CN103086862B - Hydroxydecyl quinone derivative for treating or preventing nerve diseases - Google Patents
Hydroxydecyl quinone derivative for treating or preventing nerve diseases Download PDFInfo
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- CN103086862B CN103086862B CN201310001087.XA CN201310001087A CN103086862B CN 103086862 B CN103086862 B CN 103086862B CN 201310001087 A CN201310001087 A CN 201310001087A CN 103086862 B CN103086862 B CN 103086862B
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Abstract
The invention relates to a hydroxydecyl quinone derivative for treating or preventing nerve diseases. Specifically, the invention relates to the hydroxydecyl quinone derivative as shown in formula I, a pharmaceutical composition containing the compound as shown in the formula I, and a preparation method and uses of the hydroxydecyl quinone derivative in preparation of medicaments for cerebrovascular diseases. The compound disclosed by the invention can effectively treat or prevent the diseases or disease symptoms: the cerebrovascular diseases, improve cerebral metabolism and improve mental symptoms, activate brain mitochondrial respiratory activity, improve cerebral energy metabolism of cerebral ischemia, improve the utilization rate of cerebral glucose, increase the production of cerebral triphosadenine, inhibit the generation of lipid hydroperoxide from brain mitochondria and inhibit the membrane disorder caused by overoxidation action of the brain mitochondrial membrane lipid, reduce impaired brain functions caused by chronic cerebrovascular diseases, cerebral trauma and the like, improve subjective symptoms, language, anxiety, depression, hypomnesia, intelligence decrease and other mental and behavioral disorders, promote the intelligence, and activate brain mitochondrial functions, improve the cerebral energy metabolism and improve brain functions.
Description
Technical field
The present invention relates to a kind of 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl isophthalic acid, 4-benzoquinones.Specifically, the present invention relates to 6-(10-hydroxydecyl)-2, the 3-dimethoxy-5-methyl isophthalic acid with specified property, 4-benzoquinones and preparation method thereof, and this 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl isophthalic acid, the pharmaceutical applications of 4-benzoquinones.
Background technology
Neuronal damage, neurodegenerative disease and syndrome (recovering syndrome after alzheimer's disease, multiple sclerosis, Friedreich ataxia (Friedrich ' s ataxia), brain and Spinal injury and neurotrauma, apoplexy, Parkinson's disease, alcoholism and narcolepsy (narcolepsy), operative results syndrome and anesthesia) and other illnesss many need effective treatment and prevention.
Postoperative apoplexy and cognitive defect (POSCD) syndrome are common, are particularly carrying out surgical operation on a large scale as in the elderly of heart operation or hip replacement surgery.In North America, be performed for more than the surgical operation that 2,500,000 examples are so every year, and the sickness rate of POSCD is more than 30%.Exist to interventional therapy in the urgent need to, and enough therapeutic choice also be there is no for this distressful post surgical condition.In the U.S., only with regard to heart operation, be just performed for more than 2,000,000 routine surgical operations every year.The anesthesia of Lente anesthetic medicine recovers usually to cause patient to be in the state of significant disorientation and cognitive impairment afterwards and also continues very over a long time.Even if there is newer short acting anesthesia medicine, act on after also not alleviating the anesthesia of geratic surgery patient with operation.
The sickness rate of the serious adverse events of Post operation (comprising cognitive defect and apoplexy), up to operating 30-35% on a large scale, which results in extensively and the serious quality of life problem of the hospital stay extended and affected patient and health care supplier thereof.Apoplexy after anesthesia is reduced to 1.5% or Postoperative cognitive defect can be produced substantially the improvement of significant cost savings and quality of life handling problem from the about 30% current ability reduced from about 2.5%.Many gerontal patients stand cognitive decline after surgery to have now a large amount of evidence to show.For age >70 year patient total knee replacement carry out general anesthesia contrast epidural anesthesia (there is sedative effect) prospective randomized test in, when evaluating with psychometry, the patient of 4-6% anesthesia and the surgical site infections cognitive performance of six months poorer than preoperative baseline.Another large-scale perspective contrast international research confirms that the patient of 9.9% has cognitive defect in three months after surgery, and only has an appointment in the control group of age-matched and 3% have similar damage.In the patient of age more than 75 years old, the patient of 14% has lasting cognitive defect in general anesthesia and surgical site infections.
In many cases, the neurodegeneration relevant with anoxic causes because blood circulation reduces, and with the excessive of free radical and the suppression to mitochondria activity.
Antioxidant is considered to the possible protective material reducing the brain injury caused due to general anesthesia on a large scale.Various material---antioxidant and free-radical scavengers---obtains test in animal model in cell culture, in vitro brain section and body in vitro.In these experiments, 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl isophthalic acid, 4-benzoquinones shows significant antioxidant activity and can protect brain cell not oxidative damage significantly.6-(10-hydroxydecyl)-2; 3-dimethoxy-5-methyl isophthalic acid; the oral form of 4-benzoquinones is used for the treatment of the myocardial atrophy in Friedreich ataxia as hepatoprotective; and in limited degree, be used for the treatment of alzheimer's disease [United States Patent (USP) 5; 916; 925 " Pharmaceuticalcomposition for treatment of dementia " and United States Patent (USP)s 6; 133; the people such as 322Rustin P., " Quinonederivatves for treating or preventing diseases associated with iron overload "].
In the small-sized human research that the patient suffering from cerebrovascular disease to nine carries out, give 6-(10-hydroxydecyl)-2, the 3-dimethoxy-5-methyl isophthalic acid of 90mg every day, 4-benzoquinones, and monitor cerebral electrograph and clinical symptom.Result shows 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl isophthalic acid, and the supplementary administration of 4-benzoquinones creates improvement to the EEG (electroencephalogram) of these patients and clinical symptom.
6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl isophthalic acid, the cortical neuron that the protection of 4-benzoquinones is cultivated makes it not necrosing property sex change.It even still can save cortical neuron when within 30 minutes after NMDA pulse, using again, and this shows the toxic reaction chain that described interfering effects of drug triggers due to overstimulation excitatory amino acid receptor.
Give 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl isophthalic acid to the patient suffering from Friedreich ataxia is oral, 4-benzoquinones (every day, 5mg/kg also continued 8 weeks) significantly reduces the mark of oxidative dna damage.6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl isophthalic acid, 4-benzoquinones gives 5mg/kg and the lipid peroxidation preventing iron to induce in three patients of lasting 4-9 month and myocardial damage in every day, thus causes the reduction of left ventricle dilation in these patients.
In cell culture experiment, 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl isophthalic acid, 4-benzoquinones removes various Kinds of Free Radicals.6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl isophthalic acid, 4-benzoquinones also carries out redox couple with the myohaemoglobin of high-valence state kind or oxyphorase, thus prevents the lipid peroxidation promoted by these kinds.Similarly, shown 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl isophthalic acid, 4-benzoquinones inhibits the foundation of microsomal Lipid Peroxidation of being induced by ADP-iron complexes or organic hydroperoxide.Oneself shows 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl isophthalic acid, and 4-benzoquinones so prevents the destruction of Cytochrome P450, and the destruction of described Cytochrome P450 in addition can with lipid peroxidation.
Be reported in the experimental model produced by the cerebral embolism formation in Basal Forebrain of Rats, cerebral ischemia or damage, 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl isophthalic acid, 4-benzoquinones improves learning and memory disorder, and described basal forebrain is the origin area of the acetylcholine metasystem projected in pallium, hippocampus and amygdala.In clinical trial, 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl isophthalic acid, it is effective that 4-benzoquinones is considered to for reducing mental defect (decline kept as memory and disorientation).
This area still expect to have for 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl isophthalic acid, the method for the disease-related that 4-benzoquinones can be treated.
Summary of the invention
The object of this invention is to provide a kind of for 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl isophthalic acid, the method for the disease-related that 4-benzoquinones can be treated.
The invention provides with compounds of Formula I:
According to compound of the present invention, wherein comprise the following formula I Y compound of the trace as impurity:
this impurity formula IY compound can also referred to as impurity Y in the present invention.
According to compound of the present invention, it is in high effective liquid chromatography for measuring, there is the chromatographic purity being greater than 98% and (preferably there is the chromatographic purity being greater than 98.5%, preferably there is the chromatographic purity being greater than 99.0%, preferably there is the chromatographic purity being greater than 99.2%, preferably there is the chromatographic purity being greater than 99.3%, preferably there is the chromatographic purity being greater than 99.5%.
According to compound of the present invention, it is in high effective liquid chromatography for measuring, the chromatographic content of impurity Y lower than 0.8%, preferably lower than 0.7%, preferably lower than 0.6%, preferably lower than 0.55%, preferably lower than 0.5%, preferably lower than 0.45%, preferably lower than 0.4%, preferably lower than 0.35%, preferably lower than 0.3%.In an example, the chromatographic content of impurity Y is higher than 0.02%.
According to compound of the present invention, it is in high effective liquid chromatography for measuring, and in color atlas, total chromatographic content of each impurity peaks is lower than 1.2%, preferably lower than 1.0%, preferably lower than 0.9%, preferably lower than 0.8%, preferably lower than 0.7%, preferably lower than 0.6%, preferably lower than 0.5%, preferably lower than 0.4%.
According to compound of the present invention, it places the total chromatographic content increased value of each impurity peaks after 150 days and is no more than 1.5%, preferably more than 1.25%, preferably more than 1.0%, preferably more than 0.75%, preferably more than 0.5% under 45 ° of C.
According to compound of the present invention, wherein said high performance liquid chromatography measures according to Chinese Pharmacopoeia version in 2010 two annex VD high performance liquid chromatography specifications, and described high effective liquid chromatography for measuring mode is:
(1) chromatographic condition and system suitability: be weighting agent with octadecylsilane chemically bonded silica, with methanol-water (70:30) for moving phase, ultraviolet detection wavelength is 278nm, column temperature is 30 ° of C, number of theoretical plate presses 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl isophthalic acid, 4-benzoquinones peak calculates and is not less than 2000;
(2) preparation of test soln: get the compounds of this invention, accurately weighed, add moving phase and dissolve and quantitatively dilute the solution made about containing 0.2mg in every 1ml, as need testing solution; Separately get impurity Y-shaped IY compound, accurately weighed, add moving phase and dissolve and quantitatively dilute the solution made about containing 0.2mg in every 1ml, as impurity Y solution; Precision measures need testing solution and each 1ml of impurity Y solution, puts in the measuring bottle of same 100ml, is diluted to scale by moving phase, shake up, as the contrast solution of contained I and formula IY compound;
(3) chromatogram test: get contrast solution 20 μ l injection liquid chromatography, regulate detection sensitivity, the peak height at principal constituent peak is made to be about 10% of full range, precision measures need testing solution and each 20 μ l of contrast solution again, injection liquid chromatography respectively, record color atlas is to 2.5 times of principal constituent peak retention time;
(4) chromatographic computation:
(4i) record contrast solution color atlas main peak area (i.e. the peak area of formula I, this peak area can be expressed as A1 in the present invention) and retention time thereof, and record peak area and the retention time thereof of impurity Y;
(4ii) need testing solution color atlas main peak area (this peak area can be expressed as A100 in the present invention) and retention time thereof is recorded;
(4iii) in need testing solution color atlas, the chromatographic peak of 0.05 times of any A1 of being less than is ignored, in record need testing solution color atlas, each peak area is greater than the impurity peak area of 0.05 times of A1 (this peak area can be expressed as Am in the present invention, m represents that m peak area is greater than the impurity peaks of 0.05 times of A1, and wherein impurity Y is also in these impurity) and retention time;
(4iv) according to the retention time of impurity Y in contrast solution color atlas, determine impurity Y and peak area thereof in need testing solution color atlas, and calculate the assorted chromatographic content of impurity Y.
According to compound of the present invention, in the need testing solution color atlas of wherein said high-performance liquid chromatogram determination, the chromatographic purity of the compounds of this invention can be calculated as follows:
(in above calculating formula, n represents the number of all dirt of according calculation requirement, impurity Y can be a member wherein, Σ An represents the summation of the area of all dirt of according calculation requirement, all has this implication when there is similar statement in the context of the present invention);
Or the chromatographic purity of the compounds of this invention can be calculated as follows:
According to compound of the present invention, in the need testing solution color atlas of wherein said high-performance liquid chromatogram determination, be as the criterion with main peak retention time, calculate the relative retention time of each impurity peaks.
According to compound of the present invention, in the need testing solution color atlas of wherein said high-performance liquid chromatogram determination, be as the criterion with main peak retention time, calculate the relative retention time of each impurity peaks, the relative retention time (RRt) of a certain impurity peaks can be calculated as follows:
According to compound of the present invention, in the need testing solution color atlas of wherein said high-performance liquid chromatogram determination, in the compounds of this invention, the chromatographic content of single impurity can be calculated as follows:
(in above calculating formula, m represents the impurity being numbered m of according calculation requirement, and Am represents the peak area of m impurity, all has this implication when there is similar statement in the context of the present invention, and the chromatographic content of impurity Y also can calculate with above formula);
Or the chromatographic content of single impurity can be calculated as follows in the compounds of this invention:
The chromatographic content of impurity Y also can calculate with above formula.
According to compound of the present invention, in the need testing solution color atlas of wherein said high-performance liquid chromatogram determination, in the compounds of this invention, total chromatographic content of each impurity can be calculated as follows:
Or total chromatographic content of each impurity can be calculated as follows in the compounds of this invention:
Further, the present invention another aspect provides a kind of pharmaceutical composition, wherein comprises compound described in first aspect present invention, and the acceptable auxiliary material of optional pharmacy.
According to pharmaceutical composition of the present invention, wherein comprise with compounds of Formula I:
And the acceptable auxiliary material of pharmacy.
According to pharmaceutical composition of the present invention, wherein comprise the following formula I Y compound of the trace as impurity:
According to pharmaceutical composition of the present invention, it is in high effective liquid chromatography for measuring, disregard the impurity peaks that (or deduction) relative retention time is less than 0.2, disregard any chromatographic peak being less than 0.05 times of A1 in (or deduction) need testing solution color atlas, disregard (or deduction) auxiliary material chromatographic peak, this pharmaceutical composition has the chromatographic purity being greater than 98%, preferably there is the chromatographic purity being greater than 98.5%, preferably there is the chromatographic purity being greater than 99.0%, preferably there is the chromatographic purity being greater than 99.2%, preferably there is the chromatographic purity being greater than 99.3%, preferably there is the chromatographic purity being greater than 99.5%.
According to compound of the present invention, it is in high effective liquid chromatography for measuring, total chromatographic content of impurity Y lower than 0.8%, preferably lower than 0.7%, preferably lower than 0.6%, preferably lower than 0.55%, preferably lower than 0.5%, preferably lower than 0.45%, preferably lower than 0.4%, preferably lower than 0.35%, preferably lower than 0.3%.
According to pharmaceutical composition of the present invention, it is in high effective liquid chromatography for measuring, and in color atlas, total chromatographic content of each impurity peaks is lower than 1.2%, preferably lower than 1.0%, preferably lower than 0.9%, preferably lower than 0.8%, preferably lower than 0.7%, preferably lower than 0.6%, preferably lower than 0.5%, preferably lower than 0.4%.
According to pharmaceutical composition of the present invention, it places the total chromatographic content increased value of each impurity peaks after 150 days and is no more than 1.5%, preferably more than 1.25%, preferably more than 1.0%, preferably more than 0.75%, preferably more than 0.5% under 45 ° of C.
According to pharmaceutical composition of the present invention, wherein said high performance liquid chromatography measures according to Chinese Pharmacopoeia version in 2010 two annex VD high performance liquid chromatography specifications, and described high effective liquid chromatography for measuring mode is:
(1) chromatographic condition and system suitability: be weighting agent with octadecylsilane chemically bonded silica, with methanol-water (70:30) for moving phase, ultraviolet detection wavelength is 278nm, column temperature is 30 ° of C, number of theoretical plate presses 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl isophthalic acid, 4-benzoquinones peak calculates and is not less than 2000;
(2) preparation of test soln: get pharmaceutical composition of the present invention appropriate, accurately weighed, add moving phase and dissolve and quantitatively dilute the solution made about containing 0.2mg formula I in every 1ml, as need testing solution; Separately get impurity Y-shaped IY compound, accurately weighed, add moving phase and dissolve and quantitatively dilute the solution made about containing 0.2mg in every 1ml, as impurity Y solution; Precision measures need testing solution and each 1ml of impurity Y solution, puts in the measuring bottle of same 100ml, is diluted to scale by moving phase, shake up, in contrast solution; Separately get the auxiliary material in pharmaceutical composition of the present invention, accurately weighed, add moving phase dissolving and quantitatively dilute and make the concentration corresponding with 0.2mg/ml formula I concentration, as auxiliary material solution;
(3) chromatogram test: get contrast solution 20 μ l injection liquid chromatography, regulate detection sensitivity, the peak height at principal constituent peak is made to be about 10% of full range, precision measures need testing solution and each 20 μ l of contrast solution again, injection liquid chromatography respectively, record color atlas is to 2.5 times of principal constituent peak retention time; Separately get auxiliary material solution 20 μ l injection liquid chromatography, injection liquid chromatography, record color atlas is to 2.5 times of principal constituent peak retention time;
(4) chromatographic computation:
(4i) record contrast solution color atlas main peak area (this peak area can be expressed as A1 in the present invention) and retention time thereof, and record peak area and the retention time thereof of impurity Y; ;
(4ii) need testing solution color atlas main peak area (this peak area can be expressed as A100 in the present invention) and retention time thereof is recorded; The chromatographic peak that in record auxiliary material solution color atlas, auxiliary material is formed;
(4iii) in need testing solution color atlas, the chromatographic peak corresponding with auxiliary material retention time is disregarded (or disregarding or deduct the impurity peaks that relative retention time is less than 0.2 further), in need testing solution color atlas, the chromatographic peak of 0.05 times of any A1 of being less than is ignored, in record need testing solution color atlas, each peak area is greater than the impurity peak area of 0.05 times of A1 (this peak area can be expressed as Am in the present invention, m represents that m peak area is greater than the impurity peaks of 0.05 times of A1, and wherein impurity Y is also in these impurity) and retention time.
(4iv) according to the retention time of impurity Y in contrast solution color atlas, determine impurity Y and peak area thereof in need testing solution color atlas, and calculate the assorted total chromatographic content of impurity Y.
According to pharmaceutical composition of the present invention, in the need testing solution color atlas of wherein said high-performance liquid chromatogram determination, the chromatographic purity of pharmaceutical composition of the present invention can be calculated as follows:
Or the chromatographic purity of pharmaceutical composition of the present invention can be calculated as follows:
According to pharmaceutical composition of the present invention, in the need testing solution color atlas of wherein said high-performance liquid chromatogram determination, be as the criterion with main peak retention time, calculate the relative retention time of each impurity peaks.
According to pharmaceutical composition of the present invention, in the need testing solution color atlas of wherein said high-performance liquid chromatogram determination, be as the criterion with main peak retention time, calculate the relative retention time of each impurity peaks, the relative retention time (RR) of a certain impurity peaks can be calculated as follows:
According to pharmaceutical composition of the present invention, in the need testing solution color atlas of wherein said high-performance liquid chromatogram determination, the chromatographic content according to impurity single in pharmaceutical composition of the present invention can be calculated as follows:
Or the chromatographic content according to impurity single in pharmaceutical composition of the present invention can be calculated as follows:
According to pharmaceutical composition of the present invention, in the need testing solution color atlas of wherein said high-performance liquid chromatogram determination, the total chromatographic content according to impurity each in pharmaceutical composition of the present invention can be calculated as follows:
Or the total chromatographic content according to impurity each in pharmaceutical composition of the present invention can be calculated as follows:
Again further, the present invention another aspect provides the preparation method of the compounds of this invention, and it comprises the following steps:
(i) by the dissolving crude product of formula I in good solvent;
(ii) in step (i) gained solution, add the first solvent resistant, mixing, then add the second solvent resistant, be heated to 30-40 ° of C and solution is clarified, heat filtering;
(iii) make filtrate slowly be cooled to 10 ° of below C, make crystallization, leach crystallization, dry, to obtain final product.
According to method of the present invention, the good solvent wherein described in step (i) is selected from methylene dichloride, ethyl acetate or its combination.In one embodiment, the feed ratio of described good solvent and formula I chemical combination is 3 ~ 8:1 (v:w), preferably 4 ~ 6:1.
According to method of the present invention, wherein the first solvent resistant described in step (ii) is selected from Skellysolve A, sherwood oil or its combination.In one embodiment, the feed ratio of described first solvent resistant and formula I chemical combination is 2 ~ 10:1 (v:w), preferably 3 ~ 8:1.
According to method of the present invention, wherein the second solvent resistant described in step (ii) is selected from normal hexane, hexanaphthene or its combination.In one embodiment, the feed ratio of described second solvent resistant and formula I chemical combination is 10 ~ 20:1 (v:w), preferably 13 ~ 18:1.
According to method of the present invention, wherein the heating described in step (ii) is heated to 35-37 ° of C.
According to method of the present invention, wherein the cooling described in step (iii) is cooled to 0 ~ 10 ° of C, preferably 0 ~ 5 ° of C, preferably 0 ~ 2 ° of C.
According to method of the present invention, wherein the slowly cooling described in step (iii) is with 0.01 ~ 1 ° of C/min, and preferably the speed of 0.05 ~ 0.5 ° of C/min cools.
According to method of the present invention, wherein the drying described in step (iii) is vacuum-drying under 20 ~ 45 ° of C, preferably at room temperature vacuum-drying.
Again further, the present invention another aspect provides the compounds of this invention or pharmaceutical composition is preparing the purposes in medicine again.
According to purposes of the present invention, wherein said medicine is used for following either side or many-sided disease or illness: cerebro-vascular diseases; Improve brain metabolism, improve mental symptom; The film obstacle activate brain mitochondria respiratory activity, improve the brain energy metabolism of cerebral ischemia, improve glucose utilization rate in brain, ATP in brain produced increase, suppress brain mitochondria to generate lipid peroxide, suppressing caused by brain mitochondria lipid peroxidation; The Brain function damage that chronic cerebral vascular disease and cerebral trauma etc. are caused; Improve subjective symptom, language, anxiety, depression, hypomnesis, the lower degradation mental and behavioral disorders of intelligence; Promote intelligence; Compose brain mitochondria function of living, improve brain energy metabolism, improve brain function; Improve cerebral infarction sequela, apoplexy sequela, cerebral arteriosclerosis cause feels down in spirits, realize low, affective disorder, aphasis etc.; Improve brain metabolism, protection cranial nerve cell; Mitochondriopathy; Anticoagulant, improve microcirculation; Anti-oxidant; Treatment or prevention FRDA (ataxia); Treatment or prevention neurological disorder; And improve the illness relevant to neuronal damage.
In the present invention, described neurological disorder is caused by neurotrauma.More preferably, described neurological disorder is apoplexy.More preferably, described neurological disorder is encephalomyelitis.Preferably, neurological disorder is relevant to mitochondria dysfunction.Preferably, described neurological disorder is relevant to anoxic condition.Preferably, neurological disorder is alcohol withdrawal syndrome or fetal alcohol syndrome.Preferably, neurological disorder is relevant to the neuronal damage caused by bacteriological infection or virus infection.
It is well known that formula I itself has above-mentioned therepic use, therefore the compounds of this invention or pharmaceutical composition have such use equally.
In compound described in first aspect present invention arbitrary embodiment can with other scheme arbitrary combination, also can with pharmaceutical composition described in second aspect in appoint arbitrary embodiment arbitrary combination; Similarly, in pharmaceutical composition described in second aspect present invention arbitrary embodiment can with other scheme arbitrary combination, also can with compound described in first aspect in appoint arbitrary embodiment arbitrary combination; As long as these combinations are not conflicting.
In the present invention, when calculating each impurity peak area sum, this peak area sum can be expressed as Σ An in the present invention, namely meets the peak area sum that peak area is greater than all dirt peak (altogether n) of 0.05 times of A1, disregards or deduct solvent peak, auxiliary material peak.As well known to those skilled in the art, in high performance liquid chromatography, the chromatographic peak that " impurity peaks that relative retention time is less than 0.2 " is normally formed by solvent, therefore can directly deduct these chromatographic peaks in the present invention, and not think that they are the chromatographic peaks in various material of the present invention.
In the present invention, mention the compounds of this invention or pharmaceutical composition " under 45 ° of C, place the total chromatographic content increased value of each impurity peaks after 150 days be no more than 1.5% " refer to the compounds of this invention or pharmaceutical composition be placed in 45 ° of C under place 150 days, the difference disposing the total chromatographic content of each impurity peaks in rear and the front sample of disposal relatively more like this, the total chromatographic content of each impurity peaks (%)-45 ° C after namely each impurity peaks total chromatographic content increased value=45 ° C places 150 days places the total chromatographic content of each impurity peaks (%) before 150 days.Such as, if this bright compound total chromatographic content of each impurity peaks when placing 150 days without 45 ° of C and disposing is 0.6%, and the total chromatographic content of each impurity peaks is 1.0% after measured after place disposal in 150 days through 45 ° of C, then the compounds of this invention " places the total chromatographic content increased value of each impurity peaks after 150 days " under 45 ° of C is 0.4%.
In the present invention, term " main peak ", such as, at " contrast solution color atlas main peak area " and " main peak " mentioned in " need testing solution color atlas main peak area ", represents the look peak-to-peak that in this chromatographic peak, principal constituent formula I is formed.Accordingly, in the present invention, term " impurity peaks " represents except principal constituent formula I and other chromatographic peak that is known or the basic formation of unknown materials, its precondition disregards (or deducting in advance when calculating) " in need testing solution color atlas any chromatographic peak being less than 0.05 times of A1 ", also disregard in need testing solution color atlas due to the test reagent (chromatographic peak that such as solvent produces, such as dosing solvent and moving phase difference) chromatographic peak that produces of the component (such as medicament auxiliary material) that adds especially in the chromatographic peak that produces or composition.
In the present invention, term " each impurity peak area sum " represents the peak area of any one chromatographic peak of 0.05 times of any A1 of being less than " in the need testing solution color atlas " (disregarding the chromatographic peak that solvent or auxiliary material produce equally), they add and.
The present inventor has been found that the RRt of impurity Y is between 0.70 ~ 0.90, preferably between 0.75 ~ 0.85
As well known to those skilled in the art, HPLC method is calculated for content, can usable floor area normalization method computing method, contrast solution computing method can also be used, the present invention uses the latter, with 1% contrast solution for calculating, and this kind of method ratio more accurate in area normalization method.In addition because the difference of different HPLC chromatographic process and condition determination causes the chromatographic behavior of principal constituent and impurity to have nuance, thus cause measurement result variant, this is also that those skilled in the art are acceptable.But those skilled in the art know, as long as chromatographic condition is fixed, the chromatographic behavior of material will be relatively fixing, will be relatively fixing between measurement result; Therefore, for the compounds of this invention, under the chromatographic condition that the present invention specifies, itself and impurity thereof just have relatively-stationary chromatographic behavior.
In the present invention, when carrying out chromatographic determination, the retention time of formula I can be allowed in wider time range, such as can in the scope of 5 ~ 30min, such as can in the scope of 10 ~ 25min, such as in the scope of 10 ~ 25min, can require as long as meet " chromatographic condition and system suitability ".Those skilled in the art are known, for meeting this requirement, can by suitably selecting the specification of chromatographic column and/or regulating the modes such as flow rate of mobile phase to realize, such as operable column diameter is 4.6mm, weighting agent granularity can be 5 μm, its column length can be 15 ~ 30cm (such as about 15cm, 20cm, 25cm, 30cm), and flow rate of mobile phase can regulate in the scope of 0.8 ~ 1.5ml/min, can be easy to realize above-mentioned requirements by regulating column length and flow rate of mobile phase.This is conventional technical ability for this area particularly pharmaceutical analysis those skilled in the art.In the present invention, when carrying out chromatographic determination, if not otherwise specified, use the chromatographic column that filler is octadecylsilane chemically bonded silica, namely usually said C18 post, the granularity of weighting agent is 5 μm, but the length 25cm of post.
In the present invention, the active constituents of medicine formula I mentioned, its chemistry 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl isophthalic acid by name, 4-benzoquinones, molecular formula C
19h
30o
5molecular weight 338.44, usually be also called Chinese mugwort soil also benzoquinones (Idebenone), be a kind of effective cerebro-vascular diseases medication, this medicine is brain metabolism, mental symptom improves medicine, brain mitochondria respiratory activity can be activated, improve the brain energy metabolism of cerebral ischemia, improve glucose utilization rate in brain, ATP in brain is produced to be increased, suppress brain mitochondria to generate lipid peroxide, suppress the film obstacle caused by brain mitochondria lipid peroxidation.This product toxic side effects is low, LD50 mouse, rat >10000mg/kg, rat 20mgkgd oral half a year, and dog 100mgkgd has no overt toxicity reaction for oral 1 year, without teratogenesis, carcinogenic, mutagenesis.According to document announcement, 6 routine apoplexy sequela patient oral meal this product 30mg, Tmax is 3.31 hours, and Cmax is 290 μ gml, and eliminating the transformation period is 7.69 hours, does not detect original shape medicine, be metabolite in urine, excretion rate 7.32% in urine in 24 hours.This medicine indication is clinically: the Brain function damage that chronic cerebral vascular disease and cerebral trauma etc. are caused, can improve subjective symptom, language, anxiety, depression, hypomnesis, the lower degradation mental and behavioral disorders of intelligence.The each 30mg of oral adult (1), every day 3 times, one after each meal.Its formulation products is generally tablet and every sheet amount is generally 30mg.The compounds of this invention is orange-yellow to orange crystal, crystalline powder or block, odorless; Very easily be dissolved in chloroform, methyl alcohol or dehydrated alcohol, be soluble in ethyl acetate, be insoluble in normal hexane, water-soluble hardly.mp52~55°C。Promote medicine for intelligence, brain mitochondria function of living can be composed, improve brain energy metabolism, improve brain function.What cause cerebral infarction sequela, apoplexy sequela, cerebral arteriosclerosis feels down in spirits, realizes low, affective disorder, aphasis etc. and be improved effect.
The compounds of this invention is the medicine uniquely at present with brain metabolism and the dual improvement of mental symptom, at present temporarily without direct competitive opponent; And it is cerebral metabolism, nerve cell protection agent, mitochondriopathy effectively, anticoagulant, improve microcirculation, effective antioxygenation, FRDA (ataxia) choice drug.
In addition, the compounds of this invention or pharmaceutical composition also can be used for treating neurological disorder, and for improving the illness relevant to neuronal damage.
Preferably, described neurological disorder is caused by neurotrauma.More preferably, described neurological disorder is apoplexy.More preferably, described neurological disorder is encephalomyelitis.
Preferably, described neurological disorder is relevant to mitochondria dysfunction.Preferably, described neurological disorder is relevant to anoxic condition.Preferably, described neurological disorder is alcohol withdrawal syndrome or fetal alcohol syndrome.Preferably, described neurological disorder is relevant to the neuronal damage caused by bacteriological infection or virus infection.
Embodiment
Following embodiment is intended to some preferred embodiment of the present invention is described, and limitation of the present invention is not disclosed by the content of these embodiments.
In various tests hereafter, to various material (crude product of formula I or highly finished product, impurity Y, intermediate, add the pharmaceutical composition etc. of auxiliary material), all adopt high-performance liquid chromatogram determination, specifically carry out according to Chinese Pharmacopoeia version in 2010 two annex VD high performance liquid chromatography specifications, measure mode as follows:
(1) chromatographic condition and system suitability: the chromatographic column (4.6 × 250mm with octadecylsilane chemically bonded silica being weighting agent, 5 μm), with methanol-water (70:30) for moving phase, flow velocity 1.0ml/min, ultraviolet detection wavelength is 278nm, and column temperature is 30 ° of C, and number of theoretical plate presses 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl isophthalic acid, 4-benzoquinones peak calculates and is not less than 2000;
(2) preparation of test soln: get testing compound, intermediate or pharmaceutical composition in right amount, accurately weighed, add moving phase and dissolve and quantitatively dilute the solution made and about contain 0.2mg formula I or concentration suitable with it in every 1ml, as need testing solution; Precision measures this trial-product 1ml, puts in 100ml measuring bottle, is diluted to scale by moving phase, shake up, as the contrast solution of principal constituent; Separately get impurity Y-shaped IY compound, accurately weighed, add moving phase and dissolve and quantitatively dilute the solution made about containing 0.2mg in every 1ml, as impurity Y solution; Precision measures need testing solution and each 1ml of impurity Y solution, puts in the measuring bottle of same 100ml, is diluted to scale by moving phase, shake up, as the principal constituent-impurity contrast solution of contained I and formula IY compound; The auxiliary material of separately getting it filled in compositions, accurately weighed, add moving phase dissolving and quantitatively dilute and make the concentration corresponding with 0.2mg/ml formula I concentration, as auxiliary material solution;
(3) chromatogram test: get contrast solution 20 μ l injection liquid chromatography, regulate detection sensitivity, the peak height at principal constituent peak is made to be about 10% of full range, precision measures need testing solution and each 20 μ l of various contrast solution again, injection liquid chromatography respectively, record color atlas is to 2.5 times of principal constituent peak retention time; Separately get auxiliary material solution 20 μ l injection liquid chromatography, injection liquid chromatography, record color atlas is to 2.5 times of principal constituent peak retention time;
(4) chromatographic computation:
(4i) contrast solution color atlas main peak area (this peak area can be expressed as A1 in the present invention) and retention time thereof is recorded;
(4ii) need testing solution color atlas main peak area (this peak area can be expressed as A100 in the present invention) and retention time thereof is recorded; The chromatographic peak that in record auxiliary material solution color atlas, auxiliary material is formed;
(4iii) in need testing solution color atlas, the chromatographic peak corresponding with auxiliary material retention time is disregarded (or disregarding or deduct the impurity peaks that relative retention time is less than 0.2 further), in need testing solution color atlas, the chromatographic peak of 0.05 times of any A1 of being less than is ignored, in record need testing solution color atlas, each peak area is greater than impurity peak area (this peak area can be expressed as Am in the present invention, and m represents that m peak area is greater than the impurity peaks of 0.05 times of A1) and the retention time thereof of 0.05 times of A1.
The chromatographic purity of testing compound, impurity Y, intermediate or pharmaceutical composition can be calculated as follows:
Or the chromatographic purity of testing compound, intermediate or pharmaceutical composition can be calculated as follows:
In the need testing solution color atlas of testing compound, impurity Y, intermediate or pharmaceutical composition high-performance liquid chromatogram determination, be as the criterion with main peak retention time, calculate the relative retention time of each impurity peaks, the relative retention time (RRt) of a certain impurity peaks can be calculated as follows:
In the need testing solution color atlas of the high-performance liquid chromatogram determination of testing compound, impurity Y, intermediate or pharmaceutical composition, the chromatographic content of single impurity can be calculated as follows:
Or the chromatographic content of single impurity can be calculated as follows in testing compound, impurity Y, intermediate or pharmaceutical composition:
In testing compound, impurity Y, intermediate or pharmaceutical composition, total chromatographic content of each impurity can be calculated as follows:
Or total chromatographic content of each impurity can be calculated as follows in testing compound, impurity Y, intermediate or pharmaceutical composition:
embodiment 1: prepare the compounds of this invention
The general reaction process of the present embodiment is as follows:
The preparation of (i), 10-acetoxyl group capric acid (2)
In reaction flask, add sodium hydroxide 115g (2.875mol), water 40ml, Viscotrol C 150g and cresols 45g, stir (initial reaction stage has phenomenon of foaming, and needs rapid stirring) in 180 ~ I95 ° of C, backflow 3h.Volatile matter is removed in distillation, adds water 1.5L, be adjusted to pH acidity, be heated to boil with 50% sulfuric acid (containing Congo red) in residuum.Oil-yielding stratum is divided, washed with diethylether, anhydrous sodium sulfate drying with preheated separating funnel.Filter, filtrate recycling design, adds diacetyl oxide 350ml in residuum, and after heated and stirred backflow 5 ~ 6h, fallen by reactant in the appropriate ice of people, placement is spent the night.With ether extraction several, merge organic layer, washing, anhydrous sodium sulfate drying.Filter, after filtrate recycling design, underpressure distillation, collects bp136 ~ 160 ° C/26.7Pa fraction, second time underpressure distillation, collects bp140 ~ 146 ° C/26.7Pa fraction, last underpressure distillation, collect bp140 ~ 142 ° C/26.7Pa fraction, obtain (2), yield 45.6%.
(ii), the preparation of 10-acetoxyl group decanoyl chloride (3)
In reaction flask, add 10-acetoxyl group capric acid (2), the methylene dichloride of 230g (1.0mol), after stirring and dissolving, add phosphorus pentachloride (1.2mol, available phosphorus trichloride replaces) carefully, in stirring at room temperature 2h.Reaction is finished, recycling design, underpressure distillation, collects bp135 ~ 138 ° C/66.7Pa fraction, obtains (3).
1H-NMR(CDCl
3)：δ4.03(t,2H,J=7Hz，CH
2O)，2.91(t，2H，J=6Hz，CH
2CO)，2.02(s，3H，COCH
3)，1.1~1.8(m，14H，7×CH
2)。
(iii), the preparation of 6-(10-hydroxyl-1-oxodecyl)-2,3-dimethoxy-5-cresylol (5)
In dry reaction bottle, add (3) (0.11mol), 3,4,5-trimethoxytoluene (0.1mol) and dry 1,2-ethylene dichloride 300ml solution, under 0 ~ 5 ° of C stirs, adds people's anhydrous alchlor powder 28.lg (0.207mol), continue to stir 2h in 5 ° of C, 20 ° are stirred 70h.Reaction is finished, and is poured into by reaction solution in appropriate frozen water, with dichloromethane extraction several, merges organic layer, washing, anhydrous sodium sulfate drying.Filter, filtrate recycling design, obtains oil residue (4).Sodium hydroxide 0.118mol and methyl alcohol 150ml solution is added, in stirring at room temperature 2h in (4).After recycling design, residuum is poured in suitable quantity of water, crystallization, dry, obtain crude product (5).With ether-hexane recrystallization, obtain colorless needle crystals (5), yield 79%, mp67 ° of C.
1H-NMR(CDCl
3):δ1.2~1.9(m,14hH,7×CH
2)，2.41(s,3H，Ar-CH
3),2.86(t，2H，J=7Hz，CH
2CO)，3.61(t，2H，J=7Hz，CH
2OH)，3.84，3.87(s，6H，2×CH
3O)，6.27(s，1H，Ar-H)，9.92(s，1H，Ar-OH)。
(iv), the preparation of 6-(10-acetoxyl group decyl)-2,3-dimethoxy-5-cresylol (6)
In reaction flask, add (5) (0.05mol), 5%Pd-C2g, glacial acetic acid 150ml is (containing the HClO of 70%
4(0.3ml)), under room temperature normal pressure, logical hydrogen hydrogenation 24h.Reaction is finished, and filters, and reclaims catalyzer (applying mechanically), filtrate decompression recycling design.To in oil residue, add methylene dichloride 150ml, 5% sodium hydrogen carbonate solution 100ml, stir, leave standstill, separate organic layer, anhydrous sodium sulfate drying.Filter, after filtrate recycling design, obtain colorless oil residue (6), yield 97%.
1H-NMR(CDC1
3):δ6.25(s，1H，Ar-H)，5.80(s，1H，Ar-OH)，4.0G(t，2H，J=6Hz，CH
2O)，3.85(8，6H，2×CH
3O)，3.81，2.57(t，2H，J=7Hz，Ar-CH
2)，2.23(s，3H，Ar-CH
3)，2.03(s，3H，CH
3CO)，1.2~1.8(m，16H，CH
2)。
(v), 6-(10-hydroxydecyl)-2,3-preparation of dimethoxy-5-cresylol (7)
In reaction flask, add (6) 0.101mol, sodium hydroxide 0.101mol and methyl alcohol 300ml solution, stir 24h in 5 ° of C.Reaction is finished, recycling design.Cooling, adds methylene dichloride 100ml, water 100ml in residuum, stirs, separates organic layer, anhydrous sodium sulfate drying, and filter, filtrate recycling design, obtains colorless oil residue (7), yield 95%.
1H-NMR(CDCl
3):δ6.24(s,1H,Ar-H),5.86(s,2H，Ar-OH)，3.84(s，6H，2×CH
3O)，3.80，3.61(t，2H，J=7Hz，Ar-CH
2)。
(vi), 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl isophthalic acid, the synthesis of 4-benzoquinones (1)
In reaction flask, add freshly prepd FremyShi salt (that is, nitroso-group disulfonic acid potassium [ON (SO
3k)
2]) 16g, (7) 0.022mol, DMF-water-methanol (1:1:1) 100ml and 0.17mol/L potassium dihydrogen phosphate 10ml, stir 72h in 5 ° of C.Reaction is finished, and add water 200ml, with dichloromethane extraction several, merges organic layer, washing, anhydrous sodium sulfate drying.Filter, filtrate recycling design, cooling, separate out solid, dry, obtain (1), yield 83%.IR(KBr):3550(OH),1650,1640cm
-1。
1h-NMR (CDCl
3): δ 3.97 (s, 6H, 2 × CH
3o), 2.0 (s, 3H, CH
3), 2.43 (t, 2H, J=7Hz, quinone ring-CH
2), 3.63 (t, J=6Hz, CH
3o), 1.2 ~ 1.3 (m, 14H, 7 × CH
2).MS:m/z338(M
+),320,308,195。This crude product measures according to HPLC method of the present invention, and chromatographic purity 98.2%, the chromatographic content of maximum single contaminant is 1.27%.
(vii), 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl isophthalic acid, 4-benzoquinones (1) refining
Step (i) products therefrom 1.0g is placed in the glass crystallizer of the jacketed of a 200mL, at room temperature in adding in crystallizer, formula I is dissolved completely 5mL methylene dichloride (can be described as good solvent in the present invention, namely formula I is had to the solvent of better solubleness).In crystallizer, temperature refrigerating/heating circulator bath carries out temperature programmed control (initial temperature is 24-27 ° of C, mentions that " room temperature " also refers in 24-27 ° of C temperature range when not indicating especially), and the interior magnetic stirring apparatus of crystallizer stirs.Under room temperature, 5mL sherwood oil (be can be described as the first solvent resistant in the present invention, solvent resistant refers to solvent formula I to bad solubleness) add in crystallizer, mixing, add 15ml normal hexane (can be described as the second solvent resistant in the present invention) again, settled solution becomes muddy, and heated solution temperature makes solution become clarification to 35-37 ° of C.By clear liquor filtered while hot, filtrate is placed in the 35-37 ° of C crystallizer of another 200mL, constant temperature 30 minutes, and is cooled to 0-2 ° of C and slowly crystallization with the speed of 0.1 ° of C/min, filters, washs 2 times by the second solvent resistant.Lucifuge, vacuum-drying (vacuum tightness 50mbar) 24h under room temperature, obtaining yellow needles is formula I 0.937g, and yield is 91.7%.mp54~54.5°C。
embodiment 2: prepare the compounds of this invention
Use embodiment 1 step (vi) products therefrom, the method according to embodiment 1 step (vii) is carried out, unlike the use of: 5mL methylene dichloride is good solvent, 5mL sherwood oil is the first solvent resistant, 15ml hexanaphthene is the second solvent resistant; Crystallization speed of cooling is 0.05 ° of C/min.Yield is 91.3%.mp54.5~55°C。
embodiment 3: prepare the compounds of this invention
Use embodiment 1 step (vi) products therefrom, the method according to embodiment 1 step (vii) is carried out, unlike the use of: 4mL methylene dichloride is good solvent, 7mL Skellysolve A is the first solvent resistant, 13ml normal hexane is the second solvent resistant; Crystallization speed of cooling is 0.5 ° of C/min.Yield is 90.9%.mp54~54.5°C。
embodiment 4: prepare the compounds of this invention
Use embodiment 1 step (vi) products therefrom, the method according to embodiment 1 step (vii) is carried out, unlike the use of: 4mL methylene dichloride is good solvent, 6mL Skellysolve A is the first solvent resistant, 13ml hexanaphthene is the second solvent resistant.; Crystallization speed of cooling is 0.2 ° of C/min.Yield is 90.8%.mp54~55°C。
embodiment 5: prepare the compounds of this invention
Use embodiment 1 step (vi) products therefrom, the method according to embodiment 1 step (vii) is carried out, unlike the use of: 4mL ethyl acetate is good solvent, 5mL sherwood oil is the first solvent resistant, 13ml normal hexane is the second solvent resistant.Yield is 91.5%.mp53.5~54.5°C。
embodiment 6: prepare the compounds of this invention
Use embodiment 1 step (vi) products therefrom, the method according to embodiment 1 step (vii) is carried out, unlike the use of: 4mL ethyl acetate is good solvent, 4mL sherwood oil is the first solvent resistant, 15ml hexanaphthene is the second solvent resistant.Yield is 91.7%.mp54~54.5°C。
embodiment 7: prepare the compounds of this invention
Use embodiment 1 step (vi) products therefrom, the method according to embodiment 1 step (vii) is carried out, unlike the use of: 4mL ethyl acetate is good solvent, 3mL Skellysolve A is the first solvent resistant, 18ml normal hexane is the second solvent resistant.Yield is 91.1%.mp54~54.5°C。
embodiment 8: prepare the compounds of this invention
(i), preparation 6-(10-acetoxyl group-1-oxodecyl)-2,3-dimethoxy-5-methylphenols
In the 5L reaction flask of dried and clean, mechanical stirring is installed, thermometer, 1 is added under stirring, 2-ethylene dichloride 2000ml, 3, 4, 5-trimethoxytoluene 182g (about 1mol), 10-acetoxyl group decanoyl chloride 273g (about 1.5mol), add fresh aluminum trichloride (anhydrous) powder 333g (about 2.5mol) again, reaction is started after ice-water bath is cooled to 5 ° of C, control temperature 0 ~ 5 ° of C, react after 4 days, reaction terminates, in impouring 5000ml frozen water, separate organic layer, add 1 again, 2-ethylene dichloride 2000ml extracts, merge organic layer, wash three times with water, each 1000ml, finally, desolventizing with steaming after anhydrous sodium sulfate drying, activated carbon decolorizing, obtaining colorless oil 311g, be 6-(10-acetoxyl group-1-oxodecyl)-2,3-dimethoxy-5-methylphenol, calculating its molar yield is 81.6%, HPLC chromatographic purity 97.8%.
(ii) 6-(10-acetoxyl group decyl)-2,3-dimethoxy-5-methylphenol, is prepared
In 5L hydriding reactor, add the 6-(10-acetoxyl group-1-oxodecyl)-2 that 380g is obtained by step (1), the 5%Pd-C (quality is 5% of 6-(10-acetoxyl group-1-oxodecyl)-2,3-dimethoxy-5-methylphenols) of 3-dimethoxy-5-methylphenol (about 1.0mo1), DMF3000ml, 19g.Under normal temperature and pressure, shortening stirring reaction is to no longer inhaling hydrogen, then adds dewatering agent DCC206g (about 1mol), continues stirring reaction 7h under normal temperature and pressure, and under continuing normal temperature and pressure, more than catalytic hydrogenation 10h is to no longer inhaling hydrogen.After reaction terminates, filtration catalizer, filtrate concentrates to obtain light oil 352g, is 6-(10-acetoxyl group decyl)-2,3-dimethoxy-5-methylphenol;
(iii), be hydrolyzed
Sodium hydroxide 40g (1mol), methyl alcohol 1200ml is added in above-mentioned oily matter, be cooled to 5 ° of C, after stirring 24h, underpressure distillation is except desolventizing, then adds the dissolving of 1500ml methylene dichloride, washes 3 times, be evaporated to dry after anhydrous sodium sulfate drying, obtain colorless oil 310.5g and be 6-(10-hydroxy decyl)-2,3-dimethoxy-5-methylphenol, calculating molar yield is 95.9%, HPLC chromatographic purity 98.2%, the chromatographic content of maximum single contaminant is 0.79%.
(iv), 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl isophthalic acid is prepared, 4-benzoquinones
6-(10-hydroxydecyl)-2,3-dimethoxy-5-methylphenol 324.5g (about 1mol), DMF3000ml, Cu (salen) 10g (quality is 3% of reaction substrate) is added in 5L stills for air blowing.Temperature control 35 ~ 40 ° of C, logical purity oxygen carries out catalytic oxidation, and about about 70h, TLC track to the disappearance of raw material point.Reacted rear elimination catalyzer, be evaporated to dry, then added water 2000ml and dilute, with dichloromethane extraction 2 times, each 1000ml, organic layer merges after washing 3 times, each 1000ml, and anhydrous sodium sulfate drying, underpressure distillation are to dry.With normal hexane-ether mixed solvent recrystallization, obtaining tangerine look needle-like product is formula I, yield 75%.It measures according to HPLC method of the present invention, chromatographic purity 98.73%, the chromatographic content of maximum single contaminant be 0.59% (RRt<0.7), RRt about 0.8 the chromatographic content of impurity be 0.56%.
V () uses above step (iv) products therefrom, the method with reference to embodiment 1 step (vii) is carried out, and uses: 5mL methylene dichloride is good solvent, 5mL sherwood oil is the first solvent resistant, 15ml normal hexane is the second solvent resistant.
Yield is 91.7%.mp54~54.5°C。
embodiment 9: prepare the compounds of this invention
Use embodiment 8 step (iv) products therefrom, the method with reference to embodiment 1 step (vii) is carried out, unlike the use of: 4mL ethyl acetate is good solvent, 3mL Skellysolve A is the first solvent resistant, 18ml normal hexane is the second solvent resistant.
Yield is 92.1%.mp54.5~55.0°C。
embodiment 10: prepare the compounds of this invention
(i), preparation 6-(10-acetoxyl group-1-oxodecyl)-2,3-dimethoxy-5-methylphenols
In the 5L reaction flask of dried and clean, mechanical stirring is installed, thermometer, 1 is added under stirring, 2-ethylene dichloride 2000ml, 3, 4, 5-trimethoxytoluene 182g (about 1mol), 10-acetoxyl group decanoyl chloride 273g (about 1.5mol), add fresh anhydrous aluminium acetate powder 390g (about 2.5mol) again, reaction is started after ice-water bath is cooled to 5 ° of C, temperature control 0 ~ 5 ° of C, react after 4 days, terminate reaction, in impouring 5000ml frozen water, separate organic layer, add 1 again, 2-ethylene dichloride 2000ml extracts, merge organic layer, wash 3 times, each 1000ml, organic layer is through anhydrous sodium sulfate drying, activated carbon decolorizing, steaming desolventizes, obtain colorless oil, yield 87.8%, HPLC chromatographic purity 97.4%.
(ii) 6-(10-acetoxyl group decyl)-2,3-dimethoxy-5-methylphenol, is prepared
In 5L hydriding reactor, add the 5%Pd-C (quality is 7% of reaction substrate) of 6-(10-acetoxyl group-1-oxodecyl)-2,3-dimethoxy-5-methylphenols 380g (about 1.0mol), DMF3000ml, 26.6g.Under normal temperature and pressure, shortening stirring reaction is to no longer inhaling hydrogen, then adds dewatering agent DCC206g (about 1mol), continues stirring reaction 7h under normal temperature and pressure, and under continuing normal temperature and pressure, more than catalytic hydrogenation 10h is to no longer inhaling hydrogen.Rear filtration catalizer is finished in reaction, and filtrate is concentrated to obtain light oil 356g, is 6-(10-acetoxyl group decyl)-2,3-dimethoxy-5-methylphenol.
(iii), be hydrolyzed
Sodium hydroxide 40g (1mol), methyl alcohol 1200ml is added in above-mentioned oily matter, be cooled to 5 ° of C, after stirring 24h, solvent is removed in underpressure distillation, add 1500ml methylene dichloride again to dissolve, wash 3 times, each 1000ml, be evaporated to dry after anhydrous sodium sulfate drying, obtain colorless oil 313g and be 6-(10-hydroxy decyl)-2,3-dimethoxy-5-methylphenol, calculate molar yield 96.2%, HPLC chromatographic purity 98.2%, the chromatographic content of maximum single contaminant is 0.86%.
(iv) in 5L stills for air blowing, add 6-(10-hydroxy decyl)-2,3-dimethoxy-5-methylphenol 324.5g (about 1mol), DMF3000ml, Cu (salen) 10g (quality is 3% of reaction substrate).Temperature control 35 ~ 40 ° of C, logical oxygen: the mixed gas of nitrogen=1:1 carries out catalytic oxidation, about about 70h, TLC track to the disappearance of raw material point.React rear elimination catalyzer, be evaporated to dry, add ordinary water 2000ml again to dilute, with dichloromethane extraction (1000ml × 2), organic layer merges after washing 3 times, each 1000ml, after anhydrous sodium sulfate drying, underpressure distillation is to dry, with normal hexane-ether mixed solvent recrystallization, obtain tangerine look needle-like product and be formula I end product, molar yield 75.7%.Measure according to HPLC method of the present invention, chromatographic purity 98.77%, the chromatographic content of maximum single contaminant is 0.57%(RRt<0.7), the chromatographic content of RRt about 0.8 impurity is 0.53%.
V () uses above step (iv) products therefrom, the method with reference to embodiment 1 step (vii) is carried out, and uses: 5mL methylene dichloride is good solvent, 8mL Skellysolve A is the first solvent resistant, 13ml normal hexane is the second solvent resistant.
Yield is 90.9%.mp54~54.5°C。
embodiment 11: prepare the compounds of this invention
Use embodiment 10 step (iv) products therefrom, the method with reference to embodiment 1 step (vi) is carried out, unlike the use of: 6mL ethyl acetate is good solvent, 5mL sherwood oil is the first solvent resistant, 15ml hexanaphthene is the second solvent resistant.
Yield is 92.3%.mp54.0~54.5°C。
reference examples 1: preparation I compound
Take 1.0g embodiment 1 step (vi) products therefrom in the glass crystallizer of the jacketed of a 200mL, measure 5mL methylene dichloride with graduated cylinder and add in crystallizer under room temperature formula I is dissolved completely.In crystallizer, temperature carries out temperature programmed control by a refrigerating/heating circulator bath, stirs and adopts magnetic stirring apparatus.The normal hexane measuring 35mL again adds in crystallizer under room temperature, and settled solution becomes muddy.Heated solution temperature is to 36 ° of C, and dirty solution becomes clarification.By clear liquor filtered while hot, filtrate is placed in the crystallizer of another 200mL, and now solution temperature slightly reduces, then continues to be heated to 36 ° of C, constant temperature 30 minutes, and is cooled to 0 ° of C with the speed of 0.1 ° of C/min.Along with the reduction of temperature, formula I crystal is slowly separated out, and filters, washing (using n-hexane 2 times).Under room temperature, lucifuge, vacuum-drying (vacuum tightness 50mbar) 24h, obtain 0.795g needle-like crystal product, and yield is 79.5%.
reference examples 2: preparation I compound
Take 2.0g embodiment 8 step (iv) products therefrom in the glass crystallizer of the jacketed of a 200mL, measure 10mL methylene dichloride with graduated cylinder and add in crystallizer under room temperature formula I is dissolved completely.In crystallizer, temperature carries out temperature programmed control by a refrigerating/heating circulator bath, stirs and adopts magnetic stirring apparatus.The normal hexane measuring 70mL again adds in crystallizer under room temperature, and settled solution becomes muddy.Heated solution temperature is to 36 ° of C, and dirty solution becomes clarification.By clear liquor filtered while hot, filtrate is placed in the crystallizer of another 200mL, and now solution temperature slightly reduces, then continues to be heated to 36 ° of C, constant temperature 30 minutes, and is cooled to 0 ° of C with the speed of 0.1 ° of C/min.Along with the reduction of temperature, end product formula I crystal is slowly separated out, and filters, washing (using n-hexane 2 times).Under room temperature, lucifuge, vacuum-drying (vacuum tightness 50mbar) 24h, obtain 1.58g needle-like crystal product, and yield is 79%.
prepare the method 1 of impurity Y:
Example 1 step I) gained end product (crude product for formula I) is starting material, uses to prepare liquid phase process and obtain impurity Y.Preparing chromatography system used: chromatographic column is Pure2811-C18,250mm × 8mm, particle diameter, 20 ~ 40um; Moving phase: methyl alcohol: water=70:30 (v/v); Determined wavelength 254nm; Sampling volume 2.5mL; Sample size 100mg; Column temperature is room temperature.Monitor after entering product sample introduction, collect the elutriant at the maximum contaminant peak except the effluent liquid of principal constituent peak formula I; Concentrate after desolventizing, gained resistates repeats preparative liquid chromatography wash-out again, intercepts the elutriant at above-mentioned Impurity elution peak; Repeat preparative chromatography purifying again 1 time, the product obtained analysis mode liquid chromatography for measuring chromatographic purity mentioned above, reaches 99.2%.
Structural Identification: FAB mass spectrum (m/z): 309 (M+H)
+.Ultimate analysis: measured value: C-70.11%, H-9.16%, O-20.73%.M.W.=308.31。
1H-NMR(DMSO-D
6，400mHz):δ1.26(2H,m),1.29(10H,m),1.43(2H,m),1.54(2H,m),2.41(2H,q),2.50(3H,s),3.50(2H,t),3.65(1H,s),3.80(3H,s),8.08(1H,s)。
13C-NMR(DMSO-D
6，400mHz):δ12.7(1C),21.1(1C),25.6(1C),27.2(1C),29.5(5C),32.2(1C),58.1(1C),62.8(1C),108.2(1C),142.8(1C),144.5(1C),161.1(1C),182.6(1C),187.2(1C)。Analyze accordingly, gained impurity Y is the compound with formula IY structure mentioned above.
In addition, the present inventor has been found that in test the formula I bulk drug for each crowd of the present invention preparation, and it is in HPLC described herein analyzes, the peak area of impurity Y the maximum normally in all dirt in color atlas.In addition, the present inventor also finds, the retention time of the impurity Y in the product formula IY prepared by above-mentioned preparative liquid chromatography method and formula I bulk drug is completely the same, namely prove the preparation-obtained molecular weight of above-mentioned preparative liquid phase method be 308.4 material and bulk drug in acrobatics be same substance.
The present inventor is in other test, and find to use C/MS (liquid chromatography-mass spectrography) (LC-ESI-MS) coupling, measure impurity Y in bulk drug, in ESI-MS collection of illustrative plates, show molecular weight is 308.3, consistent with the molecular weight of the impurity Y prepared especially above.
composition example 1: prepare pharmaceutical composition of the present invention (tablet)
Formula (1000 amounts): embodiment 1 step (vii) gained end product 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl isophthalic acid, 4-benzoquinones 30g, one Lactose hydrate 40g, Microcrystalline Cellulose 30g, PEG4000 consumption 9g, sodium starch glycolate 9g, Magnesium Stearate 1g, colloid silica 1g.
Method for making: the activeconstituents of recipe quantity, lactose, Microcrystalline Cellulose and 4.5g sodium starch glycolate are mixed, pulverizes and cross 80 mesh sieves; Add and pulverize in advance and cross PEG4000 and the colloid silica of 80 mesh sieves, mix, dry method is pressed into the sheet that sheet footpath is 20mm, then is smashed by this sheet and cross 20 mesh sieves; Mixed with Magnesium Stearate by gained material, compressing tablet, every sheet is 30mg containing activeconstituents, to obtain final product.
composition example 2: prepare pharmaceutical composition of the present invention (capsule)
Formula (1000 amounts): embodiment 8 step (v) gained end product 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl isophthalic acid, 4-benzoquinones 30g, one Lactose hydrate 38g, Microcrystalline Cellulose 30g, Magnesium Stearate 1g, colloid silica 1g.
Method for making: each mixing of materials of recipe quantity is even, is filled in Capsules, and every is 30mg containing activeconstituents, to obtain final product.
test example 1: the chromatographic characteristics measuring each material
Each embodiment, reference examples, routine formula I (the final formula I that such as embodiment 1 obtains in step (vii) obtained in a final step of composition above, the final formula I that such as embodiment 8 obtains in step (v)) or preparation compositions (measure the content of test capsule shell during capsule, and do not consider capsule shell), measure according to HPLC method of the present invention, the chromatographic purity of compound, the RRt of impurity Y and the parameter such as the chromatographic content of this impurity, total chromatographic content of each impurity are in table 1.
In addition, the formula I obtain above each embodiment, reference examples, composition example in a final step or pharmaceutical composition are sealed in Brown Glass Brown glass bottles and jars only, place 150 days under 45 ° of C, measure the total chromatographic content increased value of each impurity peaks, namely the total chromatographic content of each impurity peaks (%) after 45 ° of C place 150 days deducts 45 ° of C and places the total chromatographic content of each impurity peaks (%) the gained difference before 150 days, the results are shown in Table 1.
Table 1:
* represent in the color atlas of this material, except impurity Y peak, also have the impurity peaks of a RRt=0.829, total chromatographic content of two impurity peaks is 0.25%.
From table result, the compounds of this invention or composition have lower specific impurities and total impurities, and the compounds of this invention and composition also lower in high-temperature treatment rear impurity increasing amount.
In addition, contriver uses this polarity of iso-pentane little solvent same with Skellysolve A or sherwood oil to use as the first solvent resistant in the step (vii) that embodiment 1 ~ 5 is respective, in each product of result display gained, impurity Y chromatographic content is all more than 0.7%, and total chromatographic content of each impurity is more than 1.3%.
In addition, contriver uses pentamethylene or this polarity of the normal heptane solvent suitable with hexanaphthene with normal hexane to use as the second solvent resistant in the respective step (vii) of embodiment 1 ~ 8, in each product of result display gained, impurity Y chromatographic content is all more than 0.75%, and total chromatographic content of each impurity is more than 1.4%.
In addition, contriver uses the suitable solvent of propyl carbinol or this polarity of dehydrated alcohol and methylene dichloride or ethyl acetate to use as good solvent in the respective step (vii) of embodiment 1 ~ 4, in each product of result display gained, impurity Y chromatographic content is all more than 0.7%, and total chromatographic content of each impurity is more than 1.4%.
In addition, contriver is in the step (vii) that embodiment 1 ~ 3 is respective, only use the first solvent resistant and need not the second solvent resistant, the first solvent resistant by the second solvent resistant equivalent substitutes, in each product of result display gained, impurity Y chromatographic content is all more than 0.65%, and total chromatographic content of each impurity is more than 0.9%.
In addition, contriver is in the step (vii) that embodiment 1 ~ 2 is respective, only use the second solvent resistant and need not the first solvent resistant, the second solvent resistant by the first solvent resistant equivalent substitutes, in each product of result display gained, impurity Y chromatographic content is all more than 0.6%, and total chromatographic content of each impurity is more than 1.1%.
In addition, contriver finds, in each embodiment stated on the invention, when repeatedly repeating its final re-crystallization step and making the chromatographic content of impurity Y reach below 0.015%, the compounds of this invention yield can reach less than 65%, and yield can more than 85% when allowing that the chromatographic content of impurity Y reaches more than 0.02%.Therefore in an example of the present invention, the lower limit of impurity Y can be 0.02%.
test example 2: measure the performance with different chromatographic characteristics material
Some products obtained in foregoing embodiments (such as embodiment 1 step (vi) product, embodiment 8 step (iv) product, embodiment 10 step (iv) product) are done further recrystallization process, solvent for use is shown in following table 2, obtains different recrystallized product.The concrete mode of recrystallization is roughly, in the crystallizer of 35-37 ° of C, treating material is dissolved in good solvent (the formula I solvent that solubleness is high) wherein, add solvent resistant (the formula I solvent that solubleness is low) more wherein, mix, filtered while hot, filtrate is incubated 30 minutes, be cooled to 0-2 ° of C and slowly crystallization with the speed of 0.1 ° of C/min again, filter, wash 2 times by solvent resistant.Under room temperature, lucifuge, vacuum-drying (vacuum tightness 50mbar) 24h, to obtain final product.Repeat crystallization if desired.
In addition, the formula I that above each embodiment, reference examples and above-mentioned recrystallization process obtain is sealed in Brown Glass Brown glass bottles and jars only, place 150 days under 45 ° of C, measure the total chromatographic content increased value of each impurity peaks, namely the total chromatographic content of each impurity peaks (%) after 45 ° of C place 150 days deducts 45 ° of C and places the total chromatographic content of each impurity peaks (%) the gained difference before 150 days, the results are shown in Table 2.
Table 2:
| Sample | Impurity Y | Always mix when 0 | High temperature is assorted increment always |
| Ex8S () product | 0.09% | 0.37% | 0.27% |
| Ex3 product | 0.11% | 0.29% | 0.29% |
| Ex9 product | 0.15% | 0.42% | 0.48% |
| Ex2 product | 0.17% | 0.33% | 0.32% |
| Ex11 product | 0.17% | 0.46% | 0.29% |
| Ex7 product | 0.18% | 0.33% | 0.28% |
| Ex6 product | 0.20% | 0.47% | 0.33% |
| Ex1S (vii) product | 0.23% | 0.41% | 0.36% |
| Ex4 product | 0.25% | 0.47% | 0.33% |
| Ex5 product | 0.27% | 0.51% | 0.42% |
| Ex10S () product | 0.31% | 0.62% | 0.41% |
| Ex8S (iv) product normal hexane-ether (3:1) recrystallization 3 times | 0.34% | 0.52% | 0.31% |
| Ex8S (iv) product normal hexane-ether (3:1) recrystallization 2 times | 0.37% | 0.48% | 0.47% |
| Ex8S (iv) product normal hexane-ether (3:1) recrystallization 1 time | 0.42% | 0.63% | 0.63% |
| Ex10S (iv) product normal hexane-ether (2:1) recrystallization 1 time | 0.46% | 0.72% | 1.08% |
| Ex10S (iv) product normal hexane-ethanol (4:1) recrystallization 1 time | 0.49% | 0.86% | 1.24% |
| Ex1S (i) product normal hexane-ether (3:1) recrystallization 3 times | 0.51% | 1.09% | 1.42% |
| Ex10S (iv) product | 0.53% | 1.23% | 1.63% |
| Ex1S (i) product normal hexane-ether (3:1) recrystallization 2 times | 0.54% | 1.07% | 1.57% |
| Ex8S (iv) product | 0.56% | 1.27% | 1.86% |
| Ex1S (vi) product normal hexane-ether (3:1) recrystallization 1 time | 0.62% | 1.33% | 1.97% |
| Co1 product | 0.68% | 1.51% | 2.19% |
| Co2 product | 0.73% | 1.44% | 2.35% |
| Ex1Si) product normal hexane-ethanol (4:1) recrystallization 3 times | 0.80% | 1.53% | >3.0% |
| Ex1S (i) product normal hexane-ethanol (4:1) recrystallization 2 times | 0.92% | 1.79% | >5.0% |
| Ex1S (i) product normal hexane-ethanol (4:1) recrystallization 1 time | 1.06% | 1.94% | >7.5% |
| Ex1S (vi) product | 1.27% | 2.24% | >10.0% |
In upper table " sample " hurdle, Ex represents embodiment, and such as " Ex1 " represents embodiment 1; Co represents reference examples, and such as " Co1 " represents reference examples 1; S represents step, and such as " S (v) " represents step (v).Upper table " impurity Y " represents the chromatographic content of impurity Y; " always to mix when 0 " total chromatographic content of each impurity when representing 0; After " high temperature is assorted increment always " represents that 45 ° of C place 150 days, the total chromatographic content increased value of each impurity peaks, the total chromatographic content of each impurity peaks (%) after namely 45 ° of C place 150 days deducts 45 ° of C and places the total chromatographic content of each impurity peaks (%) the gained difference before 150 days.The present inventor have been surprisingly found that, at impurity Y content lower than 0.45%, particularly lower than 0.4% time, formula I is lower in the increasing amount change of total impurities after high-temperature treatment, and when this foreign matter content is higher than 0.4%, particularly higher than 0.45% time, formula I increases greatly in the increasing amount of total impurities after high-temperature treatment.
Claims (41)
1. a material medicine, its active constituents of medicine is with compounds of Formula I:
I；
And wherein comprise the following formula I Y compound of the trace as impurity:
IY；
This material medicine, in high effective liquid chromatography for measuring, has the chromatographic purity being greater than 98%, and the chromatographic content of formula IY compound is lower than 0.45%.
2. the material medicine of claim 1, it is in high effective liquid chromatography for measuring, and the chromatographic content of formula IY compound is lower than 0.4%.
3. the material medicine of claim 1, it is in high effective liquid chromatography for measuring, has the chromatographic purity being greater than 98.5%.
4. the material medicine of claim 1, it is in high effective liquid chromatography for measuring, has the chromatographic purity being greater than 99.0%.
5. the material medicine of claim 1, it is in high effective liquid chromatography for measuring, has the chromatographic purity being greater than 99.2%.
6. the material medicine of claim 1, it is in high effective liquid chromatography for measuring, has the chromatographic purity being greater than 99.3%.
7. the material medicine of claim 1, it is in high effective liquid chromatography for measuring, has the chromatographic purity being greater than 99.5%.
8. the material medicine of claim 1, it is in high effective liquid chromatography for measuring, and the chromatographic content of formula IY compound is higher than 0.02%.
9. the material medicine of claim 1, it is in high effective liquid chromatography for measuring, and the chromatographic content of formula IY compound is lower than 0.35%.
10. the material medicine of claim 1, it is in high effective liquid chromatography for measuring, and the chromatographic content of formula IY compound is lower than 0.3%.
The material medicine of 11. claims 1, it places the total chromatographic content increased value of each impurity peaks after 150 days and is no more than 1.0% under 45 ° of C.
The material medicine of 12. claims 1, it places the total chromatographic content increased value of each impurity peaks after 150 days and is no more than 0.75% under 45 ° of C.
The medicine of 13. any one of claim 1 to 12, wherein said high performance liquid chromatography measures according to Chinese Pharmacopoeia version in 2010 two annex VD high performance liquid chromatography specifications, and described high effective liquid chromatography for measuring mode is:
(1) chromatographic condition and system suitability: be weighting agent with octadecylsilane chemically bonded silica, take volume ratio as the methanol-water of 70:30 be moving phase, ultraviolet detection wavelength is 278nm, column temperature is 30 ° of C, number of theoretical plate presses 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl isophthalic acid, 4-benzoquinones peak calculates and is not less than 2000;
(2) preparation of test soln: get described material medicine, accurately weighed, add moving phase and dissolve and quantitatively dilute the solution made containing 0.2mg in every 1ml, as need testing solution; Another modus ponens IY compound, accurately weighed, add moving phase and dissolve and quantitatively dilute the solution made containing 0.2mg in every 1ml, as formula IY compound solution; Precision measures need testing solution and each 1ml of formula IY compound solution, puts in the measuring bottle of same 100ml, is diluted to scale by moving phase, shake up, as the contrast solution of contained I and formula IY compound;
(3) chromatogram test: get contrast solution 20 μ l injection liquid chromatography, regulate detection sensitivity, the peak height at principal constituent peak is made to be 10% of full range, precision measures need testing solution and each 20 μ l of contrast solution again, injection liquid chromatography respectively, record color atlas is to 2.5 times of principal constituent peak retention time;
(4) chromatographic computation:
(4i) record contrast solution color atlas main peak area and retention time thereof, this main peak area is the peak area of formula I and is expressed as A1, and the peak area of recording IY compound and retention time thereof;
(4ii) record need testing solution color atlas main peak area and retention time thereof, this main peak area is expressed as A100;
(4iii) in need testing solution color atlas, the chromatographic peak of 0.05 times of any A1 of being less than is ignored, in record need testing solution color atlas, each peak area is greater than impurity peak area and the retention time thereof of 0.05 times of A1, this impurity peak area is expressed as Am, m represents that m peak area is greater than the impurity peaks of 0.05 times of A1, and its Chinese style IY compound is also one in these impurity;
(4iv) according to the retention time of contrast solution color atlas Chinese style IY compound, need testing solution color atlas Chinese style IY compound and peak area thereof is determined, and the chromatographic content of calculating formula IY compound;
And,
The chromatographic purity of material medicine is calculated as follows according to the need testing solution color atlas of high-performance liquid chromatogram determination:
，
The chromatographic content of the single impurity in material medicine is calculated as follows according to the need testing solution color atlas of high-performance liquid chromatogram determination:
，
The chromatographic content above formula of formula IY compound calculates,
Total chromatographic content of each impurity in material medicine is calculated as follows according to the need testing solution color atlas of high-performance liquid chromatogram determination:
。
14. 1 kinds of pharmaceutical compositions, wherein comprise material medicine described in any one of claim 1-13, and the acceptable auxiliary material of optional pharmacy.
15. 1 kinds of pharmaceutical compositions, wherein comprise with compounds of Formula I:
I，
And the acceptable auxiliary material of pharmacy;
Wherein also comprise the following formula I Y compound of the trace as impurity:
IY；
This pharmaceutical composition is in high effective liquid chromatography for measuring, and the chromatographic content of formula IY compound is lower than 0.45%.
The pharmaceutical composition of 16. claims 15, it is in high effective liquid chromatography for measuring, disregard or deduct the impurity peaks that relative retention time is less than 0.2, disregard or deduct any chromatographic peak being less than 0.05 times of A1 in need testing solution color atlas, disregard or deduct auxiliary material chromatographic peak, this pharmaceutical composition has the chromatographic purity being greater than 98%.
The pharmaceutical composition of 17. claims 15, it is in high effective liquid chromatography for measuring, has the chromatographic purity being greater than 98.5%.
The pharmaceutical composition of 18. claims 15, it is in high effective liquid chromatography for measuring, has the chromatographic purity being greater than 99.0%.
The pharmaceutical composition of 19. claims 15, it is in high effective liquid chromatography for measuring, has the chromatographic purity being greater than 99.2%.
The pharmaceutical composition of 20. claims 15, it is in high effective liquid chromatography for measuring, has the chromatographic purity being greater than 99.3%.
The pharmaceutical composition of 21. claims 15, it is in high effective liquid chromatography for measuring, has the chromatographic purity being greater than 99.5%.
The pharmaceutical composition of 22. claims 15, it is in high effective liquid chromatography for measuring, and the chromatographic content of need testing solution color atlas Chinese style IY compound is lower than 0.4% and/or higher than 0.02%.
The pharmaceutical composition of 23. claims 15, it is in high effective liquid chromatography for measuring, and the chromatographic content of need testing solution color atlas Chinese style IY compound is lower than 0.35%.
The pharmaceutical composition of 24. claims 15, it is in high effective liquid chromatography for measuring, and the chromatographic content of need testing solution color atlas Chinese style IY compound is lower than 0.3%.
25. the pharmaceutical composition of claim 15, it is in high effective liquid chromatography for measuring, and in need testing solution color atlas, total chromatographic content of each impurity peaks is lower than 1.0%.
26. the pharmaceutical composition of claim 15, it is in high effective liquid chromatography for measuring, and in need testing solution color atlas, total chromatographic content of each impurity peaks is lower than 0.9%.
27. the pharmaceutical composition of claim 15, it is in high effective liquid chromatography for measuring, and in need testing solution color atlas, total chromatographic content of each impurity peaks is lower than 0.8%.
28. the pharmaceutical composition of claim 15, it is in high effective liquid chromatography for measuring, and in need testing solution color atlas, total chromatographic content of each impurity peaks is lower than 0.7%.
29. the pharmaceutical composition of claim 15, it is in high effective liquid chromatography for measuring, and in need testing solution color atlas, total chromatographic content of each impurity peaks is lower than 0.6%.
30. the pharmaceutical composition of claim 15, it is in high effective liquid chromatography for measuring, and in need testing solution color atlas, total chromatographic content of each impurity peaks is lower than 0.5%.
31. the pharmaceutical composition of claim 15, it is in high effective liquid chromatography for measuring, and in need testing solution color atlas, total chromatographic content of each impurity peaks is lower than 0.4%.
The pharmaceutical composition of 32. claims 15, it places the total chromatographic content increased value of each impurity peaks after 150 days and is no more than 1.5% under 45 ° of C.
The pharmaceutical composition of 33. claims 15, it places the total chromatographic content increased value of each impurity peaks after 150 days and is no more than 1.25% under 45 ° of C.
The pharmaceutical composition of 34. claims 15, it places the total chromatographic content increased value of each impurity peaks after 150 days and is no more than 1.0% under 45 ° of C.
The pharmaceutical composition of 35. claims 15, it places the total chromatographic content increased value of each impurity peaks after 150 days and is no more than 0.75% under 45 ° of C.
The pharmaceutical composition of 36. claims 15, it places the total chromatographic content increased value of each impurity peaks after 150 days and is no more than 0.5% under 45 ° of C.
The pharmaceutical composition of 37. any one of claim 15-36, wherein said high performance liquid chromatography measures according to Chinese Pharmacopoeia version in 2010 two annex VD high performance liquid chromatography specifications, and described high effective liquid chromatography for measuring mode is:
(1) chromatographic condition and system suitability: be weighting agent with octadecylsilane chemically bonded silica, take volume ratio as the methanol-water of 70:30 be moving phase, ultraviolet detection wavelength is 278nm, column temperature is 30 ° of C, number of theoretical plate presses 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl isophthalic acid, 4-benzoquinones peak calculates and is not less than 2000;
(2) preparation of test soln: compositions of getting it filled is appropriate, accurately weighed, adds moving phase and dissolves and quantitatively dilute the solution made containing 0.2mg formula I in every 1ml, as need testing solution; Another modus ponens IY compound, accurately weighed, add moving phase and dissolve and quantitatively dilute the solution made containing 0.2mg in every 1ml, as formula IY compound solution; Precision measures need testing solution and each 1ml of formula IY compound solution, puts in the measuring bottle of same 100ml, is diluted to scale by moving phase, shake up, in contrast solution; The auxiliary material of separately getting it filled in compositions, accurately weighed, add moving phase dissolving and quantitatively dilute and make the concentration corresponding with 0.2mg/ml formula I concentration, as auxiliary material solution;
(3) chromatogram test: get contrast solution 20 μ l injection liquid chromatography, regulate detection sensitivity, the peak height at principal constituent peak is made to be 10% of full range, precision measures need testing solution and each 20 μ l of contrast solution again, injection liquid chromatography respectively, record color atlas is to 2.5 times of principal constituent peak retention time; Separately get auxiliary material solution 20 μ l injection liquid chromatography, injection liquid chromatography, record color atlas is to 2.5 times of principal constituent peak retention time;
(4) chromatographic computation:
(4i) record contrast solution color atlas main peak area and retention time thereof, this main peak area is the peak area of formula I and is expressed as A1, and the peak area of recording IY compound and retention time thereof;
(4ii) record need testing solution color atlas main peak area and retention time thereof, this main peak area is expressed as A100; The chromatographic peak that in record auxiliary material solution color atlas, auxiliary material is formed;
(4iii) in need testing solution color atlas, the chromatographic peak corresponding with auxiliary material retention time is disregarded, and disregard or deduct the impurity peaks that relative retention time is less than 0.2, in need testing solution color atlas, the chromatographic peak of 0.05 times of any A1 of being less than is ignored, in record need testing solution color atlas, each peak area is greater than impurity peak area and the retention time thereof of 0.05 times of A1, this impurity peak area is expressed as Am, m represents that m peak area is greater than the impurity peaks of 0.05 times of A1, and its Chinese style IY compound is also one in these impurity;
(4iv) according to the retention time of contrast solution color atlas Chinese style IY compound, need testing solution color atlas Chinese style IY compound and peak area thereof is determined, and the chromatographic content of calculating formula IY compound.
38. according to the pharmaceutical composition of claim 37, and in the need testing solution color atlas of wherein said high-performance liquid chromatogram determination, the chromatographic purity of pharmaceutical composition is calculated as follows:
。
39. according to the pharmaceutical composition of claim 37, and in the need testing solution color atlas of wherein said high-performance liquid chromatogram determination, in pharmaceutical composition, the chromatographic content of single impurity is calculated as follows:
。
40. according to the pharmaceutical composition of claim 37, and in the need testing solution color atlas of wherein said high-performance liquid chromatogram determination, in pharmaceutical composition, total chromatographic content of each impurity is calculated as follows:
。
The preparation method of 41. any one of claim 1-13 medicines, it comprises the following steps:
(i) by the dissolving crude product of medicine in good solvent;
(ii) in step (i) gained solution, add the first solvent resistant, mixing, then add the second solvent resistant, be heated to 30-40 ° of C and solution is clarified, heat filtering;
(iii) make filtrate slowly be cooled to 10 ° of below C, make crystallization, leach crystallization, dry, to obtain final product,
Wherein:
Described good solvent is selected from methylene dichloride, ethyl acetate or its combination,
The first described solvent resistant is selected from Skellysolve A, sherwood oil or its combination,
The second described solvent resistant is selected from normal hexane, hexanaphthene or its combination.
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