CN103387566B - Prepare the method for 3-[[[2-[[(4-cyano-phenyl) is amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-base] carbonyl] (pyridine-2-base) is amino] ethyl propionate - Google Patents
Prepare the method for 3-[[[2-[[(4-cyano-phenyl) is amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-base] carbonyl] (pyridine-2-base) is amino] ethyl propionate Download PDFInfo
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Abstract
The open one of the present invention prepares the method for 3-[[[2-[[(4-cyano-phenyl) amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-base] carbonyl] (pyridine-2-base) is amino] ethyl propionate, it is characterized in that described method comprises and makes (4-cyano-phenyl) amino] the first step of reacting with 3-[(3-amino-4-methylamino benzoyl) (pyridine-2-base) is amino] ethyl propionate again with pair (trichloromethyl) carbonate reaction of acetic acid.Described method is simple, and cost is low.
Description
Technical field
The present invention is pharmaceutical synthesis field, the method of 3-[[[2-[[(4-cyano-phenyl) is amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-base] carbonyl] (pyridine-2-base) is amino] ethyl propionate is prepared in particular to one.
Background technology
Thrombus is mainly divided into arterial thrombus and phlebothrombosis.Venous thromboembolism is brought out to be formed by many reasons in vein blood vessel and can be caused venous thromboembolism (Venous thromboembolism, VET), its main clinical manifestation is deep venous thrombosis (deep venous thrombosis, and pulmonary infarction (pulmonary embolism DVT), PE), it is the disease of serious harm human health, pulmonary infarction is common one of breathing and cardiovascular disorder, deep venous thrombosis mainly occurs at large-scale orthopaedics Post operation, anticoagulant treatment controls thrombotic basic skills, effectively can reduce mortality ratio, prevention of recurrence.
Dabigatran etcxilate (Dabigatran etexilate, following formula 1) is a kind of new oral direct thrombin inhibitor, is converted into active part dabigatran (dabigatran) after oral absorption through esterase, produces zymoplasm restraining effect.Be mainly used in and carry out the full hip of selectivity or the adult patient phlebothrombosis of knee valve replacement and the prevention of atrial fibrillation patients apoplexy and thrombus entirely for preventing.3-[[[2-[[(4-cyano-phenyl) is amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-base] carbonyl] (pyridine-2-base) is amino] ethyl propionate (following formula 2 is called compound 2 herein) is the important intermediate of synthesis dabigatran etcxilate.
Prior art-as adopt [(4-cyano-phenyl) amino] acetic acid (following formula 3; be called compound 3 herein) and 3-[(3-amino-4-methylamino benzoyl) (pyridine-2-base) amino] ethyl propionate (following formula 4 is called compound 4 herein) as Material synthesis compound 2:
WO98/37075 and document J.Med.Chem, 2002,45,1757-1766 mentions and makees solvent, N, N with tetrahydrofuran (THF) (THF) '-carbonyl dimidazoles (CDI) is condensing agent, reflux in acetic acid, dichloromethane extraction, evaporate to dryness, obtains compound 2 (productive rate: 61%) through column chromatography.
CN1861596 mentions and selects DMF as solvent, I-hydroxybenzotriazole (HOBT) and 1-ethyl-3-(3-dimethyl propyl) carbodiimide hydrochloride (EDCI) are as condensing agent, reflux in acetic acid, ammonia neutralization, dichloromethane extraction, evaporate to dryness, obtains compound 2 through column chromatography.(productive rate: 83%).
It is solvent that WO2008095928 mentions with THF, CDI or EDCI is condensing agent, refluxes in acetic acid, obtains compound 2 with HBr salify.
WO2009111997 mentions and makees solvent with dried THF, and CDI is condensing agent, refluxes in acetic acid, dichloromethane extraction, evaporate to dryness, becomes oxalate in ethyl acetate, recrystallization, dissociates and obtains compound 2 (productive rate: 57.2%, HPLC:97.8%).
The Chinese Journal of Pharmaceuticals that Xing Songsong etc. deliver, 2010, mention in 42 (5): 321-325: compound 3 reacts in the mixed solution of DMF and THF, react with EDCI and HOBT, evaporate to dryness, make solvent with methylene dichloride again, react with compound 4, acetic acid refluxes, ammonia neutralization, dichloromethane extraction, evaporate to dryness, column chromatography obtains compound 2 (productive rate: 67%).
Inevitably there is the by product such as imidazoles, hydroxybenzotriazole in existing method, product is difficult to by simple crystallization mode purifying in reaction system, and document all adopts the means such as column chromatography or salify dissociate again to obtain purer product.
Summary of the invention
The object of the present invention is to provide a kind of method of this intermediate of synthesis of simple and easy to do, low cost.
Therefore; the invention provides the method that one prepares 3-[[[2-[[(4-cyano-phenyl) amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-base] carbonyl] (pyridine-2-base) is amino] ethyl propionate, it is characterized in that described method comprises and make (4-cyano-phenyl) amino] the first step of reacting with 3-[(3-amino-4-methylamino benzoyl) (pyridine-2-base) is amino] ethyl propionate again with pair (trichloromethyl) carbonate reaction of acetic acid.
Described method also comprises product crystallization solvent crystallization and the step with recrystallization solvent recrystallization.
According to of the present invention one preferred embodiment, described preparation method comprises the following steps:
1) in non-polar solvent, make [(4-cyano-phenyl) is amino] acetic acid and two (trichloromethyl) carbonic ether react in the presence of an organic base;
2) in non-polar solvent, step 1 is made) products therefrom and 3-[(3-amino-4-methylamino benzoyl) (pyridine-2-base) is amino] ethyl propionate reacts, reaction terminates rear evaporate to dryness, evaporate to dryness after resistates refluxes in acetic acid;
3) step 2) use recrystallization solvent recrystallization again after gained resistates crystallization solvent crystallization, obtain 3-[[[2-[[(4-cyano-phenyl) is amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-base] carbonyl] (pyridine-2-base) is amino] ethyl propionate.
According to of the present invention one preferred embodiment, described organic bases is pyridine.
According to of the present invention one preferred embodiment, described non-polar solvent is selected from methylene dichloride, tetrahydrofuran (THF) or toluene; More preferably methylene dichloride.
According to of the present invention one preferred embodiment, described crystallization solvent is selected from ethyl acetate, butylacetate or normal hexane, more preferably ethyl acetate.
According to of the present invention one preferred embodiment, described recrystallization solvent is selected from ethanol, acetone, acetonitrile, toluene or Virahol, more preferably ethanol.
According to a particularly preferred embodiment of the present invention, two (trichloromethyl) carbonic ether is condensing agent, with compound 4: compound 3: two (trichloromethyl) carbonic ether: the mol ratio of pyridine is 1: (1.0-1.2): (0.33-0.55): the ratio of (1.0-1.65) feeds intake, two (trichloromethyl) carbonic ether first reacts in methylene dichloride with compound 3, dissolve with methylene dichloride again after evaporate to dryness methylene dichloride, add compound 4 back flow reaction 15-20h, acetic acid backflow 1-2h again, dichloromethane extraction, evaporate to dryness, the crude product obtained directly obtains with ethyl acetate crystallization, use ethanol equal solvent recrystallization again.
Compared with the synthetic method of prior art, advantage of the present invention is as follows:
1) with two (trichloromethyl) carbonic ether for condensing agent, cost is low, and operation is gentle, without the need to low temperature;
2) taking methylene dichloride as solvent, without the need to heavily steaming, being easy to removing;
3) aftertreatment ethyl acetate crystallization, ethyl alcohol recrystallization, without the need to carrying out column chromatography, without the need to salify and free operation;
4) by product is few, and the product purity obtained is high.
Embodiment
Further describe the present invention by embodiment below, but described embodiment does not form limitation of the scope of the invention.Compound 3 and 4 provides by Shanghai Aobo Biomedicine Techn Co., Ltd..
HPLC condition determination is as follows:
Instrument: Waters1525-2489-2707 high performance liquid chromatograph,
Chromatographic column: C18,
Column length: 15cm,
Moving phase: (methyl alcohol: acetonitrile=55: 45): (1% diethylamine aqueous solution, phosphoric acid adjusts PH7)=58: 42,
Flow velocity: 0.6ml/min,
Wavelength: 284nm,
Column temperature: 40 DEG C,
Sample size: 5 μ L.
Embodiment 1
By compound 3 (3.4g, 0.0193mol) be dissolved in methylene dichloride (150ml), add two (trichloromethyl) carbonic ether (2.3g/0.0077mol), pyridine (1.82g, 0.0231mol), 3h is stirred at 20 DEG C.Evaporate to dryness methylene dichloride, is dissolved in methylene dichloride (75ml), transfers in four-hole bottle by residuum, compound 4 (6g, 0.0175mol) is dissolved in methylene dichloride (75ml), is added in above-mentioned solution, be heated to backflow, reaction 15-20h.Evaporate to dryness methylene dichloride, adds acetic acid (80ml) and to reflux 1.5h in residuum.Evaporate to dryness acetic acid, dissolves with methylene dichloride, washes 3-4 time, dichloromethane layer anhydrous magnesium sulfate drying.Evaporate to dryness obtains micro-Yellow amorphous thing 7.8g.Add ethyl acetate (25ml) crystallization, obtain micro-yellow solid 6g, add ethanol (30ml) recrystallization and obtain white solid 5.87g.Productive rate: 70%, m.p.:141-142 DEG C.Purity: 99.41% (being recorded by HPLC), retention time: 5.429min.
Embodiment 2
Be dissolved in methylene dichloride 600ml by compound 3 (12.g, 0.0679mol), add two (trichloromethyl) carbonic ether (8.1g, 0.0272mol), pyridine (6.45g, 0.0816mol), stirs 3h at 24 DEG C.Evaporate to dryness methylene dichloride, is dissolved in methylene dichloride (300ml), transfers in four-hole bottle by residuum, compound 4 (21.1g, 0.0617mol) is dissolved in methylene dichloride (300ml), is added in above-mentioned solution, be heated to backflow, reaction 15-20h.Evaporate to dryness methylene dichloride, adds acetic acid (350ml) and to reflux 1.5h in residuum.Evaporate to dryness acetic acid, dissolves with methylene dichloride, washes 3-4 time, dichloromethane layer anhydrous magnesium sulfate drying.Evaporate to dryness obtains micro-Yellow amorphous thing 38.8g.Add ethyl acetate (150ml) crystallization, obtain micro-yellow solid 25g, add ethanol (120ml) recrystallization and obtain white solid 22g.Productive rate 74%, m.p.:141-142 DEG C.Purity: 99.61% (being recorded by HPLC), retention time: 5.479min.
Embodiment 3
Be dissolved in methylene dichloride 1300ml by compound 3 (24.7g, 0.140mol), add two (trichloromethyl) carbonic ether (16.6g/0.056mol), pyridine (13.3g, 0.168mol), stirs 3h at 25 DEG C.Evaporate to dryness methylene dichloride, is dissolved in 600ml methylene dichloride by residuum, transfer in four-hole bottle, is dissolved in methylene dichloride (700m) l by compound 4 (40g/0.117mol), is added in above-mentioned solution, is heated to backflow, reaction 15-20h.Evaporate to dryness methylene dichloride, adds acetic acid 80ml backflow 1.5h in residuum.Evaporate to dryness acetic acid, dissolves with methylene dichloride, washes 3 times, dichloromethane layer anhydrous magnesium sulfate drying.Evaporate to dryness obtains micro-Yellow amorphous thing 66g.Add ethyl acetate (260ml) crystallization, obtain micro-yellow solid 46g, add ethanol (230ml) recrystallization and obtain white solid 43g, productive rate: 76%m.p.:141-142 DEG C.Purity: 99.5% (being recorded by HPLC), retention time: 5.508min.
Embodiment 4
Compound 3 (10g, 0.0568mol) is dissolved in heavy steamed THF450ml, N
2protection, add two (trichloromethyl) carbonic ether (6.7g/0.0227mol), pyridine (5.4g, 0.0681mol), stirs 3h at 20 DEG C.Evaporate to dryness THF, is dissolved in residuum in THF (200ml), transfers in four-hole bottle, is dissolved in by compound 4 (17.6g, 0.0516mol) in THF (250ml), is added in above-mentioned solution, is heated to backflow, reaction 15-20h.Evaporate to dryness THF, adds acetic acid (240ml) and to reflux 1.5h in residuum.Evaporate to dryness acetic acid, dissolves with methylene dichloride, washes 3-4 time, dichloromethane layer anhydrous magnesium sulfate drying.Evaporate to dryness obtains micro-Yellow amorphous thing 22.6g.Add ethyl acetate (80ml) crystallization, obtain micro-yellow solid 18g, add ethanol (90ml) recrystallization and obtain white solid 16.4g.Productive rate: 66%, m.p.:141-142 DEG C, purity: 98.54% (being recorded by HPLC), retention time: 5.419.
Claims (6)
1. prepare the method for 3-[[[2-[[(4-cyano-phenyl) is amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-base] carbonyl] (pyridine-2-base) is amino] ethyl propionate, it is characterized in that said method comprising the steps of:
1) in methylene dichloride, make [(4-cyano-phenyl) is amino] acetic acid and two (trichloromethyl) carbonic ether react in the presence of an organic base;
2) in methylene dichloride, step 1 is made) products therefrom and 3-[(3-amino-4-methylamino benzoyl) (pyridine-2-base) is amino] ethyl propionate reacts, reaction terminates rear evaporate to dryness, evaporate to dryness after resistates refluxes in acetic acid;
3) step 2) use recrystallization solvent recrystallization again after gained resistates crystallization solvent crystallization, obtain 3-[[[2-[[(4-cyano-phenyl) is amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-base] carbonyl] (pyridine-2-base) is amino] ethyl propionate
Wherein said 3-[(3-amino-4-methylamino benzoyl) (pyridine-2-base) is amino] ethyl propionate: [(4-cyano-phenyl) is amino] acetic acid: the mol ratio of two (trichloromethyl) carbonic ether is 1: 1.0-1.2: 0.33-0.55.
2. the method for claim 1, is characterized in that described organic bases is pyridine.
3. the method for claim 1, is characterized in that described crystallization solvent is selected from ethyl acetate, butylacetate or normal hexane.
4. method as claimed in claim 3, is characterized in that described crystallization solvent is ethyl acetate.
5. the method for claim 1, is characterized in that described recrystallization solvent is selected from ethanol, acetone, acetonitrile, toluene or Virahol.
6. method as claimed in claim 5, is characterized in that described recrystallization solvent is ethanol.
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| CN104744438A (en) * | 2014-12-17 | 2015-07-01 | 烟台东诚药业集团股份有限公司 | Method for synthesising and preparing dabigatran benzimidazole intermediate |
| CN105481831B (en) * | 2015-12-16 | 2018-06-12 | 开封明仁药业有限公司 | A kind of method for preparing dabigatran etexilate intermediate |
| CN110878083A (en) * | 2018-09-05 | 2020-03-13 | 连云港恒运药业有限公司 | Purification method of dabigatran etexilate intermediate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1248251A (en) * | 1997-02-18 | 2000-03-22 | 贝林格尔英格海姆法玛公司 | Disubstituted bicyclic heterocycles, their production and use as medicaments |
| CN1861596A (en) * | 2005-12-16 | 2006-11-15 | 复旦大学 | Process for synthesizing antithrombin inhibitor of non-asymmetric non-peptide kind |
| CN102268029A (en) * | 2011-05-19 | 2011-12-07 | 苏州二叶制药有限公司 | Preparation method of compound (1S, 2S, 3R, 5S)-pinanediol-L-phenylalanine-L-leucine boric acid ester |
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| ITMI20041113A1 (en) * | 2004-06-01 | 2004-09-01 | Antibioticos Spa | PROCESS FOR THE SYNTHESIS OF THE THALIDOMIDE |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1248251A (en) * | 1997-02-18 | 2000-03-22 | 贝林格尔英格海姆法玛公司 | Disubstituted bicyclic heterocycles, their production and use as medicaments |
| CN1861596A (en) * | 2005-12-16 | 2006-11-15 | 复旦大学 | Process for synthesizing antithrombin inhibitor of non-asymmetric non-peptide kind |
| CN102268029A (en) * | 2011-05-19 | 2011-12-07 | 苏州二叶制药有限公司 | Preparation method of compound (1S, 2S, 3R, 5S)-pinanediol-L-phenylalanine-L-leucine boric acid ester |
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| Title |
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| 达比加群酯的合成;邢松松 等;《中国医药工业杂志》;20101231;第41卷(第5期);第321-325页 * |
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