Background technology
Diabetes are common disease, frequently-occurring disease, and its number of patients is just along with the change of the raising of living standards of the people, the aging of population, mode of life and improving of diagnostic techniques and increase sharply.Show according to the WHO pertinent data, the morbidity of diabetes, disability rate and mortality ratio and hazard rating have occupied the 3rd of Non Communicable Diseases (NCD), it has become after cardiovascular and cerebrovascular diseases and tumour, the third-largest disease of serious threat human health, this disease is not only brought very big misery to the patient, quality of life is subjected to very big influence, returns society and brings heavy economical load.
At present, the clinical oral antidiabetic drug that is used for the treatment of type ii diabetes mainly is sulfonylurea, biguanides, alpha-glucosidase inhibitor, thiazolidinediones and MAG's row ureas etc.Wherein, insulin secretion accelerating type sulfonylurea medicine except treat first mortality higher, have 10% patient that treatment is not subsequently replied approximately.Its main adverse reaction is that hypoglycemia and body weight seriously increase.Especially more common to P-607 and Glyburide, overweight patient should not use this type of pharmacological agent.The biguanide drug that does not increase insulin secretion utilizes glucose, inhibition glucose uptake and heteroplasia to reach hypoglycemic activity by promoting cell, though be used for the treatment of diabetes at the end of the fifties, significantly untoward reactions such as digestive tube and lactic acidosis limit its use.The alpha-glucosidase inhibitor minimizing disaccharide that competition suppresses glucuroide is converted into monose, delays enteric cavity and absorbs carbohydrate, and with the reduction postprandial hyperglycemia, but untoward reactions such as gastrointestinal side effect and anaemia limit its use.On behalf of the medicine troglitazone, the euglycemic agent thiazolidinediones be subjected to three warnings of U.S. FDA because of hepatic failure causes death, and hepatotoxicity has had a strong impact on the confidence of patient to this type of medicine.
Diabetes can be divided into insulin-dependent and non-insulin-depending type.Type ii diabetes claims non insulin dependent diabetes again, be a kind of be the autoimmune disorder of feature with Regular Insulin β cell injury.In diabetic, the type accounts for 90%.It is characterized by insulin secretion and reduce, insulin resistant and liver glucose generate and increase, and these patient's fasting insulin levels may be normal or higher, and Regular Insulin discharges minimizing in early days during dining, has increased the weight of the danger of hyperinsulinemia.Therefore, the control postprandial hyperglycemia can improve type ii diabetes patient's glycemic control, and effectively the various chronic complicating diseases that occur in the prevent diabetes process reduce patient's case fatality rate.
In recent years find that the infringement of early stage phase insulin secretion ability is the important factor of type ii diabetes development.The postprandial blood sugar conditioning agent be the nineties in 20th century progress comparatively fast, the most noticeable medicine, can be at type ii diabetes patient pulsed first phase defect of insulin secretion, the first phase insulin level reduced early stage level of postprandial blood sugar immediately when the increase patient ate, the controlling blood sugar fluctuation.Therefore develop and new can recover that Regular Insulin is after the meal secreted mutually in early days and the medicine that reduces postprandial hyperglycemia becomes the novel targets of ofhypoglycemic medicine exploitation.S 21403 is just in order to recover or to substitute the hyperglycemia new drug of early stage phase insulin secretion.
S 21403 is given birth to drugmaker's development by Japanese tachibana, the medicine that has now gone on the market, United States Patent (USP) (US006133454A) has been introduced a route of synthesis (also seeing patent of invention specification sheets Granted publication CN 1108291C) that is applicable to industrial S 21403, Japanese Patent (Te Open 2001-261644) introduced the method that adds suitable-six hydrogen isoindole to (S)-benzyl Succinic Acid.Drugs of the Future 2000,25 (10) has also introduced a kind of method for preparing S 21403, these method complex synthetic route, and yield is low, operation inconvenience, the condition harshness is not suitable for suitability for industrialized production.Therefore, the invention provides a kind of new synthetic method of S 21403.
In addition, because S 21403 contains certain moisture, has certain opticity again, quality product is difficult to control, be the control that its quality can be accessed, the present invention also provides the quality controlling means of S 21403, and this method is particularly suitable for the mitiglinide calcium raw material drug, has good effect for control quality product in suitability for industrialized production.
Summary of the invention:
The invention provides a kind of preparation method of S 21403.
S 21403 English name: Mitiglinide Calcium
Chemical name: two [(2S)-and 2-benzyl-3-(suitable-six hydrogen isoindole-2-carbonyls) propionic acid] single calcium dihydrate
Structural formula:
Molecular formula and molecular weight: C
38H
48CaN
2O
62H
2O 704.91
Synthetic route provided by the invention is as follows:
Wherein the preparation route of intermediate compound I X is as follows:
Wherein
XI tetrahydrochysene imines
X is suitable-cyclohexyl-1, and the 2-dicarboximide
Suitable-six hydrogen isoindole of IX
The VIII chlorobenzene
The VII diethyl malonate
VI α-diethyl benzyl malonate
V benzyl Succinic Acid
IVS-benzyl Succinic Acid methylbenzylamine salt
IIIS-benzyl Succinic Acid
II (2S)-2-benzyl-3-(suitable-six hydrogen isoindole-2-carbonyls) propionic acid
The I S 21403 (two [(2S)-and 2-benzyl-3-(suitable-six hydrogen isoindole-2-carbonyls) propionic acid] single calcium dihydrate)
Operation steps is as follows:
Step 1, suitable-cyclohexyl-1,2-dicarboximide synthetic
Synthesizing of step 2, suitable-six hydrogen isoindole
Synthesizing of step 3, α-diethyl benzyl malonate
Synthesizing of step 4, benzyl Succinic Acid
Synthesizing of step 5, S-benzyl Succinic Acid methylbenzylamine salt
Synthesizing of step 6, S-benzyl Succinic Acid
Synthesizing of step 7, (2S)-2-benzyl-3-(suitable-six hydrogen isoindole-2-carbonyls) propionic acid
Synthesizing of step 8, S 21403 crude product
Making with extra care of step 9, S 21403
With VII, VIII is that the feedstock production S 21403 is through the reaction of 7 steps.
Total recovery %=0.455 * 0.545 * 0.191 * 0.899 * 0.857 * 0.487 * 0.932 * 100%=1.7%
The most preferred operation steps of the present invention is seen embodiment.
The present invention also comprises the quality controlling means of S 21403, and this method may further comprise the steps:
Proterties is observed, survey specific optical rotation, differentiate, check, S 21403 is carried out assay.
Concrete steps are:
This product is two [(2S)-2-benzyl-3-(suitable-six hydrogen isoindole-2-carbonyls) propionic acid] single calcium dihydrate.Contain S 21403 (C
38H
48CaN
2O
62H
2O) must not be less than 98.0%.
[proterties] this product is a white crystalline powder; Odorless, bitter.
This product is easily molten in methyl alcohol, in dehydrated alcohol and dimethyl sulfoxide (DMSO), dissolve, in water and acetonitrile in almost insoluble; Easily molten in Glacial acetic acid.
Specific optical rotation is got this product, and accurate the title decides, and adds methyl alcohol and makes the solution that every 1ml contains S 21403 10mg, measures (two appendix VI of Chinese Pharmacopoeia version in 2000 E) in accordance with the law, and specific optical rotation is+5.0 ° ~+6.5 °
This product is got in [discriminating] (1), adds methyl alcohol and makes dissolving in right amount, and thin up is made the solution that every 1ml contains S 21403 1mg, measures according to spectrophotometry (two appendix IV of Chinese Pharmacopoeia version in 2000 A), at the wavelength place of 259nm maximum absorption is arranged.
(2) it is an amount of to get this product, adds small amount of methanol and makes dissolving, and make the solution that every 1ml contains 10mg, and it is an amount of to add the ammonium oxalate test solution, promptly generates white precipitate, and precipitation is insoluble to acetic acid, but dissolves in hydrochloric acid.
(3) this product infrared Absorption collection of illustrative plates should consistent with the collection of illustrative plates of reference substance (two appendix IVC of Chinese Pharmacopoeia version in 2000)
[inspection] related substance is got this product, about 25mg, and accurate the title, decide, and puts in the 50ml measuring bottle, adds methyl alcohol 5ml and make dissolving, and thin up shakes up to scale, as need testing solution; Measure in right amount, add moving phase and be diluted to the solution solution in contrast that contains S 21403 5ug among every 1ml.According to chromatographic condition test under the assay item, get contrast solution 20 μ l and inject liquid chromatograph, regulate detection sensitivity, make the peak height of principal constituent chromatographic peak be about 10 ~ 20% of full range; Get need testing solution 20 μ l again, inject liquid chromatograph, the record color atlas is to 3 times of principal constituent peak retention time.As showing impurity peaks, desolventize outside the peak in the color atlas of need testing solution, the summation of each impurity peak area must not be greater than the main peak area (1.0%) of contrast solution.
Levoisomer chromatographic condition and system suitability test SUMICHIRAL OA-3100R (5 μ m, 4.6mm * 250mm) chiral column is a chromatographic column, with normal hexane: chloroform: methyl alcohol: trifluoracetic acid (80: 160: 7.5: 0.5) be moving phase, detect wavelength 259nm, number of theoretical plate calculates by the S 21403 peak should be not less than 1000, and the resolution of S 21403 and levoisomer meets the requirements.
The assay method precision takes by weighing the about 50mg of S 21403 raw material, puts in the 10ml measuring bottle, and it is an amount of to add methyl alcohol, adds moving phase and is diluted to scale, shakes up, and filters, as need testing solution (5mg/ml).Precision is measured need testing solution 1.0ml, puts in the 100ml measuring bottle, is diluted to scale with moving phase, mixing, and solution (1) is (0.05mg/ml) in contrast.Precision takes by weighing the about 10mg of S 21403 enantiomorph, puts in the 10ml measuring bottle, and it is an amount of to add methyl alcohol, adds moving phase and is diluted to scale, shakes up, and filters, and solution (2) (1mg/ml) in contrast.Precision is measured need testing solution, each 2ml of contrast solution (2), puts in the test tube, shakes up, in contrast solution (3).
Get contrast solution (3) 20ul and inject liquid chromatograph, S 21403 is separated with levoisomer meet the requirements.Get contrast solution (1) 20ul and inject liquid chromatograph, regulate detector sensitivity, the peak height that makes the principal constituent chromatographic peak is 10% of a full range; Get need testing solution and contrast solution (1) again, each 20ul of contrast solution (2) injects liquid chromatograph respectively, the record color atlas, in the trial-product color atlas with contrast solution (2) main peak corresponding position if any impurity peaks, its area must not be greater than 1/2 (0.5%) of the peak area of the main composition of contrast solution (1).
Muriate is got this product 0.20g, adds methyl alcohol 10ml and makes dissolving, checks (two appendix VIII of Chinese Pharmacopoeia version in 2000 A) in accordance with the law, and the contrast liquor ratio made from standard sodium chloride solution 4.0ml must not denseer (0.02%).
Methyl alcohol, ethanol, methylene dichloride, ethyl acetate, tetrahydrofuran (THF)
Precision takes by weighing methylene dichloride 45mg, tetrahydrofuran (THF) 54mg puts in the 25ml measuring bottle, adds dimethyl sulfoxide (DMSO) and is diluted to scale, shakes up, and makes the solution that every 1ml contains 1.8mg methylene dichloride and 2.16mg tetrahydrofuran (THF).Precision takes by weighing methyl alcohol 45mg, ethanol 75mg, ethyl acetate 75mg and methylene dichloride and tetrahydrofuran solution 5ml in addition, put in the same 50ml measuring bottle, add dimethyl sulfoxide (DMSO) and be diluted to scale, shake up, precision is measured 1ml and is placed the 10ml measuring bottle, and accurate inner mark solution (1mg/ml hexane solution) 1ml that adds adds dimethyl sulfoxide (DMSO) and is diluted to scale, shake up, in contrast product solution; Other gets the about 300mg of this product, and accurate the title decides, and puts in the 10ml measuring bottle, and accurate inner mark solution (1mg/ml hexane solution) 1ml that adds adds dimethyl sulfoxide (DMSO) and is diluted to scale, shakes up, as need testing solution.Get above-mentioned solution according to vapor-phase chromatography (two appendix V of Chinese Pharmacopoeia version in 2000 E mensuration), with 6% cyanogen propyl phenyl-94% dimethyl polysiloxane (press the number of theoretical plate that calculates at the methyl alcohol peak should greater than 3000) quartz capillary column, after 60 ℃ of column temperatures keep 5 minutes, be warming up to 160 ℃ of mensuration with per 1 minute 40 ℃ speed.Containing methyl alcohol must not cross 0.3% (g/g), ethanol and must not cross 0.5% (g/g), methylene dichloride and must not cross that 0.06% (g/g), ethyl acetate must not cross 0.5% (g/g), tetrahydrofuran (THF) must not be crossed 0.072% (g/g).
Moisture is got this product, measures according to aquametry (two appendix VIII of Chinese Pharmacopoeia version in 2000 M, the first method A), contains moisture and should be 4.8% ~ 6.0%.
[assay] measured according to high performance liquid chromatography (two appendix V of Chinese Pharmacopoeia version in 2000 D).
The test of chromatographic condition and system suitability with alkali purifying silica gel be weighting agent (ABZ+Plus, 5um, 15cm); With acetonitrile-water-Pentyl alcohol (40: 59: 1) (is 2.5 with the phosphorus acid for adjusting pH value) is moving phase; The detection wavelength is 210nm; Flow velocity is per minute 1.0ml; The resolution of S 21403 main peak and adjacent impurity peaks should meet the requirements; The theoretical plate number of S 21403 main peak should be not less than 2000.Repeat sample introduction 6 times, its coefficient of variation should be less than 2.0%.
Assay method: get this product, about 25mg, the accurate title, decide, and puts in the 50ml measuring bottle, adds methyl alcohol 5ml, ultrasonicly make dissolving, thin up shakes up to scale, and precision is measured 5ml and put in the 50ml measuring bottle, be diluted with water to scale, shake up, get in the 20 μ l injecting chromatographs, the record color atlas; It is an amount of that other gets the S 21403 reference substance, measures with method, presses external standard method with calculated by peak area, promptly.
This product described in the above quality controlling means be meant according to synthetic method of the present invention preparation the mitiglinide calcium product.
Quality controlling means of the present invention is according to the result of study of S 21403 physico-chemical property, purity test, dystopy isomer and projects such as optical isomer inspection, assay is worked out.
[content limit] is according to laboratory synthetic S 21403 three batch samples (lot number: 040401,040402,040403) measurement result, content is respectively 100.2%, 100.5%, and 99.8%, content is all more than 98.5%, so content limit is ordered to being less than 98.0%.
[proterties] is according to synthetic three batch samples (lot number: 040401,040402,040403), be white crystals and powder, so classify its proterties as white crystals or powder.
Solubleness: measure S 21403 solubleness and list conclusion in quality standard by two note on the use methods of Chinese Pharmacopoeia version in 2000.
Specific optical rotation: three batch samples (lot number: 040401,040402,040403) all within the limit of regulation.
[discriminating] though 1, ultraviolet spectroscopy this product a little less than the ultraviolet region absorbs, there is characteristic absorbance at the place at the 259nm wavelength, can be used for differentiating.
2, this product contains calcium, according to two appendix III of Chinese Pharmacopoeia version in 2000, can be used for differentiating.
3, infrared spectroscopy this product is a bulk drug, differentiates with the more available infrared spectroscopy of reference substance.
According to (lot number: qualification result 040401,040402,040403) all shows positive reaction, so list three discriminatings in quality standard to three batches of this product.
The HPLC method is adopted in the inspection of [inspection] related substance dystopy isomer and other related substances, with alkali purifying silica gel be weighting agent (ABZ+Plus, 5um, 15cm); With acetonitrile-water-Pentyl alcohol (59: 40: 1) (is 2.5 with the phosphorus acid for adjusting pH value) is moving phase, and interfering factors is few, and accuracy is highly sensitive.
Muriate is pressed two appendix VIII of Chinese Pharmacopoeia version in 2000 A and is checked, three batches of (lot numbers: 040401,040402,040403) all less than 0.02% of this product.
Methyl alcohol, ethanol, methylene dichloride, ethyl acetate, the solvent of tetrahydrofuran (THF) for using in synthetic are defined as two, three class noxious solvents by ICH, through methodological study, list it in quality standard.
Moisture this product contains 2 crystal water, measures according to aquametry (two appendix VIII of Chinese Pharmacopoeia version in 2000 M, the first method A), and three batch sample measurement results are all 4.8% ~ 6.0%.
[assay] HPLC method interfering factors is few, and accuracy is highly sensitive, so detection method of content has been selected the HPLC method for use.Chromatographic condition is selected with the related substance inspection.
Synthetic method of the present invention, the yield height, cost is low, is convenient to operation, and condition is simple, is fit to suitability for industrialized production.
Quality controlling means of the present invention, accuracy, highly sensitive, help the quality surveillance of production process.
Embodiment:
Further specify the present invention by the following examples, but not as limitation of the present invention.
Embodiment 1
Step 1, suitable-cyclohexyl-1,2-dicarboximide synthetic
With the tetrahydrochysene imines (30g 199mmol) is dissolved in methyl alcohol (1000ml), adds 10%Pd/C (0.3g), logical hydrogen, stirring at room 28 hours finishes to not inhaling hydrogen, filter, filtrate concentrate white crystals.Quality is: 30.2g; Yield is: 99.3%.
Synthesizing of step 2, suitable-six hydrogen isoindole
With Lithium Aluminium Hydride (18.6g, 490mmol) join in the exsiccant tetrahydrofuran (THF) (150ml), stir and drip suitable-cyclohexyl-1,2-dicarboximide (30g down, tetrahydrofuran (THF) 196mmol) (500ml) solution, rate of addition refluxes slightly for keeping tetrahydrofuran solution.After all adding, reaction solution was refluxed 30 hours, cooling adds less water and decomposes excessive Lithium Aluminium Hydride, with the sedimentation and filtration that produces, filtrate concentrates, and residue extracts 3 times with ether (500ml), after the merging ether adds anhydrous sodium sulfate drying, filter, concentrate, the residue underpressure distillation gets product.Quality is: 19.6g; Yield is: 79.9%.
Synthesizing of step 3, α-diethyl benzyl malonate
In three-necked bottle, add dehydrated alcohol 500ml, add sodium Metal 99.5 23g, after treating the sodium Metal 99.5 total overall reaction, to add the Calcium Chloride Powder Anhydrous drying tube on the cold pouring pipe, drip diethyl malonate 166g by dropping funnel, after dropwising, in 2 ~ 3 hours, drip chlorobenzene 126.5g, dripped complete reflux 8 ~ 11 hours, after reaction was finished, cooling concentrated to steam and removes ethanol, add water 500ml in the residue, jolt, add the chlorination sodium salt and analyse layering, organic layer adds water 500ml washing again, layering, the organic layer vacuum fractionation gets product.Quality is: 118g; Yield is: 45.5%.
Synthesizing of step 4, benzyl Succinic Acid
With α-diethyl benzyl malonate (75g, 300mmol) with alpha bromoisobutyric acid ethyl ester (51g, 300mmol) join (sodium 7.5g is dissolved among the dehydrated alcohol 100ml and makes) among the sodium ethylate 100ml, finish, temperature rising reflux concentrates after 12 hours and desolvates, residue is with 3N sulfuric acid 200ml acidifying, with ether 500ml extraction, ether layer concentrate oily matter, oily matter put into contain potassium hydroxide 70g, in the mixed solution of ethanol 280ml and water 180ml, reflux concentrated ethanol after 4 hours, residue adds 6N hydrochloric acid 400ml acidifying, with ether 500ml extraction 2 times, combined ether layer concentrate faint yellow solid, faint yellow solid divided to join outer bath temperature for three times be decarboxylation in 160 ~ 170 ℃ the reaction flask, after finishing, continue heating 15 hours, cool off solid, and with 10 times of water recrystallizations.Quality is: 34g; Yield is: 54.5%; Fusing point is: 160 ~ 161 °.
Synthesizing of step 5, S-benzyl Succinic Acid methylbenzylamine salt
(20.8g 100mmol), adds dehydrated alcohol 500ml dissolving to add the benzyl Succinic Acid in reaction flask, drip R-methylbenzylamine (24.24g, 200mmol) dropwise, be heated to backflow, treat that white solid dissolves fully after, crystallization is left standstill in cooling, room temperature is placed and to be spent the night, and filters, dry 1 crystallization, add 20 times of dehydrated alcohol recrystallizations, the double product that gets.Quality is: 8.6g; Yield is: 19.1%; Specific rotation: [α]
26 D=-12 ~ 13 (C=1, H
2O).
Synthesizing of step 6, S-benzyl Succinic Acid
Will be among the S-benzyl Succinic Acid methylbenzylamine salt 45g add 2N hydrochloric acid 120ml, stirring at room 1 hour adds the 250ml extracted with diethyl ether 2 times, layering, combined ether layer, anhydrous sodium sulfate drying, concentrate white solid.Quality is: 18.7g; Yield is: 89.9%; Specific rotation: [α]
26 D=-27 (C=2, ethyl acetate), [α]
26 D=-103 (C=15, methyl alcohol); Fusing point: 159 ~ 161 °.
Synthesizing of step 7, (2S)-2-benzyl-3-(suitable-six hydrogen isoindole-2-carbonyls) propionic acid
(55.4g, dichloromethane solution 810mmol) (300ml) are cooled to 0 ℃ with imidazoles, dripping thionyl chloride (14.5ml, dichloromethane solution 200mmol) (100ml) after stirring 1 hour under 0 ℃, adds S-benzyl Succinic Acid (20.8g in reaction solution, 100mmol), 0 ℃ was stirred 2 hours down, drips suitable-six hydrogen isoindole (13.0g, dichloromethane solution 100mmol) (100ml), dropwise and slowly rise to stirred overnight at room temperature, add 1N hydrochloric acid 200ml in the reaction solution and stir after 1 hour, separatory, organic layer washing, concentrating under reduced pressure, the residue acetic acid ethyl dissolution extracts 2 times combining water layer with saturated sodium bicarbonate solution 200ml, wash with ethyl acetate, the water intaking layer transfers to acidity with concentrated hydrochloric acid, and water layer extracts with ethyl acetate 200ml, washing, the organic layer anhydrous sodium sulfate drying, concentrating under reduced pressure gets oily matter.Quality is: 27.0g, and yield is: 85.7%, specific rotation: [α]
24 D=-3.5 (C=1.04, methyl alcohol).
Synthesizing of step 8, S 21403 crude product
(2S)-2-benzyl-3-(suitable-six hydrogen isoindole-2-carbonyls) propionic acid (40.4g, ethanolic soln 128mmol) (150ml), and adding 2N sodium hydroxide (64ml, 128mmol), concentrating under reduced pressure, residue adds water 30ml dissolving, under the vigorous stirring, drips Calcium Chloride Powder Anhydrous (28.4g, aqueous solution 100ml 256ml), stir after 1 hour, filter, the dry crude product that gets.Quality is: 44g; Yield is: 48.7%; Fusing point is: 179 ~ 185 °.
Making with extra care of step 9, S 21403
Take by weighing the S 21403 crude product, 40 ℃ down with 95% dissolve with ethanol of 20 times of weight, be incubated 1 hour, reduce to room temperature and leave standstill crystallization.Filter, drying gets elaboration.Quality is: 41g; Yield is: 93.2%.