CN105218514A - The preparation method of Zaltoprofen - Google Patents
The preparation method of Zaltoprofen Download PDFInfo
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- CN105218514A CN105218514A CN201510719368.8A CN201510719368A CN105218514A CN 105218514 A CN105218514 A CN 105218514A CN 201510719368 A CN201510719368 A CN 201510719368A CN 105218514 A CN105218514 A CN 105218514A
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- ethyl acetate
- zaltoprofen
- propyloic
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- acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D337/00—Heterocyclic compounds containing rings of more than six members having one sulfur atom as the only ring hetero atom
- C07D337/02—Seven-membered rings
- C07D337/06—Seven-membered rings condensed with carbocyclic rings or ring systems
- C07D337/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
- C07D337/14—[b,f]-condensed
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Abstract
The invention belongs to the preparation field of NSAID (non-steroidal anti-inflammatory drug), relate to a kind of preparation method of Zaltoprofen in particular.Intermediate (II) 5-(1-propyloic in the reactor) 2-thiophenyl toluylic acid and the vitriol oil, phosphoric acid mixing acid stirring reaction; Add ethyl acetate, ice and water in room temperature downhill reaction liquid, collect ethyl acetate layer liquid, respectively with saturated sodium bicarbonate, sodium chloride solution washing, dry, distillation and concentration, crystallisation by cooling, filters, crystallized from ethyl acetate drip washing, dry, obtain Zaltoprofen product.This preparation method is simple to operate, and raw material availability and product yield improve, little to environmental influence, are applicable to suitability for industrialized production.
Description
Technical field
The invention belongs to the preparation field of NSAID (non-steroidal anti-inflammatory drug), relate to a kind of preparation method of Zaltoprofen in particular.
Background technology
Zaltoprofen (Zaltoprofen I), chemistry (±)-2-(10-oxo-10,11-dihydro-dibenzo [b, f] thiotropilium-2-yl by name) propionic acid, a kind of NSAID (non-steroidal anti-inflammatory drug) developed by Japanese chemiphar company, this medicine on September 1st, 1993 in Japanese Initial Public Offering.For the anti-inflammatory analgesic of arthritis deformans, scapulohumeral periarthritis, Lumbago, neck shoulder wrist syndrome etc., and postoperative, injure the anti-inflammatory analgesic after exodontia outward.It mainly passes through to suppress the synthesis of prostaglandin(PG), blocking-up inflammatory mediator works.This product selectively acting in inflammation part, and to other organ if stomach and kidney are without effect, has the features such as efficient, side effect is little compared with similar drugs, thus market is favourably welcome.Zaltoprofen, its its molecular formula is: C
17h
14o
3s; Molecular weight is: 298.36; Chemical structural formula is as follows:
The report of existing document, the synthetic method of Zaltoprofen is mainly divided into two large classes: one is first obtain 5-(1-propyloic by the synthesis of different approach) 2-thiophenyl toluylic acid (II), then obtain target product Zaltoprofen (I) by being closed into ring; Another kind of method first synthesizes 10,11-dihydro-dibenzo [b, f] thiotropilium-10-ketone (III), then on 2 of its female ring, introduces isopropyl acid group, obtains Zaltoprofen (I).
Above-mentioned two large class synthetic methods are specific as follows:
The first kind: with o-chlorobenzene acetic acid methyl esters for starting raw material obtains compound 5-(1-propyloic through different route of synthesis respectively) 2-thiophenyl toluylic acid (II), then obtain Zaltoprofen (I) by ring-closure reaction:
Equations of The Second Kind: take o-chloroacetophenone as starting raw material, obtain compound 10,11-dihydro-dibenzo [b, f] thiotropilium-10-ketone (III) through different steps, then introduce isopropyl acid group on 2 of female ring, obtain Zaltoprofen (I):
Above-mentioned two kinds of methods are from different angles to synthesize Zaltoprofen (I) respectively, but two class synthetic methods exist that step is all longer, reaction and the not enough problem such as last handling process is loaded down with trivial details.
Summary of the invention
The object of the invention is to provide a kind of new Zaltoprofen preparation method, and the method is based on above-mentioned first kind method, is different from the reaction method of its final step, uses different reaction reagents and post-treating method.When the present invention is applied to the manufacture of Zaltoprofen, have easily simple to operate, raw material availability and product yield improve, little to environmental influence, are applicable to the feature of suitability for industrialized production.
Zaltoprofen preparation method provided by the invention comprises the following steps: intermediate (II) 5-(1-propyloic in the reactor) 2-thiophenyl toluylic acid and the vitriol oil, phosphoric acid mixing acid stirring reaction, ethyl acetate, ice and water mixed solvent is added in room temperature downhill reaction liquid, collect ethyl acetate layer liquid, respectively with saturated sodium bicarbonate, sodium chloride solution washing, dry, distillation and concentration, crystallisation by cooling, filters, crystallized from ethyl acetate drip washing, drying, obtains Zaltoprofen product.
Zaltoprofen preparation method provided by the invention comprises the following steps:
A () is with 5-(1-propyloic) 2-thiophenyl toluylic acid is starting raw material, by intermediate (II) 5-(1-propyloic) 2-thiophenyl toluylic acid, the vitriol oil, phosphoric acid adds in reactor, at 50 ± 2 DEG C, after stirring reaction 5-6 hour, stir and be cooled to room temperature.
B () adds ethyl acetate, ice (for cooling) and water and stirs in reaction solution, separate ethyl acetate layer, respectively with saturated sodium bicarbonate, saturated sodium-chloride washing, anhydrous sodium sulfate drying, air distillation is concentrated into 1/5 amount, then stir and be cooled to 5 DEG C of crystallizatioies, filter, and with a small amount of ethyl acetate drip washing, dry, obtain off-white color solid phase prod, i.e. Zaltoprofen salable product.
5-(1-propyloic) 2-thiophenyl toluylic acid, the vitriol oil, phosphoric acid mass ratio be: 1:1-5:1.
The mass ratio of organic solvent ethyl acetate and water is 1:1.
The invention provides the preparation method that Zaltoprofen is new.The present invention uses 5-(1-propyloic) 2-thiophenyl toluylic acid is raw material, uses the vitriol oil and phosphoric acid to prepare Zaltoprofen.This preparation method is simple to operate, and raw material availability and product yield improve, little to environmental influence, are applicable to suitability for industrialized production.
Embodiment
Below in conjunction with specific embodiment, elaborate the present invention further.The experimental technique of unreceipted actual conditions in embodiment, usually conveniently condition and the condition described in handbook, or according to the condition that manufacturer advises; General-purpose equipment used, material, reagent etc., if no special instructions, all can obtain from commercial channels.
Embodiment 1
A, by vitriol oil 100g under () room temperature, phosphoric acid 20g drops in 250mL reactor, then stir and be warming up to 50 DEG C, then in 1 hour, 5-(1-propyloic is added in batches) 2-thiophenyl toluylic acid 20g, then stir and be warming up to 50 ± 2 DEG C, insulation reaction 5h, be then down to room temperature.
B () adds 125g ethyl acetate, 50g ice in reaction solution, be stirred to after dissolving completely, then after adding 75g water stirring 30min, leave standstill, separate ethyl acetate layer, 100g extraction into ethyl acetate is added, combined ethyl acetate layer, respectively with 100g saturated sodium bicarbonate, the washing of 100g saturated nacl aqueous solution in water layer, anhydrous sodium sulfate drying, distillation and concentration to 1/5 is measured, and then stirs and is cooled to 5 DEG C of crystallizatioies, and (14-16 hour) is spent the night in holding temperature making beating.Filter, and with a small amount of ethyl acetate drip washing filter cake, at 40 DEG C, forced air drying can obtain off-white color solid phase prod and Zaltoprofen (I) 13.0g, yield 69.1%, measuring through HPLC, is qualified product.
Embodiment 2
A, by vitriol oil 100g under () room temperature, phosphoric acid 20g drops in 250mL reactor, then stir and be warming up to 50 DEG C, then in 1 hour, 5-(1-propyloic is added in batches) 2-thiophenyl toluylic acid 20g, then stir and be warming up to 50 ± 2 DEG C, insulation reaction 5h, be then down to room temperature.
B () adds 125g ethyl acetate, 50g ice in reaction solution, be stirred to after dissolving completely, then after adding 75g water stirring 30min, leave standstill, separate ethyl acetate layer, 100g extraction into ethyl acetate is added, combined ethyl acetate layer, respectively with 100g saturated sodium bicarbonate, the washing of 100g saturated nacl aqueous solution in water layer, anhydrous sodium sulfate drying, distillation and concentration to 1/5 is measured, and then stirs and is cooled to 5 DEG C of crystallizatioies, and holding temperature making beating is spent the night.Filter, and with a small amount of ethyl acetate drip washing filter cake, at 40 DEG C, forced air drying can obtain off-white color solid phase prod and Zaltoprofen (I) 12.8g, yield 68.1%, measuring through HPLC, is qualified product.
Embodiment 3
A, by vitriol oil 800g under () room temperature, phosphatase 11 60g drops in 2L reactor, then stir and be warming up to 50 DEG C, then in 1 hour, 5-(1-propyloic is added in batches) 2-thiophenyl toluylic acid 160g, then stir and be warming up to 50 ± 2 DEG C, insulation reaction 5h, be then down to room temperature.
B () adds 1000g ethyl acetate, 400g ice in reaction solution, be stirred to after dissolving completely, then after adding 600g water stirring 30min, leave standstill, separate ethyl acetate layer, 800g extraction into ethyl acetate is added, combined ethyl acetate layer, respectively with 800g saturated sodium bicarbonate, the washing of 800g saturated nacl aqueous solution in water layer, anhydrous sodium sulfate drying, distillation and concentration to 1/5 is measured, and then stirs and is cooled to 5 DEG C of crystallizatioies, and holding temperature making beating is spent the night.Filter, and with a small amount of ethyl acetate drip washing filter cake, at 40 DEG C, forced air drying can obtain off-white color solid phase prod and Zaltoprofen (I) 10.2g, yield 67.6%, measuring through HPLC, is qualified product.
Embodiment 4
A, by vitriol oil 80kg under () room temperature, phosphatase 11 6kg drops in 200 reactors, then stir and be warming up to 50 DEG C, then in 1 hour, 5-(1-propyloic is added in batches) 2-thiophenyl toluylic acid 16kg, then stir and be warming up to 50 ± 2 DEG C, insulation reaction 5h, be then down to room temperature.
B () adds 100kg ethyl acetate, 40kg ice in reaction solution, be stirred to after dissolving completely, then after adding 60kg water stirring 30min, leave standstill, separate ethyl acetate layer, 80kg extraction into ethyl acetate is added, combined ethyl acetate layer, respectively with 80kg saturated sodium bicarbonate, the washing of 80kg saturated nacl aqueous solution in water layer, anhydrous sodium sulfate drying, distillation and concentration to 1/5 is measured, and then stirs and is cooled to 5 DEG C of crystallizatioies, and holding temperature making beating is spent the night.Filter, and with a small amount of ethyl acetate drip washing filter cake, at 40 DEG C, forced air drying can obtain off-white color solid phase prod and Zaltoprofen (I) 10.5kg, yield 69.6%, measuring through HPLC, is qualified product.
Claims (4)
1. a Zaltoprofen preparation method, is characterized in that comprising the following steps: intermediate (II) 5-(1-propyloic in the reactor) 2-thiophenyl toluylic acid and the vitriol oil, phosphoric acid mixing acid stirring reaction; Add ethyl acetate, ice and water in room temperature downhill reaction liquid, collect ethyl acetate layer liquid, respectively with saturated sodium bicarbonate, sodium chloride solution washing, dry, distillation and concentration, crystallisation by cooling, filters, crystallized from ethyl acetate drip washing, dry, obtain Zaltoprofen product.
2. a Zaltoprofen preparation method, is characterized in that comprising the following steps:
A () is with 5-(1-propyloic) 2-thiophenyl toluylic acid is starting raw material, by intermediate (II) 5-(1-propyloic) 2-thiophenyl toluylic acid, the vitriol oil, phosphoric acid adds in reactor, at 50 ± 2 DEG C, after stirring reaction 5-6 hour, stir and be cooled to room temperature;
B () adds ethyl acetate, ice and water and stirs in reaction solution, separate ethyl acetate layer, respectively with saturated sodium bicarbonate, saturated sodium-chloride washing, anhydrous sodium sulfate drying, air distillation is concentrated into 1/5 amount, then stir and be cooled to 5 DEG C of crystallizatioies, filter, and with a small amount of ethyl acetate drip washing, dry, obtain off-white color solid phase prod, i.e. Zaltoprofen salable product.
3. method according to claim 1 and 2, is characterized in that described 5-(1-propyloic) 2-thiophenyl toluylic acid, the vitriol oil, phosphoric acid mass ratio be: 1:1-5:1.
4. method according to claim 1 and 2, is characterized in that the mass ratio of described ethyl acetate and water is 1:1.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106117244A (en) * | 2016-06-24 | 2016-11-16 | 瑞阳制药有限公司 | The process for purification of Cefditoren pivoxil Cephalosporins |
| CN110407804A (en) * | 2019-07-18 | 2019-11-05 | 河南后羿制药有限公司 | The cyclisation method of application and Zaltoprofen of the micro passage reaction in the cyclization reaction of Zaltoprofen |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005289949A (en) * | 2004-04-06 | 2005-10-20 | Tokuyama Corp | Method for preparing ketone compound |
| CN101812049A (en) * | 2009-02-19 | 2010-08-25 | 严洁 | Method for preparing zaltoprofen |
| CN104185633A (en) * | 2012-04-24 | 2014-12-03 | 日本化学药品株式会社 | Method for producing zaltoprofen and derivative thereof |
-
2015
- 2015-10-30 CN CN201510719368.8A patent/CN105218514A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005289949A (en) * | 2004-04-06 | 2005-10-20 | Tokuyama Corp | Method for preparing ketone compound |
| CN101812049A (en) * | 2009-02-19 | 2010-08-25 | 严洁 | Method for preparing zaltoprofen |
| CN104185633A (en) * | 2012-04-24 | 2014-12-03 | 日本化学药品株式会社 | Method for producing zaltoprofen and derivative thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106117244A (en) * | 2016-06-24 | 2016-11-16 | 瑞阳制药有限公司 | The process for purification of Cefditoren pivoxil Cephalosporins |
| CN110407804A (en) * | 2019-07-18 | 2019-11-05 | 河南后羿制药有限公司 | The cyclisation method of application and Zaltoprofen of the micro passage reaction in the cyclization reaction of Zaltoprofen |
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Application publication date: 20160106 |