CN104193737A - Method for synthesizing rivaroxaban impurity - Google Patents
Method for synthesizing rivaroxaban impurity Download PDFInfo
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- CN104193737A CN104193737A CN201410409527.XA CN201410409527A CN104193737A CN 104193737 A CN104193737 A CN 104193737A CN 201410409527 A CN201410409527 A CN 201410409527A CN 104193737 A CN104193737 A CN 104193737A
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- 0 O=C1O[C@](CN(C(c2ccccc22)=O)C2=O)CC1C*c1ccc(*CC(CCOC2)C2=O)cc1 Chemical compound O=C1O[C@](CN(C(c2ccccc22)=O)C2=O)CC1C*c1ccc(*CC(CCOC2)C2=O)cc1 0.000 description 4
- CJYGXJZUIBVLOT-LJQANCHMSA-N CC(COCCNc(cc1)ccc1N(C[C@H](CN(C(c1ccccc11)=O)C1=O)OC1)C1=O)=O Chemical compound CC(COCCNc(cc1)ccc1N(C[C@H](CN(C(c1ccccc11)=O)C1=O)OC1)C1=O)=O CJYGXJZUIBVLOT-LJQANCHMSA-N 0.000 description 1
- LJANJCYFLYAMFE-KBPLZSHQSA-N CC1(C(C(N2C[C@@H]3OC3)=O)=CC=CC1)C2=O Chemical compound CC1(C(C(N2C[C@@H]3OC3)=O)=CC=CC1)C2=O LJANJCYFLYAMFE-KBPLZSHQSA-N 0.000 description 1
- MHCRLDZZHOVFEE-UHFFFAOYSA-N Nc(cc1)ccc1N(CCOC1)C1=O Chemical compound Nc(cc1)ccc1N(CCOC1)C1=O MHCRLDZZHOVFEE-UHFFFAOYSA-N 0.000 description 1
- PWNUVZXBKPKCOT-WJDWOHSUSA-N O/C(/CN(C(c1c2cccc1)=O)C2=O)=C\Nc(cc1)ccc1N(CCOC1)C1=O Chemical compound O/C(/CN(C(c1c2cccc1)=O)C2=O)=C\Nc(cc1)ccc1N(CCOC1)C1=O PWNUVZXBKPKCOT-WJDWOHSUSA-N 0.000 description 1
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—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
- 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
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Abstract
The invention discloses a method for synthesizing a rivaroxaban impurity and relates to a method for synthesizing acetyl-oxamide as a rivaroxaban impurity. The method comprises the following steps: (1) reacting a compound I with a compound II to obtain an intermediate III; (2) reacting the intermediate III obtained in the step (1) with CDI to obtain an intermediate IV; (3) reacting the intermediate IV obtained in the step (2) with methylamine to obtain an intermediate V; and (4) reacting the intermediate V obtained in the step (3) with acetylchloride to obtain a target compound TM. The method is firstly and directionally designed to synthesize the rivaroxaban impurity, namely, acetyl-oxamide and has the advantages of reasonable synthetic route, easily available raw materials, simple and feasible operation, high yield and high purity.
Description
Technical field
The invention belongs to technical field of pharmaceutical chemistry, particularly a kind of synthetic method of razaxaban impurity acetyl oxamide.
Background technology
Razaxaban (Rivaroxaban, trade(brand)name Xarelto), chemical name is the chloro-N-of 5-(((5S)-2-oxo-3-(4-(3-oxo morpholine-4-yl) phenyl)-1,3-oxazoles quinoline-5-yl) methyl) thiophene-2-carboxamide derivatives, and structural formula is:
Razaxaban is the oral anticoagulation of the direct supressor Xa of first highly selective of the whole world.By direct supressor Xa, can interrupt endogenous and the extrinsic pathway of blood coagulation waterfall, the generation of Trombin inhibiting and thrombosis.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 once, knee prosthesis postoperative patient person should take 12 days day clothes continuously, and hip replacement patient should take 35 days continuously.This medicine prevents the prevention of patients with atrial fibrillation apoplexy and the potentiality of other clinical disease in addition.Razaxaban gets the Green Light in more than 100 country in the whole world, and is successfully going on the market over 75 countries.
Chinese patent 200610081919.3 has been reported razaxaban compound and synthetic method thereof, the method is with 4-(4-aminophenyl)-3-morpholone mai and (S)-(+)-N-(2, 3-ethoxycarbonyl propyl) phthalic imidine is starting raw material, through condensation reaction, ring closure reaction, deprotection reaction obtains 4-[4-[(5S)-5-(amino methyl)-2-oxo-3-oxazolidinyl] phenyl]-3-morpholone mai, 4-[4-[(5S)-5-(amino methyl)-2-oxo-3-oxazolidinyl] phenyl]-3-morpholone mai or its salt and 5-chlorothiophene-2-carboxylic acid obtain razaxaban under the effect of condensing agent 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI).Reaction scheme is as follows:
Organic Process Research & Development 2003; 7; 533-546 has reported another synthetic method of razaxaban; 4-(4-the aminophenyl)-3-morpholone mai of take is starting raw material; through twice substitution reaction, ring closure reaction, deprotection, obtain 4-[4-[(5S)-5-(amino methyl)-2-oxo-3-oxazolidinyl] phenyl]-3-morpholone mai trifluoroacetate, obtain razaxaban with the condensation of 5-chlorothiophene-2-acyl chlorides.
The present invention is using above route to prepare in the process of razaxaban, by impurity analysis, find a kind of impurity, according to mass spectrum, nuclear-magnetism and Liquid Detection, and by contrasting with the liquid phase of former triturate, determine synthetic impurity and former to grind tablet impurity consistent in retention time.Therefore the impurity of determining former triturate (nomenclature of drug: visit auspicious appropriately, Bayer HealthCare AG company produces) is the impurity that the present invention finds, referred to as: " acetyl oxamide ", also referred to as " compound TM ".In import registered standard, this foreign matter content requires to be controlled in 0.15 %.Therefore be the needs of quality control, be necessary this impurity to carry out the preparation of standard reference material, for the detection of corresponding product.
But do not have at present bibliographical information this impurity structure and synthetic method, the present invention, through structural characterization, proves that its structure is as follows:
Summary of the invention
The synthetic method that the invention provides a kind of razaxaban impurity acetyl oxamide, said method comprising the steps of:
(1) Compound I and Compound I I reaction obtain intermediate III;
(2) intermediate III step (1) being made is reacted and is obtained intermediate compound IV with CDI;
(3) intermediate compound IV step (2) being made is reacted with methylamine and is obtained intermediate V;
(4) intermediate V step (3) being made and excess acetyl chloride obtain target compound TM (cutting down husky class impurity acetyl oxamide);
Wherein, Compound I is 4-aminophenyl-morpholine-3-ketone;
Compound I I is (S)-N-epoxypropyl phthalic imidine;
Compound III is 2-((2R)-2-hydroxyl-3-{[4-(3-oxo-4-morpholinyl) phenyl] amino } propyl group)-1H-isoindole-1,3 (2H)-diketone;
Compound IV is 2-[[(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-5-oxazolidinyl] methyl]-1H-isoindole-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-oxo morpholine-4-yl) phenyl)-1,3-oxazoles quinoline-5-yl) methyl) ethanamide.
CDI is N, N'-carbonyl dimidazoles
The temperature of reaction of step (1), step (2), step (3) and step (4) is-20～150 ℃.
Solvent in step (1), step (2), step (3) and step (4) is selected from: one or more in ethanol, Virahol, toluene, acetone, methylene dichloride and water.
In step (1), the mol ratio of Compound I and Compound I I is 1: 0.5～1: 2.
In step (2), compound III is reacted with CDI and is obtained middle compound IV, and the mol ratio of compound III and CDI is 1: 0.5～1: 10.
Compound IV is reacted with methylamine and is obtained intermediate V in step (3), and compound IV and equivalence ratio methylamine are 1: 0.5～1: 10, and described methylamine is the solution of all kinds of SOLVENTS such as methylamine, aqueous methylamine solution, methylethylolamine solution and various content.
Compound V and excess acetyl chloride obtain target product in step (4), and compound IV and equivalence ratio methylamine are 1: 0.5～1: 5.
Through above operation, impurity acetyl-oxamide that can synthesis of high purity.
Because the structure of this compound is from unexposed, for this reason, the invention provides a kind of compound TM, structure is as follows:
The present invention also provides the application in razaxaban quality control with described compound TM.
Described razaxaban quality control comprises the mensuration of assay and the related impurities content of razaxaban, and the method for relevant assay is as follows:
Razaxaban sample preparation: take razaxaban formulation samples 10mg and be added in 50ml volumetric flask, dissolve quantitatively to 50ml with mix reagent, shake up, obtain.HPLC quantitative sample injection 5 μ L, record color atlas and see accompanying drawing 5.
Acetyl oxamide biased sample preparation: take acetyl oxamide sample 10mg, be added in 50ml volumetric flask, dissolve quantitatively to quantitatively to 50ml with mix reagent, shake up, obtain.HPLC quantitative sample injection 5 μ L, record color atlas and see accompanying drawing 6.
Chromatographic condition is as follows:
Chromatographic column: octadecylsilane chemically bonded silica is weighting agent (Purospher Star RP-18endcapped, 55mm*4.0mm, 3 μ m)
Moving phase: the phosphoric acid solution of 0.01mol/L of take is mobile phase A, is Mobile phase B by acetonitrile
Flow velocity: 1ml/min
Column temperature: 35 ℃
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 (the phosphoric acid 6.7ml that gets 11.5g or 85%, is diluted with water to 10.0L) 3:2.
The reagent that the present invention is used and raw material be commercially available obtaining all.
Each optimum condition in preparation method of the present invention can arbitrary combination obtain each preferred embodiment of the present invention.
Beneficial effect of the present invention has been to provide a kind of preparation method of razaxaban impurity, can be used as reference substance for the qualitative, quantitative research of impurity in razaxaban quality approach, control the content of bulk drug related substance, guarantee the quality of bulk drug, the inventive method yield is high in addition, purity is high, uses solvent low toxicity cheap, and working method easy steps is few.
Accompanying drawing explanation
Fig. 1 compound IV mass spectrum
Fig. 2 compound TM mass spectrum
Fig. 3 compound TM nuclear-magnetism
1h-NMR
Fig. 4 compound TM nuclear-magnetism
13c-NMR
Fig. 5 compound TM liquid phase figure
The former triturate liquid phase of Fig. 6 figure
Fig. 7 compound TM and former triturate liquid phase comparison diagram (peak that 3.0min overlaps is acetyl oxamide impurity)
Embodiment
With embodiment, further illustrate the present invention below, but the present invention is not limited.
Embodiment 1:2-((2R)-2-hydroxyl-3-{[4-(3-oxo-4-morpholinyl) phenyl] amino } propyl group)-1H-isoindole-1,3 (2H)-diketone synthetic
At 20-25 ℃, by 25g, (Compound I is thrown in tri-mouthfuls of reaction flasks of 500mL, adds Virahol 150mL, starts to stir, and adds Compound I I 34.36g, 85 ± 5 ℃ of back flow reaction 24h.TLC (developping agent DCM:MeOH: ammoniacal liquor=20:1:0.1) some plate shows extent of reaction.After having reacted, being cooled to 25 ± 5 ℃ has a large amount of white solids to separate out, and filters, and filter cake, with isopropyl alcohol wash 80mL * 2, is drained, and collects filter cake, obtains compound III 43.7g, yield 85% at 50 ± 5 ℃ of dry 12h.
Embodiment 2:
At 20-25 ℃, 42g compound III is joined in 500mL there-necked flask, be added in 100mL toluene and dissolve, then add N, N'-carbonyl dimidazoles (CDI) 24.11g is in system, and system is heated to 110 ± 5 ℃ of back flow reaction 5h.(developping agent is methylene dichloride to TLC: methyl alcohol: ammoniacal liquor=20:1:0.1) detection reaction.After reacting completely, be down to room temperature ℃, add ethanol 50mL, stir 30min.Remove by filter mother liquor, collect 50 ℃ of air blast of filter cake and dry 12 hours, the compound IV of getting profit 42g, yield 93%.
MS:[M+H]
+＝422，[M+Na]
+＝444。
Embodiment 3:
At 20-25 ℃, 42g compound IV joins in tri-mouthfuls of reaction flasks of 500mL, adds 150mL dehydrated alcohol, opens and stirs, and adds first ammonia soln 24.38g (25mL), 80 ℃ of back flow reaction 1h.
TLC (developping agent DCM:MeOH: ammoniacal liquor=20:1:0.1) detection reaction.After reacting completely, be cooled to 40 ℃ ± 5 ℃ and add 50mL ethanol solution hydrochloride, control temperature and remain on 30 ± 5 ℃, separate out a large amount of white, be down to 20-25 ℃, filter, 60mL * 2 dehydrated alcohol is washed, and 50 ± 5 ℃ of oven dry obtain compound V 30g, yield 91%.
Embodiment 4:
Get 50mL single port reaction flask, add 1g compound V, add 10mL acetone solution, the system of falling is cooled to 0-5 ℃, drips Acetyl Chloride 98Min. 0.94g, and temperature is controlled at 0-5 ℃, finish, (developping agent DCM:MeOH: ammoniacal liquor=20:1:0.1) monitoring reacts completely, continues to stir 15min to TLC.System is filtered, and 5mL * 2 acetone is washed, and 5mL * 2 normal hexane is washed, and drains.The methylene dichloride that the volume ratio of take is 1:1 and methyl alcohol are crossed 200 order silicagel columns after dissolution with solvents, with this solvent as elutriant wash-out, collect elutriant, revolve and steam to doing to obtain white solid powder, add 10mL normal hexane, filter, 10mL normal hexane is washed, drain, 25 ± 5 ℃ of vacuum-drying 12h obtain compound TM0.85g product, yield 83%.HPLC purity detecting is 99.96%.
1H-NMR(400MHz，DMSO-d6)：δ1.835(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)：δ41.37,47.30,49.00,53.15,63.47,67.71,71.47,118.29,125.94,136.53,137.02,154.12,165.94,169.96；MS:[M+Na]+＝356.1。
Embodiment 5:
Cut down the assay of husky class and being determined as follows of related impurities content:
Razaxaban sample preparation: take razaxaban formulation samples 10mg and be added in 50ml volumetric flask, dissolve quantitatively to 50ml with mix reagent, shake up, obtain.HPLC quantitative sample injection 5 μ L, record color atlas and see accompanying drawing 5.
Acetyl oxamide biased sample preparation: take acetyl oxamide sample 10mg, be added in 50ml volumetric flask, dissolve quantitatively to quantitatively to 50ml with mix reagent, shake up, obtain.HPLC quantitative sample injection 5 μ L, record color atlas and see accompanying drawing 6.
Chromatographic condition is as follows:
Chromatographic column: octadecylsilane chemically bonded silica is weighting agent (Purospher Star RP-18endcapped, 55mm*4.0mm, 3 μ m)
Moving phase: the phosphoric acid solution of 0.01mol/L of take is mobile phase A, is Mobile phase B by acetonitrile
Flow velocity: 1ml/min
Column temperature: 35 ℃
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 (the phosphoric acid 6.7ml that gets 11.5g or 85%, is diluted with water to 10.0L) 3:2.
Claims (10)
1. a preparation method of compound TM, is characterized in that, comprises following steps:
(1) Compound I and Compound I I reaction obtain intermediate III;
(2) intermediate III step (1) being made is reacted and is obtained intermediate compound IV with CDI;
(3) intermediate compound IV step (2) being made is reacted with methylamine and is obtained intermediate V;
(4) the intermediate V and the excess acetyl chloride that step (3) are made obtain target compound TM;
2. preparation method according to claim 1, is characterized in that: the temperature of reaction of step (1), step (2), step (3) and step (4) is-20～150 ℃.
3. preparation method according to claim 1, is characterized in that: the solvent in step (1), step (2), step (3) and step (4) is selected from: one or more in ethanol, Virahol, toluene, acetone, methylene dichloride and water.
4. preparation method according to claim 1, is characterized in that: in step (1), Compound I and Compound I I reaction obtain middle compound III, and the mol ratio of Compound I and Compound I I is 1: 0.5～1: 5.
5. preparation method according to claim 1, is characterized in that: in step (2), compound III is reacted with CDI and obtained middle compound IV, and the mol ratio of compound III and CDI is 1: 0.5～1: 10.
6. preparation method according to claim 1, it is characterized in that: in step (3), compound IV is reacted with methylamine and obtained intermediate V, compound IV and equivalence ratio methylamine are 1: 0.5～1: 10, and described methylamine is all kinds of SOLVENTS and the various content such as methylamine, aqueous methylamine solution, methylethylolamine solution.
7. preparation method according to claim 1, is characterized in that: in step (4), compound V and excess acetyl chloride obtain target product TM, and compound V and mol ratio Acetyl Chloride 98Min. are 1: 0.5～1: 5.
8. preparation method according to claim 1, is characterized in that: the reaction of step (1), step (2), step (3) and step (4) is as follows:
At 20-25 ℃, 25g Compound I is thrown in tri-mouthfuls of reaction flasks of 500mL, added Virahol 150mL, start to stir, add Compound I I 34.36g, 85 ± 5 ℃ of back flow reaction 24h, with the TLC point plate that developping agent is DCM:MeOH: ammoniacal liquor=20:1:0.1, show extent of reaction, after having reacted, being cooled to 25 ± 5 ℃ has a large amount of white solids to separate out, and filters, filter cake is used isopropyl alcohol wash 80mL * 2, drain, collect filter cake, at 50 ± 5 ℃ of dry 12h, obtain compound III;
At 20-25 ℃, 42g compound III is joined in 500mL there-necked flask, be added in 100mL toluene and dissolve, add N, N'-carbonyl dimidazoles 24.11g is in system again, and system is heated to 110 ± 5 ℃ of back flow reaction 5h, it with developping agent, is methylene dichloride: the TLC detection reaction of methyl alcohol: ammoniacal liquor=20:1:0., after reacting completely, be down to room temperature ℃, add ethanol 50mL, stir 30min, remove by filter mother liquor, collect 50 ℃ of air blast of filter cake and dry 12 hours, the compound IV of getting profit;
At 20-25 ℃, 42g compound IV joins in tri-mouthfuls of reaction flasks of 500mL, adds 150mL dehydrated alcohol, open and stir, add first ammonia soln 24.38g, 80 ℃ of back flow reaction 1h, with developping agent, be the TLC detection reaction of DCM:MeOH: ammoniacal liquor=20:1:0.1, after reacting completely, be cooled to 40 ℃ ± 5 ℃ and add 50mL ethanol solution hydrochloride, control temperature and remain on 30 ± 5 ℃, separate out a large amount of white, be down to 20-25 ℃, filter, 60mL * 2 dehydrated alcohol is washed, and 50 ± 5 ℃ of oven dry obtain compound V;
Get 50mL single port reaction flask, add 1g compound V, add 10mL acetone solution, the system of falling is cooled to 0-5 ℃, drip Acetyl Chloride 98Min. 0.94g, temperature is controlled at 0-5 ℃, finish, with the TLC monitoring that developping agent is DCM:MeOH: ammoniacal liquor=20:1:0.1, react completely, continue to stir 15min, system is filtered, 5mL * 2 acetone is washed, 5mL * 2 normal hexane is washed, drain, the methylene dichloride that the volume ratio of take is 1:1 and methyl alcohol are crossed 200 order silicagel columns after dissolution with solvents, with this solvent as elutriant wash-out, collect elutriant, revolve and steam to doing to obtain white solid powder, add 10mL normal hexane, filter, 10mL normal hexane is washed, drain, 25 ± 5 ℃ of vacuum-drying 12h obtain compound TM.
9. compound TM, structure is as follows:
10. the application of compound claimed in claim 9 in razaxaban quality control.
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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 |
| CN104807934A (en) * | 2015-04-30 | 2015-07-29 | 成都百裕科技制药有限公司 | 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 |
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| CN104807934A (en) * | 2015-04-30 | 2015-07-29 | 成都百裕科技制药有限公司 | Normal-phase high performance liquid chromatography detection method of isoindole diketone compounds |
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| 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 |
| CN111721858A (en) * | 2020-06-03 | 2020-09-29 | 杭州华东医药集团新药研究院有限公司 | Method for determining genotoxic impurities in rivaroxaban |
| 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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