CN102417449A - Method for preparing 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid - Google Patents
Method for preparing 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid Download PDFInfo
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- CN102417449A CN102417449A CN2012100039407A CN201210003940A CN102417449A CN 102417449 A CN102417449 A CN 102417449A CN 2012100039407 A CN2012100039407 A CN 2012100039407A CN 201210003940 A CN201210003940 A CN 201210003940A CN 102417449 A CN102417449 A CN 102417449A
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- methoxy
- difluoro
- cyclo propyl
- phenyl aldehyde
- benzoic acid
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Abstract
The invention discloses a method for preparing 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid. The method is characterized by comprising the following steps of: obtaining crude 3-hydroxy-4-difluoromethoxybenzaldehyde by using 3,4-dihydroxybenzaldehyde; washing the crude product and absorbing to remove an unreacted raw material, namely the 3,4-dihydroxybenzaldehyde, and recrystallizing to obtain 3-hydroxy-4-difluoromethoxybenzaldehyde; reacting the 3-hydroxy-4-difluoromethoxybenzaldehyde and bromomethylcyclopropane to form 3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde; and oxidizing the 3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde, and recrystallizing by using a solvent to obtain the 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid. Reaction conditions are mild, impurities cannot be generated easily, the period is short, and the method is easy to operate and is favorable for industrialized large-scale production.
Description
Technical field
The present invention relates to the novel method of a kind of synthetic 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid, 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid is the key intermediate of synthetic roflumilast.
Background technology
Roflumilast (Roflumilast) is the phosphoesterase IV suppressor factor of present unique taking orally treatment chronic obstructive pulmonary disease by Switzerland Nycomed company and the development of U.S. Forest company.Roflumilast is in the listing that gets the Green Light of European Union and the U.S..
3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid is an one of which key intermediate in roflumilast synthetic, and its compound method has following several kinds at present:
(1), the synthetic route among the WO2005026095, with 3,4-resorcylic acid ester be raw material earlier with the reaction of brooethyl Trimetylene, with the difluorochloromethane reaction, last hydrolysis obtains 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid then.Reaction yield is low, needs column chromatography purification, is not suitable for industriallization; Reaction needed is used monochlorodifluoromethane gas.
(2), WO2008006509 and J Med Chem.2008; 51 (24): the synthetic route among the 7673-7688; With 3, the 4-Dihydroxy benzaldehyde is a raw material, reacts under alkaline condition with difluoro Monochloro Acetic Acid sodium or difluoro Monochloro Acetic Acid methyl esters earlier; With the reaction of brooethyl Trimetylene, obtain 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid with the Textone oxidation at last then.Need column chromatography, be not suitable for industriallization; Textone has strong oxidizing property, and potential safety hazard is big during operation, produces chloro impurity during reaction.
(3), the synthetic route among the US6822114, be raw material with the pyrocatechol, with the reaction of brooethyl Trimetylene, bromination, alkylation, carbonylation and hydrolysis obtain 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid then earlier.Need repeatedly distillation purifying, need low-temp reaction, use CO gas and difluorochloromethane gas, be not suitable for industriallization.
(4), the synthetic route among the CN102093194, be raw material with 3-nitro-4-difluoro-methoxy-benzoic acid methyl esters, obtain 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid through alkylation, reduction, diazotization, hydrolysis, alkylation and hydrolysis.Need use difluorochloromethane gas,
The problem of reported method existence at present: chlorinated secondary product in the oxidising process, reaction yield is low, and the separation and purification mode is not suitable for industriallization,
Summary of the invention
The object of the present invention is to provide the method for a kind of 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid.
The present invention seeks to carry out through following technical scheme:
1, with 3, the 4-Dihydroxy benzaldehyde is a raw material, gets 3-hydroxyl-4-difluoro-methoxy phenyl aldehyde bullion through alkylation, through purifying, obtains 3-hydroxyl-4-difluoro-methoxy phenyl aldehyde;
2, the reaction of 3-hydroxyl-4-difluoro-methoxy phenyl aldehyde and brooethyl Trimetylene obtains 3-cyclo propyl methoxy-4-difluoro-methoxy phenyl aldehyde;
3,3-cyclo propyl methoxy-4-difluoro-methoxy phenyl aldehyde gets 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid bullion with the oxygenant oxidation, refining 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid.
Purification process comprises the steps: to use water washing described in the process 1, removes unreactedly 3 then with sorbent material, and the 4-Dihydroxy benzaldehyde obtains 3-hydroxyl-4-difluoro-methoxy phenyl aldehyde with solvent crystallization at last.Said sorbent material is zeyssatite, silica gel, alchlor, molecular sieve and composition thereof.Said solvent is ETHYLE ACETATE and sherwood oil.
Oxygenant described in the process 3 is hydrogen peroxide, metachloroperbenzoic acid, Peracetic Acid.The method of said refining 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid is a recrystallization.The said solvent of recrystallization is toluene and sherwood oil.
The present invention has following beneficial effect: 1, solved the issues of purification of 3-hydroxyl-4-difluoro-methoxy phenyl aldehyde, avoided being not suitable for industrialized column chromatography method; 2, avoided the problem of chlorinated impurities in 3-cyclo propyl methoxy-4-difluoro-methoxy oxidation of Benzaldehyde process; 3, invention a kind of 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid crystalline condition.
Embodiment
Through embodiment the present invention is carried out concrete description below; Be necessary to be pointed out that at this following examples only are used for the present invention is further specified; Can not be interpreted as the restriction to protection domain of the present invention, the person skilled in the art in this field can make some nonessential improvement and adjustment to the present invention according to the invention described above content.
Embodiment 1
In three mouthfuls of reaction flasks, add DMF 1400ml, 3 successively, 4-Dihydroxy benzaldehyde 138.1g, difluoro sodium chloroacetate 152.5g, sodium hydroxide 40g and water 60ml are warming up to the 80-120 degree, stir reaction down 4-5 hour.Filter, concentrate the back and add ETHYLE ACETATE and water, and with ethyl acetate extraction 2 times, with hot wash 2 times, get 3-hydroxyl-4-difluoro-methoxy phenyl aldehyde bullion after concentrated behind the combined ethyl acetate.
With acetic acid ethyl dissolution 3-hydroxyl-4-difluoro-methoxy phenyl aldehyde bullion, with silica gel and diatomite adsorption raw material, filtering and concentrating.Liquid concentrator is used recrystallization from ethyl acetate/petroleum ether, gets 3-hydroxyl-4-difluoro-methoxy phenyl aldehyde white solid 60g.
In there-necked flask, add acetonitrile 400ml, 3-hydroxyl-4-difluoro-methoxy phenyl aldehyde 56.4g, salt of wormwood 28.3g, brooethyl Trimetylene 52.7g washes with the 100ml acetonitrile.The about 4-6 of heating reflux reaction hour, the TLC detection reaction was accomplished after-filtration, concentrate 3-cyclo propyl methoxy-about 75g of 4-difluoro-methoxy phenyl aldehyde reddish-brown liquid, directly be used for next step.
In 3-cyclo propyl methoxy-4-difluoro-methoxy phenyl aldehyde bullion, add Tetrabutyl amonium bromide 3.6g, 120ml hydrogen peroxide (content 35%), about 12 hours at 100-110 degree stirring reaction.Add entry 100ml after the cooling, separate out solid, filter and with wash solid.Solid gets 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid white to light yellow solid 68g with toluene/sherwood oil heating recrystallization.
Embodiment 2
In three mouthfuls of reaction flasks, add DMF 1400ml, 3 successively, 4-Dihydroxy benzaldehyde 138.1g, difluoro ethyl chloroacetate 158.5g, salt of wormwood 138g are warming up to the 80-120 degree, stir reaction down 4-5 hour.Filter, concentrate the back and add ETHYLE ACETATE and water, and with ethyl acetate extraction 2 times, combined ethyl acetate is with hot wash 2 times, gets 3-hydroxyl-4-difluoro-methoxy phenyl aldehyde bullion after concentrated.
With acetic acid ethyl dissolution 3-hydroxyl-4-difluoro-methoxy phenyl aldehyde bullion, with silica gel and diatomite adsorption raw material, filtering and concentrating.Liquid concentrator is used recrystallization from ethyl acetate/petroleum ether, gets 3-hydroxyl-4-difluoro-methoxy phenyl aldehyde white solid 58g.
In there-necked flask, add acetonitrile 400ml, 3-hydroxyl-4-difluoro-methoxy phenyl aldehyde 56.4g, salt of wormwood 28.3g, brooethyl Trimetylene 52.7g washes with the 100ml acetonitrile.The about 4-6 of heating reflux reaction hour, the TLC detection reaction was accomplished after-filtration, concentrate 3-cyclo propyl methoxy-about 75g of 4-difluoro-methoxy phenyl aldehyde reddish-brown liquid, directly be used for next step.
In 3-cyclo propyl methoxy-4-difluoro-methoxy phenyl aldehyde, add Tetrabutyl amonium bromide 3.6g, 120ml hydrogen peroxide (content 35%), about 12 hours at 100-110 degree stirring reaction.Add entry 100ml after the cooling, separate out solid, filter and with wash solid.Solid gets 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid white to light yellow solid 68g with toluene/sherwood oil heating recrystallization.
Embodiment 3
Obtain 3-cyclo propyl methoxy-4-difluoro-methoxy phenyl aldehyde reddish-brown liquid 75g with embodiment 1.
In 3-cyclo propyl methoxy-4-difluoro-methoxy phenyl aldehyde, add acetate 120ml, Tetrabutyl amonium bromide 3.6g, metachloroperbenzoic acid (content 85%) 122g, about 12 hours at 100-110 degree stirring reaction.Add entry 100ml after the cooling, separate out solid, filter and with wash solid.Solid gets 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid white to light yellow solid 66g with toluene/sherwood oil heating recrystallization.
Embodiment 4
Obtain 3-cyclo propyl methoxy-4-difluoro-methoxy phenyl aldehyde reddish-brown liquid 75g with embodiment 2.
In 3-cyclo propyl methoxy-4-difluoro-methoxy phenyl aldehyde, add acetate 120ml, Tetrabutyl amonium bromide 3.6g, metachloroperbenzoic acid (content 85%) 122g, about 12 hours at 100-110 degree stirring reaction.Add entry 100ml after the cooling, separate out solid, filter and with wash solid.Solid gets 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid white to light yellow solid 66g with toluene/sherwood oil heating recrystallization.
Embodiment 5
Obtain 3-cyclo propyl methoxy-4-difluoro-methoxy phenyl aldehyde reddish-brown liquid 75g with embodiment 1.
In 3-cyclo propyl methoxy-4-difluoro-methoxy phenyl aldehyde, add Tetrabutyl amonium bromide 3.6g, Peracetic Acid (content 35%) 115ml, about 12 hours at 20-30 degree stirring reaction.Add entry 100ml after the cooling, separate out solid, filter and with wash solid.Solid gets 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid white to light yellow solid 68g with toluene/sherwood oil heating recrystallization.
Embodiment 6
Obtain 3-cyclo propyl methoxy-4-difluoro-methoxy phenyl aldehyde reddish-brown liquid 75g with embodiment 2.
In 3-cyclo propyl methoxy-4-difluoro-methoxy phenyl aldehyde, add Tetrabutyl amonium bromide 3.6g, Peracetic Acid (content 35%) 115ml, about 12 hours at 20-30 degree stirring reaction.Add entry 100ml after the cooling, separate out solid, filter and with wash solid.Solid gets 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid white to light yellow solid 68g with toluene/sherwood oil heating recrystallization.
Claims (7)
1. the preparation method of 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid is characterized in that, comprises the steps:
(1) with 3, the 4-Dihydroxy benzaldehyde is a raw material, and alkylation gets 3-hydroxyl-4-difluoro-methoxy phenyl aldehyde bullion, through purifying, obtains 3-hydroxyl-4-difluoro-methoxy phenyl aldehyde;
(2) reaction of 3-hydroxyl-4-difluoro-methoxy phenyl aldehyde and brooethyl Trimetylene obtains 3-cyclo propyl methoxy-4-difluoro-methoxy phenyl aldehyde;
(3) 3-cyclo propyl methoxy-4-difluoro-methoxy phenyl aldehyde gets 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid bullion with the oxygenant oxidation, refining 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid.
2. according to the said method of claim 1, it is characterized in that said purification process comprises the steps: to use water washing, remove unreactedly 3 then with sorbent material that the 4-Dihydroxy benzaldehyde obtains 3-hydroxyl-4-difluoro-methoxy phenyl aldehyde with solvent crystallization at last.
3. according to the said method of claim 2, it is characterized in that said sorbent material is zeyssatite, silica gel, alchlor, molecular sieve and composition thereof.
4. according to the said method of claim 2, it is characterized in that said solvent is ETHYLE ACETATE and sherwood oil.
5. according to the said method of claim 1, it is characterized in that said oxygenant is hydrogen peroxide, metachloroperbenzoic acid, Peracetic Acid.
6. according to the said method of claim 1, it is characterized in that the method for said refining 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid is a recrystallization.
7. according to the said method of claim 6, it is characterized in that the said solvent of recrystallization is toluene and sherwood oil.
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| CN2012100039407A CN102417449A (en) | 2012-01-09 | 2012-01-09 | Method for preparing 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid |
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| CN2012100039407A CN102417449A (en) | 2012-01-09 | 2012-01-09 | Method for preparing 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103304408A (en) * | 2013-06-05 | 2013-09-18 | 威海迪素制药有限公司 | Preparation method of roflumilast intermediate 3-cyclopropyl methoxy-4-difluoromethoxybenzoic acid |
| CN110746297A (en) * | 2019-10-31 | 2020-02-04 | 润泰化学（泰兴）有限公司 | Preparation method of 2,2, 4-trimethyl-3-hydroxy methyl valerate, water-based industrial paint for steel structure and preparation method of water-based industrial paint |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101490004A (en) * | 2006-07-14 | 2009-07-22 | 奇斯药制品公司 | Derivatives of 1-phenyl-2-pyridynyl alkylene alcohols as phosphodiesterase inhibitors |
| CN102093194A (en) * | 2010-12-24 | 2011-06-15 | 江苏先声药物研究有限公司 | New method for synthesizing 3-cyclopropyl methoxy-4-(difluoromethoxy) benzoic acid |
-
2012
- 2012-01-09 CN CN2012100039407A patent/CN102417449A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101490004A (en) * | 2006-07-14 | 2009-07-22 | 奇斯药制品公司 | Derivatives of 1-phenyl-2-pyridynyl alkylene alcohols as phosphodiesterase inhibitors |
| CN102093194A (en) * | 2010-12-24 | 2011-06-15 | 江苏先声药物研究有限公司 | New method for synthesizing 3-cyclopropyl methoxy-4-(difluoromethoxy) benzoic acid |
Non-Patent Citations (1)
| Title |
|---|
| 钟永刚等: "罗氟斯特的合成", 《中国医药工业杂志》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103304408A (en) * | 2013-06-05 | 2013-09-18 | 威海迪素制药有限公司 | Preparation method of roflumilast intermediate 3-cyclopropyl methoxy-4-difluoromethoxybenzoic acid |
| CN103304408B (en) * | 2013-06-05 | 2016-10-05 | 威海迪素制药有限公司 | The preparation of roflumilast intermediate 3-ring the third methoxyl group-4-difluoro-methoxy-benzoic acid |
| CN110746297A (en) * | 2019-10-31 | 2020-02-04 | 润泰化学（泰兴）有限公司 | Preparation method of 2,2, 4-trimethyl-3-hydroxy methyl valerate, water-based industrial paint for steel structure and preparation method of water-based industrial paint |
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Application publication date: 20120418 |