CN103833724A - Preparation method of 5-penphene-2-formyl chloride - Google Patents
Preparation method of 5-penphene-2-formyl chloride Download PDFInfo
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- CN103833724A CN103833724A CN201310004387.3A CN201310004387A CN103833724A CN 103833724 A CN103833724 A CN 103833724A CN 201310004387 A CN201310004387 A CN 201310004387A CN 103833724 A CN103833724 A CN 103833724A
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- chlorothiophene
- preparation
- formyl chloride
- triphosgene
- organic amine
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- DJCGIWVUKCNCAT-UHFFFAOYSA-N Cc1ccc(C(Cl)=O)[s]1 Chemical compound Cc1ccc(C(Cl)=O)[s]1 DJCGIWVUKCNCAT-UHFFFAOYSA-N 0.000 description 1
- QZLSBOVWPHXCLT-UHFFFAOYSA-N OC(c([s]1)ccc1Cl)=O Chemical compound OC(c([s]1)ccc1Cl)=O QZLSBOVWPHXCLT-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the technical field of a preparation method of 5-penphene-2-formyl chloride. The preparation method is characterized in that 5-penphene-2-carboxylic acid is taken as an initial raw material to react with chloro-reagent diphosgene or triphosgene in the presence of an organic amine catalyst, so as to prepare the 5-penphene-2-formyl chloride. The preparation method has the advantages that the process is simple, the production is safe and reliable, the reaction yield is high, the production cost is low, three wastes are not basically generated, a product is high in purity and has few impurities, and the preparation method is very suitable for industrial production. The 5-penphene-2-formyl chloride prepared by utilizing the preparation method is taken as an intermediate to prepare Rivaroxaban.
Description
Technical field
The present invention relates to preparation method's technical field of a kind of key intermediate 5-chlorothiophene-2-formyl chloride of razaxaban.
Background technology
Razaxaban is oxazolidinone compounds, the chemistry chloro-N-({(5S of 5-by name)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-oxazolidine-5-yl }-methyl)-2-thenoyl amine, its structure is following formula (I).Razaxaban is used as the direct inhibitor of factor Xa, and can be used as preventing and/or treating the medicine of thromboembolism illness, especially for hip joint or the replacement knee in arthroplasty adult patients of selecting a time, to prevent venous thrombosis (VTE); For NVAF patient, to reduce its palsy and systemic embolism; Treatment Acute coronary event, particularly ambiguity angina pectoris.
5-chlorothiophene-2-formyl chloride (III) is the key intermediate of synthetic razaxaban, has all reported this method in many pieces of documents, and synthetic route is as follows
In prior art, there are many pieces of documents all to disclose to utilize 5-chlorothiophene-2-carboxylic acid (II) to prepare 5-chlorothiophene-2-formyl chloride (III) for starting raw material.Such as disclosing in CN1906191B, 5-chlorothiophene-2-carboxylic acid is suspended in toluene, be heated to 75-80 ℃, at this temperature, drip thionyl chloride, at the temperature refluxing again, stir, until gas stops, cooling after, sulfur oxychloride is removed in underpressure distillation, obtains 5-chlorothiophene-2-formyl chloride solution of concentration about 30% in toluene.Be solvent such as openly adopting methylene dichloride in US2008051578A1 and US201134453, at N, under the catalysis of N '-dimethyl formamide, 5-chlorothiophene-2-carboxylic acid and excessive sulfur oxychloride or oxalyl chloride reflux 16 hours, after completion of the reaction, vacuum is revolved steaming, and 5-chlorothiophene-2-formyl chloride of obtaining is not purified can directly drop into next step reaction.Such as disclosing take ethyl acetate as solvent in US6906063 B2, at N, under the catalysis of N '-dimethyl formamide, 5-chlorothiophene-2-carboxylic acid reacts 2 hours with oxalyl chloride at 0 ℃, and after completion of the reaction, vacuum is revolved steaming, the 5-chlorothiophene-2-formyl chloride crude product obtaining.
The method of prior art has all adopted sulfur oxychloride or oxalyl chloride to prepare key intermediate 5-chlorothiophene-2-formyl chloride as chlorinating agent.Sulfur oxychloride is as the reaction classics of chlorinating agent, also more complete; But the serious corrosion of sulfur oxychloride to equipment, contains a large amount of asphyxiant sulfurous gas in industrial tail gas, belong to one of strict gas of controlling of national environmental protection, three wastes difficult treatment.And the transportation of sulfur oxychloride and use be subject to strict control, very high to conversion unit sealing requirements, production operation poor stability.Oxalyl chloride is not only to air-sensitive, runs into moisture and can occur to decompose and emit poisonous gas CO, CO
2and HCl.In addition, oxalyl chloride has high toxicity and corrodibility, can seriously stimulate eyes, skin and respiratory tract.The reagent bottle that holds oxalyl chloride must be preserved under shady and cool, dry environment, and strict seal.
Summary of the invention
Object of the present invention is exactly for the deficiencies in the prior art, provide a kind of safe and reliable, production cost is low, substantially without three wastes generation, be suitable for the preparation method of 5-chlorothiophene-2-formyl chloride of suitability for industrialized production, prepare razaxaban with this.
For reaching above-mentioned purpose, the technical scheme that the present invention takes is as follows:
The preparation method of 5-chlorothiophene-2-formyl chloride, the method is take 5-chlorothiophene-2-carboxylic acid as raw material, reacts and obtains target product III with chlorinating agent under the katalysis of organic amine:
Described chlorinating agent is triphosgene or trichloromethylchloroformate.Preferably triphosgene.
Described triphosgene refers to two (trichloromethyl) carbonic ether, and trichloromethylchloroformate refers to superpalite.
The preparation method of above-mentioned 5-chlorothiophene-2-formyl chloride, preferred operation steps is: in first organic amine catalyzer being joined in the organic solvent of raw material 5-chlorothiophene-2-carboxylic acid (II), then the organic solvent that adds chlorinating agent, reacts completely, and obtains 5-chlorothiophene-2-formyl chloride of oily.Temperature of reaction is preferably at 0～50 ℃, and further preferred dropping temperature is in room temperature; 1～40 hour reaction times, preferably at 10～30 hours.
The preparation method of above-mentioned 5-chlorothiophene-2-formyl chloride, organic amine used is the alkaline organics such as diethylamine, triethylamine, pyridine, N-methylmorpholine, DMF or DMAP, preferably triethylamine or pyridine.The add-on of organic amine is catalytic amount.
The preparation method of above-mentioned 5-chlorothiophene-2-formyl chloride, further controlling reaction mass molar ratio is raw material (II): triphosgene: organic amine is 1:(0.4～3): (0.5～1), preferred mol ratio is 1:(0.6～1.2): (0.8～1).
The preparation method of above-mentioned 5-chlorothiophene-2-formyl chloride, solvent used can be halide reagent, as methylene dichloride, trichloromethane etc.; Esters solvent, as ethyl acetate, isopropyl acetate etc.; Hydrocarbon polymer, as normal hexane, benzene, toluene, hexanaphthene etc.; Ethers reagent is as tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane etc.; Preferred organic solvent is methylene dichloride.The most handy same solvent of organic solvent of the organic solvent of raw material (II) and chlorinating agent, the meltage that consumption of organic solvent is solute.
5-chlorothiophene-2-formyl chloride prepared by aforesaid method of the present invention is prepared razaxaban as intermediate, and step is as follows:
(1) 4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidine-3-yl] phenyl } morpholine-3-keto hydrochloride (IV) solvent in aqueous phase system, add anhydrous sodium carbonate free, then add acetone and make mixed solvent.5-chlorothiophene-2-the formyl chloride obtaining with the present invention reacts in 8～12 ℃, then reaction mixture is heated to 50 ℃, after having reacted, is cooled to room temperature, and suction filtration is precipitated product, i.e. razaxaban crude product.
(2) razaxaban Glacial acetic acid recrystallization step (1) being obtained, is cooled to 20 ℃, and suction filtration obtains white crystalline powder, with a small amount of Glacial acetic acid and water washing, obtains razaxaban.
The reaction mechanism that triphosgene and trichloromethylchloroformate are decomposed into phosgene is as follows: a part triphosgene and trichloromethylchloroformate can produce respectively three molecules and two molecule phosgene.
The chlorinating agent that trichloromethylchloroformate or triphosgene replace traditional sulfur oxychloride or oxalyl chloride to prepare as acyl chlorides, the product purity that obtains is high, impurity is few, participates in subsequent reactions and obtains highly purified razaxaban.Its useful effect is embodied in: processing condition are reasonable, get rid of with serious pollution sulfur oxychloride and oxalyl chloride, fundamentally eliminated traditional technology potential safety hazard, the three wastes are difficult to the problems such as processing, safety simple to operate, be convenient to metering, reaction time is short, and reaction yield is high, and production cost is low, substantially produce without the three wastes, environment-friendly and green, byproduct hydrogen chloride absorbs the technical hydrochloric acid that can prepare 30% through double tower, have larger implementary value and social economic value.
Embodiment
By following examples, the present invention will be further described, but protection scope of the present invention is not limited to this.
The preparation of embodiment 1:5-chlorothiophene-2-formyl chloride
In 250ml four-hole bottle, add 14.5g (0.09mol) 5-chlorothiophene-2-carboxylic acid, add 150ml methylene dichloride and 12.5ml(0.09mol) triethylamine dissolving, connect drying installation and acid gas absorption plant.26.7g (0.09mol) triphosgene is dissolved in to (1.8mol/L) in 50ml methylene dichloride, at room temperature splashes in four-hole bottle, stirring and refluxing 20 hours.After having reacted, in system, add appropriate anhydrous magnesium sulfate, stir, suction filtration, revolves steaming mother liquor, obtains yellow oil 17g, crude product yield 100%.
The preparation of embodiment 2:5-chlorothiophene-2-formyl chloride
In 250ml four-hole bottle, add 14.5g (0.09mol) 5-chlorothiophene-2-carboxylic acid, add 150ml methylene dichloride and 7.2g(0.09mol) pyridine dissolving, connect drying installation and acid gas absorption plant, at room temperature the dichloromethane solution of triphosgene (26.7g/50ml=1.8mol/L) is splashed in four-hole bottle to stirring and refluxing 20 hours.After having reacted, in system, add appropriate anhydrous sodium sulphate, stir, suction filtration, revolves steaming mother liquor, obtains yellow oil 17.5g, crude product yield 100%.
The preparation of embodiment 3:5-chlorothiophene-2-formyl chloride
In 250ml four-hole bottle, add 8.1g (0.05mol) 5-chlorothiophene-2-carboxylic acid, add 100ml methylene dichloride and 5.5ml (0.04mol) triethylamine to dissolve, connect drying installation and acid gas absorption plant, the dichloromethane solution of triphosgene (26.7g/50ml=1.8mol/L) is splashed in four-hole bottle to stirring and refluxing 8 hours at 40 ℃.After having reacted, in system, add appropriate anhydrous magnesium sulfate, stir, suction filtration, revolves steaming mother liquor, obtains yellow oil and insoluble solid (raw material).GC detection reaction is incomplete, yield 84%.
The preparation of embodiment 4:5-chlorothiophene-2-formyl chloride
In 250ml four-hole bottle, add 8.1g (0.05mol) 5-chlorothiophene-2-carboxylic acid, add 80m toluene and 5.5ml (0.04mol) triethylamine to dissolve, connect drying installation and acid gas absorption plant, the toluene solution of triphosgene (26.7g/50ml=1.8mol/L) is splashed in four-hole bottle to stirring and refluxing 18 hours at 20 ℃.After having reacted, in system, add appropriate anhydrous magnesium sulfate, stir, suction filtration, revolves steaming mother liquor, obtains yellow oil 17.3g, yield 100%.
Embodiment 5: the preparation of razaxaban
In 250ml four-hole bottle, add 4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidine-3-yl] phenyl } morpholine-3-keto hydrochloride 15.0g (0.045mol), add again 76ml water, 5.9g anhydrous sodium carbonate, stir to clarify, then add 34ml acetone.The toluene solution (17g/50ml) that starts to drip 5-chlorothiophene-2-formyl chloride that previous step makes, dropwises and is heated to 50 ℃, after reacting completely, is chilled to room temperature, filters, and obtains razaxaban crude product 19.2g, yield 96.5% after dry.By 100ml Glacial acetic acid recrystallization for razaxaban crude product, be cooled to 18 ℃, after suction filtration, the dry 17.5g that obtains.HPLC analyzes content 99.8%.
Claims (10)
- The preparation method of 1.5-chlorothiophene-2-formyl chloride, the method is take 5-chlorothiophene-2-carboxylic acid as raw material, reacts and obtains target product III with chlorinating agent under the katalysis of organic amine:
Described chlorinating agent is triphosgene or trichloromethylchloroformate. - 2. the preparation method of 5-chlorothiophene-2-formyl chloride as claimed in claim 1, is characterized in that: chlorinating agent is triphosgene.
- 3. the preparation method of 5-chlorothiophene-2-formyl chloride as claimed in claim 1 or 2, it is characterized in that: concrete operation step is: in first organic amine catalyzer being joined in the organic solvent of raw material 5-chlorothiophene-2-carboxylic acid (II), then add the organic solvent of chlorinating agent, react completely, obtain 5-chlorothiophene-2-formyl chloride of oily.
- 4. the preparation method of 5-chlorothiophene-2-formyl chloride as claimed in claim 1, is characterized in that: reaction temperature is 0～50 ℃.
- 5. the preparation method of 5-chlorothiophene-2-formyl chloride as claimed in claim 1, is characterized in that: reaction temperature is room temperature.
- 6. the preparation method of 5-chlorothiophene-2-formyl chloride as claimed in claim 1, is characterized in that: organic amine is diethylamine, triethylamine, pyridine, N-methylmorpholine, DMF or DMAP.
- 7. the preparation method of 5-chlorothiophene-2-formyl chloride as claimed in claim 6, is characterized in that: organic amine is triethylamine or pyridine.
- 8. the preparation method of 5-chlorothiophene-2-formyl chloride as claimed in claim 1, is characterized in that: reaction mass molar ratio is raw material (II): triphosgene: organic amine is 1:(0.4～3): (0.5～1).
- 9. the preparation method of 5-chlorothiophene-2-formyl chloride as claimed in claim 8, is characterized in that: reaction mass molar ratio is raw material (II): triphosgene: organic amine is 1:(0.6～1.2): (0.8～1).
- 10. the preparation method of 5-chlorothiophene-2-formyl chloride as claimed in claim 1, is characterized in that: the solvent that reaction is used is methylene dichloride.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201310004387.3A CN103833724A (en) | 2012-11-20 | 2013-01-07 | Preparation method of 5-penphene-2-formyl chloride |
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| CN201210472799 | 2012-11-20 | ||
| CN201210472799.5 | 2012-11-20 | ||
| CN201310004387.3A CN103833724A (en) | 2012-11-20 | 2013-01-07 | Preparation method of 5-penphene-2-formyl chloride |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104211694A (en) * | 2014-08-14 | 2014-12-17 | 广东东阳光药业有限公司 | Improved method for preparing Xa factor inhibitor |
| CN104592013A (en) * | 2014-12-31 | 2015-05-06 | 东莞市长安东阳光铝业研发有限公司 | Method for synthesizing p-fluorobenzoyl chloride |
| CN105777738A (en) * | 2014-12-16 | 2016-07-20 | 南京生命能科技开发有限公司 | Rivaroxaban bulk drug and preparation method thereof |
| CN106187993A (en) * | 2016-07-15 | 2016-12-07 | 黑龙江鑫创生物科技开发有限公司 | A kind of micro passage reaction synthesizes the method for 5 chlorine 2 formyl chloride thiophene |
| CN108675956A (en) * | 2018-04-12 | 2018-10-19 | 杭州金仕源医药化工有限公司 | A kind of preparation method of nikethamidum |
| CN114989133A (en) * | 2022-06-16 | 2022-09-02 | 河南立诺制药有限公司 | Environment-friendly preparation method of 2-thiopheneacetyl chloride |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104211694A (en) * | 2014-08-14 | 2014-12-17 | 广东东阳光药业有限公司 | Improved method for preparing Xa factor inhibitor |
| CN105777738A (en) * | 2014-12-16 | 2016-07-20 | 南京生命能科技开发有限公司 | Rivaroxaban bulk drug and preparation method thereof |
| CN104592013A (en) * | 2014-12-31 | 2015-05-06 | 东莞市长安东阳光铝业研发有限公司 | Method for synthesizing p-fluorobenzoyl chloride |
| CN106187993A (en) * | 2016-07-15 | 2016-12-07 | 黑龙江鑫创生物科技开发有限公司 | A kind of micro passage reaction synthesizes the method for 5 chlorine 2 formyl chloride thiophene |
| CN108675956A (en) * | 2018-04-12 | 2018-10-19 | 杭州金仕源医药化工有限公司 | A kind of preparation method of nikethamidum |
| CN114989133A (en) * | 2022-06-16 | 2022-09-02 | 河南立诺制药有限公司 | Environment-friendly preparation method of 2-thiopheneacetyl chloride |
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