride solution is added after reaction, has separated for TLC monitoring
Machine layer, THF aqueous layer extracted merge organic layer, wash, and concentrate is slowly dropped into ice water by concentration, and solid is precipitated, and filter,
Water mashing, obtains product Intermediate II 98g, yield 91%.HRMS(ESI+):calcd for C22H30O3[M+H]+341.2111,
found 341.2109.
Embodiment 2: the preparation of intermediate III
Intermediate II 30g (88.18mmol) is weighed, puts into single neck bottle of 500mL, the glacial acetic acid of 300mL is added,
It is stirred at room temperature, is slowly dropped into the perchloric acid of 2.5mL (44.09mmol), control reaction temperature is lower than 25 DEG C.TLC monitoring, reaction knot
Reaction solution is slowly dropped into ice water by Shu Hou, and solid is precipitated, and is filtered, is obtained product Intermediate III 20g, yield: 77%.
HRMS(ESI+):calcd for C20H25O2[M+H]+297.1849,found 297.1847.
Embodiment 3: the preparation of intermediate compound IV
Intermediate III 10g (33.76mmol) is weighed, is dissolved in the THF of 100mL, the sulphur of 2.5g (8.44mmol) is added
Sour mercury adds 30% sulfuric acid solution of 30mL, stirs at 60 DEG C, and TLC monitoring, after reaction, saturated sodium bicarbonate is molten
Liquid adjusts pH, and methylene chloride aqueous layer extracted merges organic layer, washes, dry, column chromatography.Product Intermediate IV 4.8g is obtained, is received
Rate: 45%.HRMS(ESI+):calcd for C20H27O3[M+H]+315.1955,found 315.1957.1H NMR
(300MHz,CDCl3):δ1.12(s,3H,–CH3),2.30(s,3H,–CH3), 1.26-2.89 (m, 18H), 5.70 (s, 1H ,=
CH).
Embodiment 4: the preparation of impurity compound A
It weighs intermediate compound IV 2g (6.37mmol), four trichloride hydrate indium 0.93g (3.18mmol) put into 50mL's
In single neck bottle, the ethylene glycol of 1.8mL (31.85mmol) is added, the hexamethylene of 20mL is warming up to return stirring, and TLC is monitored, instead
Saturated sodium bicarbonate solution is added after answering and adjusts pH, water layer makes to be extracted with dichloromethane, and merges organic layer, washes, and it is dry,
Column chromatographs to obtain impurity in products compound A 0.98g, yield: 38%.HRMS(ESI+):calcd for C24H35O5[M+H]+
403.2453,found 403.2450.1H NMR(300MHz,CDCl3):δ0.67(s,3H,–CH3),0.91-2.68(m,
19H),1.29(s,3H,–CH3),3.69-4.03(m,8H,–OCH2), 5.58 (d, J=6.0Hz, 1H ,=CH)
Embodiment 5: the preparation of impurity compound B and impurity compound C
It weighs disodium hydrogen phosphate 35.29g (248.61mmol), hexachloroacetone 2.1mL (13.67mmol), 30% hydrogen peroxide
90mL (745.8mmol), is added in the three-necked bottle of 250mL.Methylene chloride 100mL is added.Nitrogen protection is cooled to 0 DEG C, stirs
Impurity compound A 10g (24.86mmol) is added after mixing a hour.36 hours of insulated and stirred are added sodium thiosulfate and quench
It goes out reaction, water layer makes to be extracted with dichloromethane, and merges organic layer, washes, dry.PE:EA=3:1 recrystallization, obtains target product
Impurity compound B 6.55g, yield: 90%.HRMS(ESI+):calcd for C24H35O6[M+H]+419.2357,found
419.2358.1H NMR(300MHz,CDCl3):δ0.74(s,3H,–CH3),0.86-2.66(m,19H),1.33(s,3H,–
CH3),3.83-3.93(m,8H,–OCH2), 6.12 (t, J=3.0Hz, 1H ,=CH).Mother liquor column chromatography (PE:EA=8:1) obtains miscellaneous
Matter compound C 1.4g, yield: 45%.HRMS(ESI+):calcd for C24H35O6[M+H]+419.2357,found
419.2360.1H NMR(300MHz,CDCl3):δ0.88(s,3H,–CH3),0.86-2.76(m,19H),1.07(s,3H,–
CH3),3.76-4.08(m,8H,–OCH2), 5.82 (d, J=6.00Hz, 1H ,=CH).
Embodiment 6: the preparation of impurity compound D
It weighs magnesium chips 2.92g (121.67mmol), dimethylatedρ-bromoaniline 2g (10.05mmol) is added to the three of 250mL
In neck bottle, measures anhydrous THF 20mL and pour into reaction flask, an iodine is added, be warming up to 50 DEG C of initiation reactions, reaction is drawn
It distributes complete, removes oil bath, weigh dimethylatedρ-bromoaniline 20g (100.50mmol) and be dissolved in the anhydrous THF of 200mL, slowly drip
Enter reaction solution, control reaction temperature is lower than 35 DEG C.Drop finishes, and is stirred at room temperature two hours and obtains grey black Grignard Reagent.Weigh impurity
Compound B 15g (35.89mmol), puts into the three-necked bottle of 500mL, and the stannous chloride of 1.5g (15.07mmol) is added,
The anhydrous THF of 50mL, nitrogen protection are cooled to 5 DEG C, and the Grignard Reagent made is slowly dropped into reaction flask, control reaction temperature
Degree is lower than 10 DEG C.Drop finishes, 10 hours of insulated and stirred.Saturated ammonium chloride solution quenching reaction is added, water layer methylene chloride extracts,
Merge organic layer, wash, dry, column chromatography obtains impurity compound D 5.6g, yield: 29%.HRMS(ESI+):calcd for
C32H46NO6[M+H]+540.3320,found 540.3318.
Embodiment 7: the preparation of impurity compound G
Impurity compound D 5.00g (9.28mmol) is weighed, is put into single neck bottle of 100mL, 10g is added
Ice water 60mL, 2 hours of insulated and stirred, TLC monitoring, reaction knot is added in the potassium acid sulfate of (73.44mmol) after being cooled to 0 DEG C
Saturated sodium bicarbonate solution is added after beam and adjusts pH to 7-8, methylene chloride aqueous layer extracted is added, merges organic layer, washes, does
Dry, column chromatography obtains impurity compound G 2.5g, single crystal diffraction figure is as shown in figure 5, yield: 63%.HRMS(ESI+):calcd
for C28H36NO3[M+H]+434.2690,found 434.2688.1H NMR(300MHz,CDCl3):δ0.64(s,3H,–
CH3),1.43-2.71(m,17H),2.31(s,3H,–COCH3),2.92(s,6H,N–CH3), 4.25 (d, J=9.00Hz, 1H ,-
CH) .5.74 (s, 1H ,=CH), 6.66 (d, J=9.00Hz, 2H, Ar-H), 6.99 (d, J=9.00Hz, 2H, Ar-H)
Embodiment 8: the preparation of impurity compound J
It measures acetic anhydride 4.7mL (46.08mmol), is added in single neck bottle of 50mL, is cooled to -10 DEG C, instill high chlorine
Sour 0.26mL (4.61mmol) is continued after being cooled to -30 DEG C of one hours of stirring, is slowly dropped into containing 2.00g (4.61mmol)
The dichloromethane solution (20mL) of impurity compound G, control reaction temperature are lower than -20 DEG C, and drop finishes, and keeps -20 DEG C of stirrings 2 small
When, TLC monitoring reaction terminates.Reaction solution being poured into the solution of saturated acetic acid sodium and adjusts pH, water layer is extracted with dichloromethane,
Merge organic layer, wash, dry, column chromatography obtains impurity compound J 1.29g, single crystal diffraction figure such as Fig. 6, yield: 59%.
HRMS(ESI+):calcd for C30H38NO4[M+H]+476.2795,found 476.2794.1H NMR(300MHz,
CDCl3):δ0.69(s,3H,–CH3),1.15-2.58(m,17H),2.08(s,3H,–COCH3),2.12(s,3H,–COCH3),
2.93(s,6H,N–CH3), 4.27 (d, J=9.00Hz, 1H ,-CH) .5.74 (s, 1H ,=CH), 6.69 (d, J=9.00Hz,
2H, Ar-H), 7.02 (d, J=9.00Hz, 2H, Ar-H)
Embodiment 9: the preparation of impurity compound E
It weighs magnesium chips 9.19g (382.78mmol), dimethylatedρ-bromoaniline 3.81g (19.14mmol) is added to 500mL
Three-necked bottle in, measure anhydrous THF 40mL and pour into reaction flask, an iodine is added, be warming up to 50 DEG C of initiation reactions, instead
It should cause and finish, remove oil bath, weigh dimethylatedρ-bromoaniline 38.09g (191.39mmol) and be dissolved in the anhydrous THF of 400mL,
It is slowly dropped into reaction solution, control reaction temperature is lower than 35 DEG C.Drop finishes, and is stirred at room temperature two hours and obtains grey black Grignard Reagent.Claim
Impurity compound C 10g (23.92mmol) is taken, is put into the three-necked bottle of 500mL, the chlorination of 4.76g (47.84mmol) is added
Cuprous, the anhydrous THF of 20mL, nitrogen protection is cooled to 5 DEG C, and the Grignard Reagent made is slowly dropped into reaction flask, and control is anti-
Answer temperature lower than 10 DEG C.Drop finishes, 10 hours of insulated and stirred.Saturated ammonium chloride solution quenching reaction, water layer methylene chloride is added
Extraction merges organic layer, washes, dry, and column chromatography obtains impurity compound E 1.42g, yield: 11%.HRMS(ESI+):
calcd for C32H46NO6[M+H]+540.3320,found 540.3319.
Embodiment 10: the preparation of impurity compound H
Impurity compound E 1.50g (2.78mmol) is weighed, is put into single neck bottle of 50mL, 3.03g is added
Ice water 30mL, 2 hours of insulated and stirred, TLC monitoring, reaction knot is added in the potassium acid sulfate of (22.26mmol) after being cooled to 0 DEG C
Saturated sodium bicarbonate solution is added after beam and adjusts pH to 7-8, methylene chloride aqueous layer extracted is added, merges organic layer, washes, does
Dry, column chromatography obtains impurity compound H 0.72g, yield: 60%.HRMS(ESI+):calcd for C28H36NO3[M+H]+
434.2690,found 434.2688.1H NMR(300MHz,CDCl3):δ0.64(s,3H,–CH3),1.43-2.74(m,
17H),2.31(s,3H,–COCH3),2.91(s,6H,N–CH3), 4.25 (d, J=9.00Hz, 1H ,-CH) .5.74 (s, 1H ,=
), CH 6.65 (d, J=9.00Hz, 2H, Ar-H), 6.99 (d, J=6.00Hz, 2H, Ar-H)
Embodiment 11: the preparation of impurity compound K
It measures acetic anhydride 1.59mL (15.59mmol), is added in single neck bottle of 25mL, is cooled to -10 DEG C, instill high chlorine
Sour 0.09mL (1.56mmol) is continued after being cooled to -30 DEG C of one hours of stirring, is slowly dropped into containing 0.45g (1.04mmol)
The dichloromethane solution (10mL) of impurity compound H, control reaction temperature are lower than -20 DEG C, and drop finishes, and keeps -20 DEG C of stirrings 2 small
When, TLC monitoring reaction terminates.Reaction solution being poured into the solution of saturated acetic acid sodium and adjusts pH, water layer is extracted with dichloromethane,
Merge organic layer, wash, dry, column chromatography obtains impurity compound K 0.21g, nucleus magnetic hydrogen spectrum figure is as shown in figure 3, yield:
43%.HRMS(ESI+):calcd for C30H38NO4[M+H]+476.2795,found 476.2793.1H NMR(300MHz,
CDCl3):δ0.69(s,3H,–CH3),1.16-2.62(m,17H),2.09(s,3H,–COCH3),2.12(s,3H,–COCH3),
2.94(s,6H,N–CH3), 4.28 (d, J=6.00Hz, 1H ,-CH) .5.75 (s, 1H ,=CH), 6.71 (s, 2H, Ar-H),
7.04 (d, J=9.00Hz, 2H, Ar-H)
Embodiment 12: the preparation of impurity compound F
It weighs magnesium chips 34.45g (1.44mol), dimethylatedρ-bromoaniline 9.52g (47.85mmol) is added to 1000mL's
It in three-necked bottle, measures anhydrous THF 100mL and pours into reaction flask, an iodine is added, be warming up to 50 DEG C of initiation reactions, react
Initiation finishes, and removes oil bath, weighs dimethylatedρ-bromoaniline 95.22g (478.47mmol) and is dissolved in the anhydrous THF of 600mL, delays
Slow to instill reaction solution, control reaction temperature is lower than 35 DEG C.Drop finishes, and is stirred at room temperature two hours and obtains grey black Grignard Reagent.It weighs
Intermediate V 20g (47.84mmol), puts into the three-necked bottle of 1000mL, and the protochloride of 23.8g (239.23mmol) is added
Copper, the anhydrous THF of 100mL, nitrogen protection are cooled to 15 DEG C, the Grignard Reagent made are slowly dropped into reaction flask, and control is anti-
Answer temperature lower than 30 DEG C.Drop finishes, 10 hours of insulated and stirred.Saturated ammonium chloride solution quenching reaction, water layer methylene chloride is added
Extraction merges organic layer, washes, dry, and column chromatography obtains impurity compound F 3.88g, yield: 15%.HRMS(ESI+):
calcd for C32H46NO6[M+H]+540.3320,found 540.3320.
Embodiment 13: the preparation of impurity compound I
Impurity compound F 2.50g (4.64mmol) is weighed, is put into single neck bottle of 50mL, 6.32g is added
Ice water 30mL, 2 hours of insulated and stirred, TLC monitoring, reaction knot is added in the potassium acid sulfate of (46.40mmol) after being cooled to 0 DEG C
Saturated sodium bicarbonate solution is added after beam and adjusts pH to 7-8, methylene chloride aqueous layer extracted is added, merges organic layer, washes, does
Dry, column chromatography obtains impurity compound I 0.70g, yield: 35%.HRMS(ESI+):calcd for C28H36NO3[M+H]+
434.2690,found 434.2691.1H NMR(300MHz,CDCl3):δ0.73(s,3H,–CH3),1.16-2.58(m,
17H),2.26(s,3H,–COCH3),2.93(s,6H,N–CH3), 5.52 (t, J=3.00Hz, 1H ,=CH), 6.645 (d, J=
9.00Hz, 2H, Ar-H), 7.345 (d, J=9.00Hz, 2H, Ar-H)
Embodiment 14: the preparation of impurity compound L
It measures acetic anhydride 1.2mL (11.78mmol), is added in single neck bottle of 25mL, is cooled to -10 DEG C, instill high chlorine
Sour 0.07mL (1.18mmol) is continued after being cooled to -30 DEG C of one hours of stirring, is slowly dropped into containing 0.51g (1.18mmol)
The dichloromethane solution (20mL) of impurity compound I, control reaction temperature are lower than -20 DEG C, and drop finishes, and keeps -20 DEG C of stirrings 2 small
When, TLC monitoring reaction terminates.Reaction solution being poured into the solution of saturated acetic acid sodium and adjusts pH, water layer is extracted with dichloromethane,
Merge organic layer, wash, dry, column chromatography obtains impurity compound L 0.14g, yield: 25%.HRMS(ESI+):calcd
for C30H38NO4[M+H]+476.2795,found 476.2793.1H NMR(300MHz,CDCl3):δ0.71(s,3H,–
CH3),1.15-2.59(m,17H),2.09(s,3H,–COCH3),2.13(s,3H,–COCH3),2.94(s,6H,N–CH3),
4.28 (d, J=6.00Hz, 1H ,-CH) .5.75 (s, 1H ,=CH), 6.71 (s, 2H, Ar-H), 7.03 (d, J=6.00Hz, 2H,
Ar-H) (nucleus magnetic hydrogen spectrum figure is as shown in Figure 4)
Embodiment 15: the preparation of intermediate VII
It weighing magnesium chips 5.17g (215.31mmol), bromobenzene 1.68g (10.77mmol) is added in the three-necked bottle of 250mL,
It measuring anhydrous THF 20mL to pour into reaction flask, an iodine is added, be warming up to 50 DEG C of initiation reactions, reaction, which causes, to be finished,
Oil bath is removed, bromobenzene 16.79g (107.66mmol) is weighed and is dissolved in the anhydrous THF of 150mL, is slowly dropped into reaction solution, control is anti-
Answer temperature lower than 35 DEG C.Drop finishes, and is stirred at room temperature two hours and obtains grey black Grignard Reagent.Weigh intermediate VI 15g
(35.89mmol), puts into the three-necked bottle of 500mL, the stannous chloride of 1.79g (17.94mmol) is added, 50mL's is anhydrous
THF, nitrogen protection are cooled to 0 DEG C, and the Grignard Reagent made is slowly dropped into reaction flask, and control reaction temperature is lower than 5 DEG C.
Drop finishes, 8 hours of insulated and stirred.Saturated ammonium chloride solution quenching reaction is added, the extraction of water layer methylene chloride merges organic layer,
Washing, dry, column chromatography obtains intermediate VII 11.58g, yield: 65%.
Embodiment 16: the preparation of intermediate VIII
Intermediate VII 9.00g (18.13mmol) is weighed, is put into the reaction flask of 250mL, ethyl alcohol 90mL is added,
8.5% sulfuric acid solution 10mL, room temperature reaction, TLC monitoring, after reaction, saturated sodium bicarbonate solution adjusts pH, dichloromethane
Alkane aqueous layer extracted merges organic layer, washes, dry, and column chromatographs to obtain intermediate VIII 5.8g, yield 82%.HRMS(ESI+):
calcd for C26H31O3[M+H]+391.2268,found 391.2270.
Embodiment 17: the preparation of intermediate compound I X
It measures concentrated sulfuric acid 1.00mL (19.22mmol), concentrated nitric acid 3.00mL (64.06mmol) is added to the three-necked bottle of 25mL
In, 10 DEG C are cooled to hereinafter, intermediate VIII 5.00g (12.81mmol) is slowly added into reaction flask after ten minutes by stirring
In, control temperature is lower than 10 DEG C.It finishes, insulated and stirred, TLC monitoring, after reaction saturated sodium bicarbonate solution adjusting pH, two
Chloromethanes aqueous layer extracted merges organic layer, washes, dry, and column chromatographs to obtain product Intermediate IX 2.5g, yield: 45%.HRMS
(ESI+):calcd for C26H30NO5[M+H]+436.2118,found 436.2119.
Embodiment 18: the preparation of intermediate X
It measures acetic anhydride 4.7mL (45.96mmol), is added in single neck bottle of 50mL, is cooled to -10 DEG C, instill high chlorine
Sour 0.3mL (4.60mmol) is continued after being cooled to -30 DEG C of one hours of stirring, is slowly dropped into intermediate containing 2g (4.60mmol)
The dichloromethane solution (20mL) of body IX, control reaction temperature are lower than -20 DEG C, and drop finishes, and keeps -20 DEG C of 2 hours of stirring, TLC
Monitoring reaction terminates.Reaction solution is poured into the solution of saturated acetic acid sodium and adjusts pH, water layer is extracted with dichloromethane, and is associated with
Machine layer is washed, dry, and column chromatography obtains intermediate X 0.86g, yield: 39%.HRMS(ESI+):calcd for C28H32NO6
[M+H]+478.2224,found 478.2225.1H NMR(300MHz,CDCl3):δ0.33(s,3H,–CH3),1.16-2.67
(m,19H),2.20(s,3H,–COCH3), 4.44 (d, J=9.00Hz, 1H ,-CH) .5.75 (s, 1H ,=CH), 7.28 (d, J=
9.00Hz, 2H, Ar-H), 8.08 (d, J=9.00Hz, 2H, Ar-H)
Embodiment 19: the preparation of impurity compound M
Intermediate X 0.8g (1.68mmol) is weighed, is dissolved in the methylene chloride of 10mL, 0.05g (0.84mmol) is added
The glacial acetic acid of 0.5mL (8.40mmol) is added dropwise in zinc powder, room temperature, and drop finishes, is stirred at room temperature, TLC monitoring, and reaction, which terminates to filter, removes dezincify
Saturated sodium bicarbonate is added in filtrate and adjusts pH for powder, and water layer makes to be extracted with dichloromethane, and merges organic layer, washes, dry, column
Chromatograph to obtain impurity compound M 0.45g, yield: 60%.HRMS(ESI+):calcd for C28H34NO4[M+H]+448.2482,
found 448.2480；1H NMR(300MHz,CDCl3):δ0.28(s,3H,–CH3),1.19-2.81(m,19H),2.02(s,
3H,–COCH3), 2.06 (s, 3H ,-COCH), 4.30 (d, J=6.00Hz, 1H ,-CH) .5.71 (s, 1H ,=CH), 6.60 (d, J
=9.00Hz, 2H, Ar-H), 6.86 (d, J=6.00Hz, 2H, Ar-H)
Uliprista acetate relevant chiral impurity of the present invention can be detected by this field common detection methods,
Such as the high-efficient liquid phase chromatogram that Fig. 1 is uliprista acetate, Fig. 2 is the liquid chromatogram of impurity compound K, other impurities chemical combination
Object conventionally can also be detected similarly.
Claims (14)
1. chiral impurity compound or its salt, the compound structure such as following formula: compound A-M is any shown:
Compound A:
Compound B:
Compound C:
Compound D:
Compound E:
Compound F:
Compound G:
Compound H:
Compound I:
Compound J:
Compound K:
Compound L:
Compound M:
。
2. chiral impurity compound or its salt according to claim 1, wherein salt is inorganic acid salt or acylate；It is inorganic
Acid is selected from hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid or perchloric acid；Organic acid is selected from acetic acid, trifluoro second
Acid, propionic acid, acrylic acid, caproic acid, pentamethylene propionic acid, glycolic acid, pyruvic acid, oxalic acid, (D) or (L) malic acid, fumaric acid, Malaysia
Acid, benzoic acid, hydroxybenzoic acid, gamma-hydroxybutyric acid, methoxy benzoic acid, phthalic acid, methanesulfonic acid, ethanesulfonic acid, naphthalene -1-
Sulfonic acid, naphthalene-2-sulfonic acid, p-methyl benzenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, cinnamic acid, dodecyl sulphate, glucose
Acid, glutamic acid, aspartic acid, stearic acid, mandelic acid, succinic acid or malonic acid.
3. the preparation method of compound or its salt claimed in claims 1-2 comprising following (1), (2) or (3):
(1) with 3- ketal, i.e. intermediate compound I is starting material, and addition reaction obtains intermediate II, then is deprotected in acid condition
Intermediate III is obtained, acts on obtaining intermediate compound IV by hydrolysis oxidation, finally upper blocking group obtains impurity compound A, passes through
Oxidation reaction obtains impurity compound B and impurity compound C, respectively carry out grignard reaction after obtain impurity compound D with it is miscellaneous
Matter compound E, deprotection group obtains impurity compound G and impurity compound H in acid condition, finally through acetylation
Reaction step obtains impurity compound J and impurity compound K, and reaction equation is as follows:
(2) with the bis- ketal oxidation products of 3,20-, i.e. intermediate V is reaction starting material, obtains impurity chemical combination by grignard reaction
Object F, then deprotection group obtains impurity compound I in acid condition, finally obtains by acetylization reaction step miscellaneous
Matter compound L, reaction equation are as follows:
(3) with the bis- ketal oxidation products of 3,20-, i.e. intermediate VI is reaction starting material, obtains intermediate by grignard reaction
VII, deprotection group obtains intermediate VIII under acid condition, obtains intermediate compound I X by nitration reaction, passes through acetylation
Reaction obtains intermediate X, finally obtains impurity compound M by reduction reaction, reaction equation is as follows:
4. preparation method according to claim 3, which is characterized in that
(1) addition reaction described in:
Compound I is dissolved in solvent, and acetylene gas room temperature reaction is passed through under alkaline condition；Preferably, the solvent is tetrahydro furan
It mutters, acetonitrile, acetone, one of dioxane or a variety of；Preferably, alkali be selected from lithium hydroxide, sodium hydroxide, potassium hydroxide,
Sodium ethoxide, sodium methoxide, potassium tert-butoxide, lithium diisopropylamine or n-BuLi, more preferable potassium tert-butoxide；Preferable reaction temperature 0-
25℃。
5. preparation method according to claim 3, which is characterized in that (1) reaction of intermediate II deprotection base in:
Compound II carries out the reaction of deprotection base under conditions of diluted acid；Diluted acid is selected from formic acid, acetic acid, hydrochloric acid, sulfuric acid, height
Chloric acid or dust technology etc., preferably acetic acid；Preferably, reaction temperature is 0-25 DEG C, reaction time 1-4h.
6. preparation method according to claim 3, which is characterized in that (1) hydrolysis oxidation of the intermediate III in reacts:
Compound III is dissolved in solvent, and catalyst is added under acid condition；Preferably, acid is selected from formic acid, acetic acid, hydrochloric acid, sulphur
Acid, nitric acid or perchloric acid；Selected catalyst is mercuric sulfate or mercury oxide；Selected solvent be tetrahydrofuran, acetonitrile, methanol, ethyl alcohol,
Acetone, one of methylene chloride or a variety of；Preferably, reaction temperature is 30-60 DEG C, reaction time 2-5h.
7. preparation method according to claim 3, which is characterized in that
(1) blocking group in intermediate compound IV in:
Compound IV is dissolved in solvent, and Louis acid catalysis is added；Lewis acid is selected from alchlor, ferric trichloride, four chlorinations
Titanium, boron trifluoride, antimony pentafluoride, indium trichloride, preferably indium trichloride；Selected solvent be methylene chloride, tetrahydrofuran, acetonitrile,
One of dioxane is a variety of；Preferred reaction temperature is 30-80 DEG C, reaction time 2-6h.
8. preparation method according to claim 3, which is characterized in that (1) oxidation reaction of impurity compound A in:
Compound A is dissolved in solvent, under alkaline condition, oxidant is added and catalyst reacts at room temperature；Alkali is selected from pyridine, phosphoric acid
Hydrogen dipotassium, potassium dihydrogen phosphate, disodium hydrogen phosphate or sodium dihydrogen phosphate；Oxidant be hydrogen peroxide or metachloroperbenzoic acid, preferably
Hydrogen peroxide；Catalyst is hexachloroacetone or Hexafluoro acetone etc.；Selected solvent is methylene chloride, tetrahydrofuran, acetone, in acetonitrile
It is one or more；- 10-10 DEG C of reaction temperature.
9. preparation method according to claim 3, which is characterized in that (1) following any grignard reaction in~(3):
Reaction raw materials be under solvent, catalyst with 4- (mono- dimethylamino of N, N) phenyl-magnesium-bromide Grignard Reagent or
Phenyl-magnesium-bromide Grignard Reagent carries out addition；Preferably, catalyst is frerrous chloride, ferrous bromide, zinc chloride, zinc bromide, chlorine
Change cuprous or cuprous bromide；Solvent is methylene chloride, tetrahydrofuran, acetonitrile, one of acetone or a variety of；Reaction raw materials dative
Family name's reagent molar ratio is preferably 1:1.5-5, and reaction temperature is preferably -10-40 DEG C, and the reaction time is preferably 2-8h.
10. preparation method according to claim 3, which is characterized in that (1) following any in acid condition in~(3)
The reaction of lower deprotection group:
Reaction raw materials are that reaction is hydrolyzed under stirring in water and diluted acid；Preferably, the acid is selected from hydrochloric acid, sulfuric acid or sulphur
Potassium hydrogen phthalate, preferably 0.2-4N HCl solution；Preferably, -10-50 DEG C of reaction temperature, reaction time 1-5h.
11. according to the method described in claim 3, it is characterized in that, any acetylization reaction below in (1)~(3):
Be use in glacial acetic acid, chloroacetic chloride, perchloric acid or acetic anhydride it is any or it is two or more carried out as acylating agent it is acylated anti-
It answers；It is preferred that glacial acetic acid is added in perchloric acid and acetic anhydride；Preferably, -40-25 DEG C of reaction temperature, preferably -10-25 DEG C；It is preferred that
Ground, the amount of glacial acetic acid account for the 1-50%V/V for the acetylation reagent volume total amount that glacial acetic acid, perchloric acid, acetic anhydride are constituted, preferably
10-15%V/V；Reaction dissolvent is preferably methylene chloride, tetrahydrofuran, acetone, one of acetonitrile or a variety of.
12. preparation method according to claim 3, which is characterized in that (3) nitration reaction described in:
Nitration reaction, the preferably concentrated sulfuric acid are carried out under conditions of nitron and sulfuric acid, reaction temperature is preferably -15-10 DEG C, instead
Preferably 1-5h between seasonable, the nitrating agent is preferably concentrated nitric acid, fuming nitric aicd or potassium nitrate.
13. preparation method according to claim 3, which is characterized in that (3) reduction reaction described in:
Compound X is dissolved in solvent, and catalyst is added, and carries out reduction reaction；Preferable reaction temperature is 25-40 DEG C, the reaction time
For 6-12h；Preferably, catalyst is palladium carbon, iron powder, Raney's nickel or zinc powder, preferably palladium carbon；Reducing agent is hydrogen, dilute hydrochloric acid, vinegar
Acid or dilute sulfuric acid；Solvent is methylene chloride, tetrahydrofuran, methanol, ethyl alcohol, acetonitrile, one of dioxane or a variety of.
14. compound or its salt of any of claims 1 or 2 according to the uliprista acetate quality of the pharmaceutical preparations detect in be used as impurity pair
According to the application of product.
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| CN112010918A (en) * | 2020-09-25 | 2020-12-01 | 湖南新合新生物医药有限公司 | Method for converting 17-carbonyl of steroid hormone substance into beta hydroxyl and preparation method of ubbi ketal impurity |
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