CN104193737B - A kind of synthetic method of razaxaban impurity - Google Patents
A kind of synthetic method of razaxaban impurity Download PDFInfo
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- CN104193737B CN104193737B CN201410409527.XA CN201410409527A CN104193737B CN 104193737 B CN104193737 B CN 104193737B CN 201410409527 A CN201410409527 A CN 201410409527A CN 104193737 B CN104193737 B CN 104193737B
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- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
Abstract
The present invention is the synthetic method of a kind of razaxaban impurity, relates to the synthetic method of a kind of razaxaban impurity acetyl oxamides, and described method comprises the steps of (1) compound I and Compound II per is obtained by reacting intermediate III；(2) intermediate III that step (1) prepares is obtained by reacting intermediate compound IV with CDI；(3) intermediate compound IV that step (2) prepares is obtained by reacting intermediate V with methylamine；(4) the intermediate V that step (3) prepares is obtained target compound TM with excess acetyl chloride；Present invention rational design first also synthesizes razaxaban impurity acetyl-oxamides, and synthetic route is reasonable, and raw material is easy to get, and operation is simple, and yield is high, and purity is high.
Description
Technical field
The invention belongs to technical field of pharmaceutical chemistry, particularly to the synthetic method of a kind of razaxaban impurity acetyl oxamides.
Background technology
Razaxaban (Rivaroxaban, trade name Xarelto), chemical name is the chloro-N-of 5-(((5S)-2-oxo-3-(4-(3-oxomorpholin-4-base) phenyl)-1,3-oxazoline-5-base) methyl) thiophene-2-carboxamide derivatives, structural formula is:
Razaxaban is the oral anticoagulation of first the direct inhibitive factor Xa of high selectivity in the whole world.Endogenous and the extrinsic pathway of blood coagulation waterfall can be interrupted, it is suppressed that the generation of thrombin and thrombosis by direct inhibitive factor Xa.Razaxaban is developed by Johnson & Johnson and Beyer Co., Ltd, for the anticoagulant of select a time hip joint or replacement knee in arthroplasty adult patients, to prevent venous thrombosis (VTE).Razaxaban sheet is the new oral anticoagulation that unique a kind of curative effect is better than Enoxaparin all the time, and day takes once, and knee prosthesis postoperative patient person should take 12 days continuously, and hip replacement patient should take 35 days continuously.This medicine also has the prevention of prevention patients with atrial fibrillation apoplexy and the potentiality of other clinical disease.Razaxaban gets the Green Light in more than 100 country in the whole world, and is successfully listing more than 75 countries.
Chinese patent 200610081919.3 reports razaxaban compound and synthetic method thereof, the method be with 4-(4-aminophenyl)-3-morpholone and (S)-(+)-N-(2, 3-ethoxycarbonyl propyl) phthalimide is initiation material, through condensation reaction, ring closure reaction, deprotection reaction obtains 4-[4-[(5S)-5-(amino methyl)-2-oxo-3-oxazolidinyl] phenyl]-3-morpholone, 4-[4-[(5S)-5-(amino methyl)-2-oxo-3-oxazolidinyl] phenyl]-3-morpholone or its salt obtain razaxaban with 5-chlorothiophene-2-carboxylic acid under the effect of condensing agent 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI).Reaction scheme is as follows:
OrganicProcessResearch&Development2003; 7; 533-546 reports another synthetic method of razaxaban; with 4-(4-aminophenyl)-3-morpholone for initiation material; obtain 4-[4-[(5S)-5-(amino methyl)-2-oxo-3-oxazolidinyl] phenyl]-3-morpholone trifluoroacetate through twice substitution reaction, ring closure reaction, deprotection, obtain razaxaban with 5-chlorothiophene-2-acyl chlorides condensation.
The present invention prepares in the process of razaxaban at the above route of use, pass through impurity analysis, it has been found that a kind of impurity, according to mass spectrum, nuclear-magnetism and Liquid Detection, and by contrasting with the liquid phase of former triturate, it is determined that the impurity of synthesis with former grind tablet impurity in retention time consistent.It is thus determined that the impurity of former triturate (nomenclature of drug: visit auspicious appropriate, BayerHealthCareAG company produces) is the impurity that present invention discover that, referred to as: " acetyl oxamides ", also referred to as " compound TM ".In import registered standard, this impurity content requires to control within 0.15%.Therefore it is the needs of quality control, it is necessary to this impurity is carried out the preparation of standard reference material, for the detection of corresponding product.
But not having bibliographical information this impurity structure and synthetic method at present, the present invention is through structural characterization, it was demonstrated that its structure is as follows:
Summary of the invention
The present invention provides the synthetic method of a kind of razaxaban impurity acetyl oxamides, said method comprising the steps of:
(1) compound I and Compound II per are obtained by reacting intermediate III；
(2) intermediate III that step (1) prepares is obtained by reacting intermediate compound IV with CDI；
(3) intermediate compound IV that step (2) prepares is obtained by reacting intermediate V with methylamine；
(4) intermediate V step (3) prepared and excess acetyl chloride obtain target compound TM (cutting down husky class impurity acetyl oxamides)；
Wherein, compound I is 4-aminophenyl-morpholine-3-ketone；
Compound II per is (S)-N-glycidyl phthalimide；
Compound II per I is 2-((2R)-2-hydroxyl-3-{ [4-(3-oxo-4-morpholinyl) phenyl] amino } propyl group)-1H-iso-indoles-1,3 (2H)-diketone；
Compound IV is 2-[[(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-5-oxazolidinyl] methyl]-1H-iso-indoles-1,3 (2H)-diketone；
Compound V is 4-[4-[(5S)-5-(aminomethyl)-2-carbonyl-3-oxazolidinyl] phenyl]-3-morpholine keto hydrochloride；
Compound TM is (S)-N-((2-oxo-3-(4-(3-oxomorpholin-4-base) phenyl)-1,3-oxazoline-5-base) methyl) acetamide.
CDI is N, N'-carbonyl dimidazoles
The reaction temperature of step (1), step (2), step (3) and step (4) is-20～150 DEG C.
Solvent in step (1), step (2), step (3) and step (4) is selected from: one or more in ethanol, isopropanol, toluene, acetone, dichloromethane and water.
In step (1), the mol ratio of compound I and Compound II per is 1: 0.5～1: 2.
In step (2), Compound II per I and CDI is obtained by reacting middle compound IV, and the mol ratio of Compound II per I and CDI is 1: 0.5～1: 10.
In step (3), compound IV and methylamine are obtained by reacting the equivalent proportion with methylamine of intermediate V, compound IV is 1: 0.5～1: 10, and described methylamine is the solution of the various solvents such as methylamine, methylamine water solution, methylethylolamine solution and various content.
In step (4), compound V and excess acetyl chloride obtain target product, and the equivalent proportion with methylamine of compound IV is 1: 0.5～1: 5.
Through above operation, it is possible to the impurity acetyl-oxamides of synthesis of high purity.
Owing to the structure of this compound is from unexposed, for this, the present invention provides a kind of compound TM, and structure is as follows:
The present invention also provides for described compound TM application in razaxaban quality control.
Described razaxaban quality control includes the assay of razaxaban and the mensuration of related impurities content, and the method about assay is as follows:
Razaxaban sample preparation: weigh razaxaban formulation samples 10mg and add to 50ml volumetric flask, dissolve quantitatively to 50ml with mix reagent, shake up, to obtain final product.HPLC quantitative sample injection 5 μ L, record chromatogram is shown in accompanying drawing 5.
Acetyl oxamides biased sample is prepared: weigh acetyl oxamides sample 10mg, adds to 50ml volumetric flask, dissolves quantitatively to quantitatively to 50ml with mix reagent, shakes up, to obtain final product.HPLC quantitative sample injection 5 μ L, record chromatogram is shown in accompanying drawing 6.
Chromatographic condition is as follows:
Chromatographic column: octadecylsilane chemically bonded silica is filler (PurospherStarRP-18endcapped, 55mm*4.0mm, 3 μm)
Mobile phase: with the phosphoric acid solution of 0.01mol/L for mobile phase A, is Mobile phase B by acetonitrile
Flow velocity: 1ml/min
Column temperature: 35 DEG C
Wavelength: 250nm
Gradient elution order:
| Time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 92 | 8 |
| 24.0 | 49 | 51 |
| 24.1 | 92 | 8 |
| 29 | 92 | 8 |
Note: mixed solvent is acetonitrile-0.01mol/L phosphoric acid solution (taking the phosphoric acid 6.7ml of 11.5g or 85%, be diluted with water to 10.0L) 3:2.
Reagent used by the present invention and raw material are all commercially.
Namely each optimum condition in the preparation method of the present invention combination in any can obtain each preferred embodiment of the present invention.
The beneficial effects of the present invention is the preparation method providing a kind of razaxaban impurity, can as reference substance for the qualitative, quantitative research of impurity in razaxaban quality research, control crude drug and have the content of related substance, ensure the quality of crude drug, additionally the inventive method yield is high, purity is high, uses solvent low toxicity cheap, and operational approach easy steps is few.
Accompanying drawing explanation
Fig. 1 compound IV mass spectrum
Fig. 2 compound TM mass spectrum
Fig. 3 compound TM nuclear-magnetism1H-NMR
Fig. 4 compound TM nuclear-magnetism13C-NMR
Fig. 5 compound TM liquid phase figure
The former triturate liquid phase figure of Fig. 6
Fig. 7 compound TM and former triturate liquid phase comparison diagram (peak that 3.0min overlaps is acetyl oxamides impurity)
Detailed description of the invention
Further illustrate the present invention by embodiment below, but the present invention is not intended to be limited thereto.
The synthesis of embodiment 1:2-((2R)-2-hydroxyl-3-{ [4-(3-oxo-4-morpholinyl) phenyl] amino } propyl group)-1H-iso-indoles-1,3 (2H)-diketone
At 20-25 DEG C, by 25g, (compound I throws in tri-mouthfuls of reaction bulbs of 500mL, adds isopropanol 150mL, starts stirring, adds Compound II per 34.36g, 85 ± 5 DEG C of back flow reaction 24h.TLC (developing solvent DCM:MeOH: ammonia=20:1:0.1) puts plate display extent of reaction.After having reacted, being cooled to 25 ± 5 DEG C has a large amount of white solid to precipitate out, and filters, filter cake isopropyl alcohol wash 80mL × 2, drains, and collects filter cake, obtains Compound II per I43.7g, yield 85% at 50 ± 5 DEG C of dry 12h.
Embodiment 2:
At 20-25 DEG C, being joined in 500mL there-necked flask by 42g Compound II per I, be added in 100mL toluene and dissolve, add N, N'-carbonyl dimidazoles (CDI) 24.11g in system, system is heated to 110 ± 5 DEG C of back flow reaction 5h.TLC (developing solvent is dichloromethane: methanol: ammonia=20:1:0.1) detects reaction.After reacting completely, it is down to room temperature DEG C, adds ethanol 50mL, stir 30min.Being filtered to remove mother solution, collect 50 DEG C of air blast of filter cake and dry 12 hours, get profit compound IV42g, yield 93%.
MS:[M+H]+=422, [M+Na]+=444.
Embodiment 3:
At 20-25 DEG C, 42g compound IV joins in tri-mouthfuls of reaction bulbs of 500mL, adds 150mL dehydrated alcohol, opens stirring, adds first ammonia spirit 24.38g (25mL), 80 DEG C of back flow reaction 1h.
TLC (developing solvent DCM:MeOH: ammonia=20:1:0.1) detects reaction.After reacting completely, being cooled to 40 DEG C ± 5 DEG C and add 50mL ethanol solution hydrochloride, control temperature and be maintained at 30 ± 5 DEG C, precipitate out a large amount of white, be down to 20-25 DEG C, filter, 60mL × 2 dehydrated alcohol is washed, and 50 ± 5 DEG C of drying obtain compound V30g, yield 91%.
Embodiment 4:
Take 50mL single port reaction bulb, add 1g compound V, add 10mL acetone solution, the system of dropping is cooled to 0-5 DEG C, drips chloroacetic chloride 0.94g, and temperature controls at 0-5 DEG C, finishing, TLC (developing solvent DCM:MeOH: ammonia=20:1:0.1) monitoring reacts completely, and continues stirring 15min.System filters, and 5mL × 2 acetone is washed, and 5mL × 2 normal hexane is washed, and drains.With volume ratio be 1:1 dichloromethane and methanol for solvent dissolve after cross 200 order silicagel columns, with this solvent as elution, collect eluent, rotation is steamed to doing to obtain white solid powder, adds 10mL normal hexane, filters, 10mL normal hexane is washed, draining, 25 ± 5 DEG C of vacuum drying 12h obtain compound TM0.85g product, yield 83%.HPLC purity detecting is 99.96%.
1H-NMR (400MHz, DMSO-d6): δ 1.835 (3H, s, CH3), 3.37 (2H, t, CH2), 3.63 (2H, t, CH2), 3.77 (1H, dd, CH2), 3.963 (2H, t, CH2), 4.13 (1H, dd, CH2), 4.17 (2H, s, CH2), 4.72 (1H, m, CH), 7.42 (2H, d, ArH), 7.57 (2H, d, ArH), 8.338 (1H, br, NH)；13C-NMR (400MHz, DMSO): δ 41.37,47.30,49.00,53.15,63.47,67.71,71.47,118.29,125.94,136.53,137.02,154.12,165.94,169.96；MS:[M+Na] +=356.1.
Embodiment 5:
Cut down the husky assay of class and being determined as follows of related impurities content:
Razaxaban sample preparation: weigh razaxaban formulation samples 10mg and add to 50ml volumetric flask, dissolve quantitatively to 50ml with mix reagent, shake up, to obtain final product.HPLC quantitative sample injection 5 μ L, record chromatogram is shown in accompanying drawing 5.
Acetyl oxamides biased sample is prepared: weigh acetyl oxamides sample 10mg, adds to 50ml volumetric flask, dissolves quantitatively to quantitatively to 50ml with mix reagent, shakes up, to obtain final product.HPLC quantitative sample injection 5 μ L, record chromatogram is shown in accompanying drawing 6.
Chromatographic condition is as follows:
Chromatographic column: octadecylsilane chemically bonded silica is filler (PurospherStarRP-18endcapped, 55mm*4.0mm, 3 μm)
Mobile phase: with the phosphoric acid solution of 0.01mol/L for mobile phase A, is Mobile phase B by acetonitrile
Flow velocity: 1ml/min
Column temperature: 35 DEG C
Wavelength: 250nm
Gradient elution order:
| Time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 92 | 8 |
| 24.0 | 49 | 51 |
| 24.1 | 92 | 8 |
| 29 | 92 | 8 |
Note: mixed solvent is acetonitrile-0.01mol/L phosphoric acid solution (taking the phosphoric acid 6.7ml of 11.5g or 85%, be diluted with water to 10.0L) 3:2.
Claims (8)
1. the preparation method of a compound TM, it is characterised in that comprise the steps of
(1) compound I and Compound II per are obtained by reacting intermediate III；
(2) intermediate III that step (1) prepares is obtained by reacting intermediate compound IV with CDI；
(3) intermediate compound IV that step (2) prepares is obtained intermediate V with methylamine, methylamine water solution or methylethylolamine solution reaction；
(4) the intermediate V that step (3) prepares is obtained target compound TM with excess acetyl chloride；
2. preparation method according to claim 1, it is characterised in that: step (1), step (2), step (3) reaction temperature be-20～150 DEG C.
3. preparation method according to claim 1, it is characterised in that: the solvent in step (1), step (2), step (3) and step (4) is selected from: one or more in ethanol, isopropanol, toluene, acetone, dichloromethane and water.
4. preparation method according to claim 1, it is characterised in that: in step (1), compound I and Compound II per are obtained by reacting middle Compound II per I, and the mol ratio of compound I and Compound II per is 1: 0.5～1: 5.
5. preparation method according to claim 1, it is characterised in that: in step (2), Compound II per I and CDI is obtained by reacting middle compound IV, and the mol ratio of Compound II per I and CDI is 1: 0.5～1: 10.
6. preparation method according to claim 1, it is characterised in that: in step (3), compound IV and methylamine are obtained by reacting the equivalent proportion with methylamine of intermediate V, compound IV is 1: 0.5～1: 10.
7. preparation method according to claim 1, it is characterised in that: in step (4), compound V and excess acetyl chloride obtain the mol ratio with chloroacetic chloride of target product TM, compound V is 1: 0.5～1: 5.
8. preparation method according to claim 1, it is characterised in that: the reaction of step (1), step (2), step (3) and step (4) is as follows:
At 20-25 DEG C, 25g compound I is thrown in tri-mouthfuls of reaction bulbs of 500mL, add isopropanol 150mL, start stirring, add Compound II per 34.36g, 85 ± 5 DEG C of back flow reaction 24h, it it is DCM:MeOH with developing solvent: the TLC point plate display extent of reaction of ammonia=20:1:0.1, after having reacted, being cooled to 25 ± 5 DEG C has a large amount of white solid to precipitate out, and filters, filter cake isopropyl alcohol wash 80mL × 2, drain, collect filter cake, obtain Compound II per I at 50 ± 5 DEG C of dry 12h；
At 20-25 DEG C, 42g Compound II per I is joined in 500mL there-necked flask, be added in 100mL toluene and dissolve, add CDI24.11g in system, system is heated to 110 ± 5 DEG C of back flow reaction 5h, is dichloromethane with developing solvent: methanol: the TLC detection reaction of ammonia=20:1:0., after reacting completely, it is down to room temperature, add ethanol 50mL, stir 30min, be filtered to remove mother solution, collecting 50 DEG C of air blast of filter cake to dry 12 hours, get profit compound IV；
At 20-25 DEG C, 42g compound IV joins in tri-mouthfuls of reaction bulbs of 500mL, adds 150mL dehydrated alcohol, open stirring, add first ammonia spirit 24.38g, 80 DEG C of back flow reaction 1h, it is DCM:MeOH with developing solvent: the TLC detection reaction of ammonia=20:1:0.1, after reacting completely, is cooled to 40 DEG C ± 5 DEG C and adds 50mL ethanol solution hydrochloride, control temperature and be maintained at 30 ± 5 DEG C, precipitate out a large amount of white, be down to 20-25 DEG C, filter, 60mL × 2 dehydrated alcohol is washed, and 50 ± 5 DEG C of drying obtain compound V；
Take 50mL single port reaction bulb, add 1g compound V, add 10mL acetone solution, the system of dropping is cooled to 0-5 DEG C, dropping chloroacetic chloride 0.94g, temperature controls at 0-5 DEG C, finish, it is DCM:MeOH with developing solvent: the TLC monitoring of ammonia=20:1:0.1 reacts completely, continue stirring 15min, system filters, 5mL × 2 acetone is washed, 5mL × 2 normal hexane is washed, drain, with volume ratio be 1:1 dichloromethane and methanol for solvent dissolve after cross 200 order silicagel columns, with this solvent as elution, collect eluent, rotation is steamed to doing to obtain white solid powder, add 10mL normal hexane, filter, 10mL normal hexane is washed, drain, 25 ± 5 DEG C of vacuum drying 12h obtain compound TM.
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| CN104569213A (en) * | 2015-01-23 | 2015-04-29 | 江苏正大清江制药有限公司 | Method for measuring content of (S)-(+)-N-(2,3-ethyoxyl propyl) phthalimide by adopting high performance liquid chromatography |
| CN104569212A (en) * | 2015-01-23 | 2015-04-29 | 江苏正大清江制药有限公司 | Method for measuring content of 4-(4-amino phenyl)-3-molindone by adopting high performance liquid chromatography |
| CN104807934B (en) * | 2015-04-30 | 2017-01-18 | 成都百裕制药股份有限公司 | Normal-phase high performance liquid chromatography detection method of isoindole diketone compounds |
| CN108152412A (en) * | 2017-12-20 | 2018-06-12 | 乐普药业股份有限公司 | A kind of method with liquid chromatography for separating and determining razaxaban and its in relation to substance |
| CN108546265A (en) * | 2018-06-22 | 2018-09-18 | 苏州中联化学制药有限公司 | A kind of synthetic method of Rivaroxaban intermediate |
| CN110054623A (en) * | 2019-05-29 | 2019-07-26 | 浙江燎原药业股份有限公司 | A kind of preparation method of Rivaroxaban intermediate |
| CN110372687A (en) * | 2019-06-12 | 2019-10-25 | 北京鑫开元医药科技有限公司 | A kind of Preparation method and use of 4- (4- ethylamino- phenyl) morpholine -3- ketone |
| CN110818700A (en) * | 2019-11-15 | 2020-02-21 | 湖南九典制药股份有限公司 | Oxazolidone derivative and preparation method thereof |
| CN111721858B (en) * | 2020-06-03 | 2022-07-01 | 杭州华东医药集团新药研究院有限公司 | Method for determining genotoxic impurities in rivaroxaban |
| CN113092639A (en) * | 2021-03-23 | 2021-07-09 | 郑州大学分析测试科技有限公司 | Method for detecting content of rivaroxaban related substances by ultra-performance liquid chromatography-mass spectrometry |
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Address after: 136200 No. 188 Xinxing Road, Jilin, Liaoyuan Co-patentee after: Beijing nukangda medicine Polytron Technologies Inc Patentee after: JILIN DONGMENG PHARMACEUTICAL CO., LTD. Address before: 136200 No. 188 Xinxing Road, Jilin, Liaoyuan Co-patentee before: BEIJING NUOKANGDA PHARMACEUTICAL CO., LTD. Patentee before: JILIN DONGMENG PHARMACEUTICAL CO., LTD. |
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| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20200928 Address after: Building 7, area 2, No.31, Kechuang 13th Street, Daxing Economic and Technological Development Zone, Beijing 100176 Patentee after: Beijing Nuokangda Pharmaceutical Technology Co.,Ltd. Address before: 136200 No. 188 Xinxing Road, Jilin, Liaoyuan Patentee before: JILIN DONGMENG PHARMACEUTICAL Co.,Ltd. Patentee before: Beijing Nuokangda Pharmaceutical Technology Co.,Ltd. |