CN103387566A - Preparation method of 3-[[[2-[[4-cyanophenyl) amino] methyl]-1-methyl-1H-benzimidazole-5-yl] carbonyl] (pyridine-2-yl) amino] ethyl propionate - Google Patents
Preparation method of 3-[[[2-[[4-cyanophenyl) amino] methyl]-1-methyl-1H-benzimidazole-5-yl] carbonyl] (pyridine-2-yl) amino] ethyl propionate Download PDFInfo
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Abstract
The invention discloses a preparation method of 3-[[[2-[[4-cyanophenyl) amino] methyl]-1-methyl-1H-benzimidazole-5-yl] carbonyl] (pyridine-2-yl) amino] ethyl propionate. The preparation method is characterized by comprising reaction steps as follows: a first reaction of [(4-cyanophenyl) amino] acetic acid and bis(trichloromethyl) carbonate, and then a reaction of 3-[(3-amino-4-methylamino benzoyl) (pyridine-2-yl) amino] ethyl propionate and a product of the first reaction. The preparation method is simple, easy to operation and low-cost.
Description
Technical field
The present invention is the synthetic field of medicine, in particular to a kind of 3-[[[2-[[(4-cyano-phenyl for preparing) amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-yl] carbonyl] (pyridine-2-yl) amino] method of ethyl propionate.
Background technology
Thrombus mainly is divided into arterial thrombus and phlebothrombosis.Venous thromboembolism is brought out to form 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, DVT) and pulmonary infarction (pulmonary embolism, PE), it is the disease of serious harm human health, pulmonary infarction is one of common breathing and cardiovascular disorder, deep venous thrombosis is mainly to occur after large-scale bone surgery, the anticoagulant treatment is to control thrombotic basic skills, can effectively reduce mortality ratio, prevention of recurrence.
Dabigatran etcxilate (Dabigatran etexilate, following formula 1) is a kind of new oral direct thrombin inhibitor, and oral absorption is converted into active part dabigatran (dabigatran) by esterase, produces the zymoplasm restraining effect.Be mainly used in for prevention and carry out the full hip of selectivity or the adult patient phlebothrombosis of full knee valve replacement and the prevention of atrial fibrillation patients apoplexy and thrombus.The 3-[[[2-[[(4-cyano-phenyl) amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-yl] carbonyl] (pyridine-2-yl) amino] ethyl propionate (following formula 2 is called compound 2 herein) is the important intermediate of synthetic 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-yl) amino] ethyl propionate (following formula 4 is called compound 4 herein) is as raw material synthetic compound 2:
WO98/37075 and document J.Med.Chem, 2002,45,1757-1766 mention with tetrahydrofuran (THF) (THF) and make solvent, N, N '-carbonyl dimidazoles (CDI) is condensing agent, refluxes in acetic acid, dichloromethane extraction, evaporate to dryness, obtain compound 2 (productive rate: 61%) through column chromatography.
CN1861596 mentions and selects DMF as solvent, and I-hydroxybenzotriazole (HOBT) and 1-ethyl-3-(3-dimethyl propyl) carbodiimide hydrochloride (EDCI), as condensing agent, refluxes in acetic acid, ammonia neutralization, dichloromethane extraction, evaporate to dryness, obtain compound 2 through column chromatography.(productive rate: 83%).
WO2008095928 mentions take THF as solvent, and CDI or EDCI are condensing agent, refluxes in acetic acid, with the HBr salify, obtains compound 2.
WO2009111997 mentions with the dry THF that crosses and makees solvent, and CDI is condensing agent, reflux in acetic acid, dichloromethane extraction, evaporate to dryness, become oxalate in ethyl acetate, recrystallization, free obtain compound 2 (productive rate: 57.2%, HPLC:97.8%).
The Chinese Journal of Pharmaceuticals that Xing Songsong etc. deliver, 2010,42 (5): mention in 321-325: compound 3 reacts in the mixed solution of DMF and THF, with EDCI and HOBT reaction, evaporate to dryness, make solvent with methylene dichloride again, with compound 4 reactions, acetic acid refluxes, ammonia neutralization, dichloromethane extraction, evaporate to dryness, column chromatography obtain compound 2 (productive rate: 67%).
Inevitably there are the by products such as imidazoles, hydroxybenzotriazole in existing method in reaction system, product is difficult to by simple crystallization mode purifying, 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 simple and easy to do, method of synthetic this intermediate cheaply.
Therefore; the invention provides a kind of 3-[[[2-[[(4-of preparation cyano-phenyl) amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-yl] carbonyl] (pyridine-2-yl) amino] method of ethyl propionate, it is characterized in that described method comprises to make (4-cyano-phenyl) amino] acetic acid first with two (trichloromethyl) carbonate reactions again with 3-[(3-amino-4-methylamino benzoyl) (pyridine-2-yl) amino] the ethyl propionate step of reacting.
Described method also comprises that product is with crystallization solvent crystallization with the step of recrystallization solvent recrystallization.
According to of the present invention one preferred embodiment, described preparation method comprises the following steps:
1) make [(4-cyano-phenyl) amino] acetic acid and the reaction under organic bases exists of two (trichloromethyl) carbonic ether in non-polar solvent;
2) make step 1 in non-polar solvent) products therefrom and 3-[(3-amino-4-methylamino benzoyl) (pyridine-2-yl) amino] the ethyl propionate reaction, evaporate to dryness after reaction finishes, evaporate to dryness resistates refluxes in acetic acid after;
3) step 2) the gained resistates is used the recrystallization solvent recrystallization after with crystallization solvent crystallization again, obtains the 3-[[[2-[[(4-cyano-phenyl) amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-yl] carbonyl] (pyridine-2-yl) 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, take compound 4: compound 3: two (trichloromethyl) carbonic ether: the mol ratio of pyridine is as 1: (1.0-1.2): (0.33-0.55): ratio (1.0-1.65) feeds intake, two (trichloromethyl) carbonic ether first reacts in methylene dichloride with compound 3, dissolve with methylene dichloride again after the 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 that obtains directly obtains with the ethyl acetate crystallization, use again ethanol equal solvent recrystallization.
Compare with the synthetic method of prior art, advantage of the present invention is as follows:
1) take two (trichloromethyl) carbonic ether as condensing agent, cost is low, and operation is gentle, need not low temperature;
2) take methylene dichloride as solvent, need not heavily to steam, be easy to remove;
3) aftertreatment ethyl acetate crystallization, ethyl alcohol recrystallization, need not to carry out column chromatography, need not salify and free operation;
4) by product is few, and the product purity that obtains is high.
Embodiment
Below further describe the present invention with embodiment, 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..
The HPLC condition determination is as follows:
Instrument: the 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 is transferred PH7)=58: 42,
Flow velocity: 0.6ml/min,
Wavelength: 284nm,
Column temperature: 40 ℃,
Sample size: 5 μ L.
Embodiment 1
Compound 3 (3.4g, 0.0193mol) is dissolved in methylene dichloride (150ml), adds two (trichloromethyl) carbonic ethers (2.3g/0.0077mol), pyridine (1.82g, 0.0231mol), stir 3h under 20 ℃.The evaporate to dryness methylene dichloride, be dissolved in methylene dichloride (75ml) with residuum, transfers in four-hole bottle, and compound 4 (6g, 0.0175mol) is dissolved in methylene dichloride (75ml), is added in above-mentioned solution, is heated to reflux reaction 15-20h.The evaporate to dryness methylene dichloride, add acetic acid (80ml) backflow 1.5h in residuum.Evaporate to dryness acetic acid, dissolve with methylene dichloride, washes the dichloromethane layer anhydrous magnesium sulfate drying 3-4 time.Evaporate to dryness obtains little yellow amorphous article 7.8g.Add ethyl acetate (25ml) crystallization, obtain little yellow solid 6g, add ethanol (30ml) recrystallization to obtain white solid 5.87g.Productive rate: 70%, m.p.:141-142 ℃.Purity: 99.41% (by HPLC, being recorded), retention time: 5.429min.
Embodiment 2
Compound 3 (12.g, 0.0679mol) is dissolved in methylene dichloride 600ml, adds two (trichloromethyl) carbonic ethers (8.1g, 0.0272mol), pyridine (6.45g, 0.0816mol), stir 3h under 24 ℃.The evaporate to dryness methylene dichloride, be dissolved in methylene dichloride (300ml) with residuum, transfers in four-hole bottle, and compound 4 (21.1g, 0.0617mol) is dissolved in methylene dichloride (300ml), is added in above-mentioned solution, is heated to reflux reaction 15-20h.The evaporate to dryness methylene dichloride, add acetic acid (350ml) backflow 1.5h in residuum.Evaporate to dryness acetic acid, dissolve with methylene dichloride, washes the dichloromethane layer anhydrous magnesium sulfate drying 3-4 time.Evaporate to dryness obtains little yellow amorphous article 38.8g.Add ethyl acetate (150ml) crystallization, obtain little yellow solid 25g, add ethanol (120ml) recrystallization to obtain white solid 22g.Productive rate 74%, m.p.:141-142 ℃.Purity: 99.61% (by HPLC, being recorded), retention time: 5.479min.
Embodiment 3
Compound 3 (24.7g, 0.140mol) is dissolved in methylene dichloride 1300ml, adds two (trichloromethyl) carbonic ethers (16.6g/0.056mol), pyridine (13.3g, 0.168mol), stir 3h under 25 ℃.The evaporate to dryness methylene dichloride, be dissolved in the 600ml methylene dichloride with residuum, transfers in four-hole bottle, and compound 4 (40g/0.117mol) is dissolved in methylene dichloride (700m) l, is added in above-mentioned solution, is heated to reflux reaction 15-20h.The evaporate to dryness methylene dichloride, add acetic acid 80ml backflow 1.5h in residuum.Evaporate to dryness acetic acid, dissolve with methylene dichloride, washes the dichloromethane layer anhydrous magnesium sulfate drying 3 times.Evaporate to dryness obtains little yellow amorphous article 66g.Add ethyl acetate (260ml) crystallization, obtain little yellow solid 46g, add ethanol (230ml) recrystallization to obtain white solid 43g, productive rate: 76%m.p.:141-142 ℃.Purity: 99.5% (by HPLC, being recorded), retention time: 5.508min.
Embodiment 4
Compound 3 (10g, 0.0568mol) is dissolved in the THF450ml that heavily steamed N
2Protection, add two (trichloromethyl) carbonic ethers (6.7g/0.0227mol), and pyridine (5.4g, 0.0681mol) stirs 3h under 20 ℃.Evaporate to dryness THF, be dissolved in residuum in THF (200ml), transfers in four-hole bottle, and compound 4 (17.6g, 0.0516mol) is dissolved in THF (250ml), is added in above-mentioned solution, is heated to reflux reaction 15-20h.Evaporate to dryness THF, add acetic acid (240ml) backflow 1.5h in residuum.Evaporate to dryness acetic acid, dissolve with methylene dichloride, washes the dichloromethane layer anhydrous magnesium sulfate drying 3-4 time.Evaporate to dryness obtains little yellow amorphous article 22.6g.Add ethyl acetate (80ml) crystallization, obtain little yellow solid 18g, add ethanol (90ml) recrystallization to obtain white solid 16.4g.Productive rate: 66%, m.p.:141-142 ℃, purity: 98.54% (by HPLC, being recorded), retention time: 5.419.
Claims (10)
1. prepare the 3-[[[2-[[(4-cyano-phenyl) amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-yl] carbonyl] (pyridine-2-yl) amino] method of ethyl propionate, it is characterized in that described method comprises to make (4-cyano-phenyl) amino] acetic acid first with two (trichloromethyl) carbonate reactions again with 3-[(3-amino-4-methylamino benzoyl) (pyridine-2-yl) amino] the ethyl propionate step of reacting.
2. the method for claim 1, is characterized in that described method also comprises after product is with crystallization solvent crystallization the step of using again the recrystallization solvent recrystallization.
3. method as claimed in claim 1 or 2 is characterized in that said method comprising the steps of:
1) make [(4-cyano-phenyl) amino] acetic acid and the reaction under organic bases exists of two (trichloromethyl) carbonic ether in non-polar solvent;
2) make step 1 in non-polar solvent) products therefrom and 3-[(3-amino-4-methylamino benzoyl) (pyridine-2-yl) amino] the ethyl propionate reaction, evaporate to dryness after reaction finishes, evaporate to dryness resistates refluxes in acetic acid after;
3) step 2) the gained resistates is used the recrystallization solvent recrystallization after with crystallization solvent crystallization again, obtains the 3-[[[2-[[(4-cyano-phenyl) amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-yl] carbonyl] (pyridine-2-yl) amino] ethyl propionate.
4. method as claimed in claim 3, is characterized in that described organic bases is pyridine.
5. method as claimed in claim 3, is characterized in that described non-polar solvent is selected from methylene dichloride, tetrahydrofuran (THF) or toluene.
6. method as claimed in claim 5, is characterized in that described non-polar solvent is methylene dichloride.
7. method as claimed in claim 2 or claim 3, is characterized in that described crystallization solvent is selected from ethyl acetate, butylacetate or normal hexane.
8. method as claimed in claim 7, is characterized in that described crystallization solvent is ethyl acetate.
9. method as claimed in claim 2 or claim 3, is characterized in that described recrystallization solvent is selected from ethanol, acetone, acetonitrile, toluene or Virahol.
10. method as claimed in claim 9, is characterized in that described recrystallization solvent is ethanol.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN105481831A (en) * | 2015-12-16 | 2016-04-13 | 开封明仁药业有限公司 | New 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 |
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Patent Citations (4)
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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 |
| US20050272934A1 (en) * | 2004-06-01 | 2005-12-08 | Antibioticos S.P.A. | Process for the synthesis of thalidomide |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN105481831A (en) * | 2015-12-16 | 2016-04-13 | 开封明仁药业有限公司 | New method for preparing dabigatran etexilate 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 |
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