CN101302213B - Preparation of cis-2-(2,4- dichlorophenyl)-2-([1,2,4]- triazole-1-methyl )-[1,3] dioxolane -4-Methyl methanesulfonate - Google Patents
Preparation of cis-2-(2,4- dichlorophenyl)-2-([1,2,4]- triazole-1-methyl )-[1,3] dioxolane -4-Methyl methanesulfonate Download PDFInfo
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Abstract
The invention relates to a preparation method for pharmaceutical intermediate cis-2-(2,4- dichlorophenyl)-2-([1,2,4]triazole-1-methyl)-[1,3] dioxolane-4-methyl methanesulfonate. The preparation method adopts a process route that m-dichlorobenzene is used as a raw material which is condensed with glycerin under the catalysis of heteropoly acid TiSiW12O40/SiO2 after friedel-crafts reaction, and is esterified with benzoyl chloride, and the product is obtained by condensing the reaction product with 1,2,4-triazole, hydrolyzing, recrystallizing and esterifying with the methylsulfonyl chloride. The invention is characterized by (1) adopting a creative process route that the m-dichlorobenzene is used as the raw material; (2) adopting the heteropoly acid TiSiW12O40/SiO2 for catalysis in the production of ketal, the heteropoly acid being repeated and having environmental and economical performances; (3) adopting sodium carbonate as an acid binding agent, avoiding the expensive and dangerous sodium hydride catalysis; and (4) adopting a recrystallization method and avoiding column chromatography, lowering the production cost and being useful for industrialization.
Description
Technical field
The invention belongs to the synthetic field of medicine.Be specifically related to the preparation method of a kind of medicine intermediate cis-2-(2,4 dichloro benzene base)-2-([1,2,4]-triazole-1-methyl)-[1,3] dioxolane-4-methylmethanesulfonate ester.
Background technology
At present, anti-infectives has become the third-largest type of medicine that the whole world is only second to medicine for cardiovascular system, medicine for central nervous system, occupies important share in world markets.Itraconazole has become the global best selling variety in 2006 years as the representative kind of anti-infection drug, and relies on its unique mode of action, and fabulous curative effect, the market share have much the trend of increase.Cis-2-(2; The 4-dichlorophenyl)-2-([1; 2,4]-triazole-1-methyl)-[1,3] dioxolane-4-methylmethanesulfonate ester (hereinafter to be referred as methanesulfonic acid active ester) is the important intermediate of synthetic antifungal drug; Simultaneously also be the essential midbody of synthetic itraconazole, the research and development of its new synthesis process are had great importance.
The structural formula of methanesulfonic acid active ester is:
Chemical name is cis-2-(2,4 dichloro benzene base)-2-([1,2,4]-triazole-1-methyl)-[1,3] dioxolane-4-methylmethanesulfonate ester.Because of relating to three-dimensional optically-active structure, synthetic difficulty is very big.At present; In the world its synthesis route mainly contain 1. US4358449 with the dichloroacetophenone be raw material through bromination, esterification after sulphuric acid catalysis and the glycerine condensation obtains behind the bromo ester under sodium methylate catalysis with 1; 2; The condensation of 4-triazole, hydrolysis, the column chromatography for separation isomer obtains cis-alcohol, obtains methanesulfonic acid active ester with the methylsulfonyl chloride esterification then.2. Journal of Medicinal Chemistry, 1983, (26) 4:611-613. report with the bromo ester under sodium hydride catalysis and 1; 2; The condensation of 4-triazole, hydrolysis, the column chromatography for separation isomer obtains cis-alcohol, obtains methanesulfonic acid active ester with the methylsulfonyl chloride esterification then.
1. operational path exists following shortcoming: at first the 2,4 dichloro benzene ethyl ketone is carried out the radical bromo, owing to there are three Wasserstoffatomss on the methyl of methyl phenyl ketone, degree of depth bromination is inevitable, inadequately economy, environmental protection; With the USP Kosher condensation time, all adopt the vitriol oil to make catalyzer and carry out condensation, inevitably produce a large amount of spent acid, aftertreatment is more loaded down with trivial details; All be after hydrolysis, cis-alcohol to be separated purification with its isomer through the method for column chromatography simultaneously, the cost height is unfavorable for big production;
2. operational path adopts sodium hydride catalysis bromo ester and 1,2, the condensation of 4-triazole; Through column chromatography for separation purification cis-alcohol; The ability spontaneous combustion in damp atmosphere because sodium hydride costs an arm and a leg is met acids, water, halogen and oxygenant etc. the intensive chemical reaction can be taken place, and is prone to cause burning or blast; So the industrial production cost is high, dangerous big, column chromatography also is unfavorable for suitability for industrialized production simultaneously.
Summary of the invention
Technical problem to be solved by this invention is to overcome above-mentioned weak point, designs a kind of new compound method, reaches easy and simple to handle, is easy to industrialized purpose.
The invention provides a kind of compound method of methanesulfonic acid active ester, method of the present invention comprises the steps: that (1) at first is raw material with the Meta Dichlorobenzene, carries out friedel-crafts reaction with bromoacetyl bromide; (2) then at heteropolyacid TiSiW
12O
40/ SiO
2Following and the glycerine condensation of catalysis; (3) with the Benzoyl chloride 99min. esterification; (4) under yellow soda ash catalysis with 1,2, the condensation of 4-triazole, behind the hydrolysis recrystallization cis-alcohol; (5) obtain product with the methylsulfonyl chloride esterification.Reaction equation is following:
It is the operational path of raw material that the present invention adopts with the Meta Dichlorobenzene.
In the inventive method in (1) step Meta Dichlorobenzene and bromoacetyl bromide carry out friedel-crafts reaction, can avoid degree of depth bromination.
Adopt solid heteropoly acid TiSiW in (2) step in the method for the present invention
12O
40/ SiO
2Catalysis is convenient to separate the recycling of renewable back, has avoided the discharging of spent acid, has the feature of environmental protection and economy.
This section deletion
Adopt yellow soda ash to make acid binding agent in (4) step in the inventive method, avoided adopting expensive, dangerous sodium hydride catalysis.
Adopt recrystallization method to avoid column chromatography in (4) step in the inventive method, production cost reduces and is beneficial to industriallization.
The present invention has following characteristics: what original creation was adopted in (1) is the operational path of raw material with the Meta Dichlorobenzene; (2) solid heteropoly acid catalysis is adopted in the production of ketal, can reuse, and has the feature of environmental protection and economy; (3) adopt yellow soda ash to make acid binding agent, avoided adopting expensive, dangerous sodium hydride catalysis; (4) adopt recrystallization method to avoid column chromatography, production cost reduces and is beneficial to industriallization.
Embodiment
The following example is described the present invention in detail.But these embodiment are anything but to the qualification of protection domain of the present invention.
(1) 2-bromo-1-(2,4 dichloro benzene base) ethyl ketone is synthetic
In the 500mL there-necked flask, put into aluminum trichloride (anhydrous) 150g (1.12mol), add Meta Dichlorobenzene 147g (1.00mol), stir under the room temperature, continued at stirring at room again 30 minutes after slowly dripping bromine acetyl bromide 201g (1.00mol) dropwises; Slowly be warming up to 50-55 ℃, and under this temperature, stirred 5 hours, reaction solution is poured into to ice in the frozen water separate; Be cooled to room temperature, extract at twice, the combined dichloromethane extracting solution with the 500mL methylene dichloride; Washing is to neutrality, anhydrous sodium sulfate drying, filtered and recycled solvent; Residue is heavily tied article, gets white pungency solid 240g, yield 90.0%.
(2) intermediate compound I is synthetic
In the 1000mL four-hole boiling flask, add and go up solid 268g, glycerine 92g, toluene and the catalyzer TiSiW that the step obtains
12O
40/ SiO
21.3g, reflux azeotropic dehydration, (being as the criterion) to divide not water outlet.Reaction finishes after-filtration and reclaims catalyzer, recycles after the regeneration, and mother liquor washs with Pottasium Hydroxide, anhydrous MgSO
4Drying obtains yellow oil (available GC analyzes) behind the decompression and solvent recovery, yield is 94%.
(3) cis bromo ester is synthetic
Add triethylamine to the 1000mL four-hole boiling flask, the above-mentioned bromide 341g of suction is chilled to after the stirring and dissolving below 10 ℃ then, drips Benzoyl chloride 99min., drips off about 3 hours.Drip off back 30 ℃ and continue reaction 2 hours down, the reclaim under reduced pressure triethylamine adds entry then, chloroform, and layering, organic phase is with salt acid elution, anhydrous Na
2SO
4Drying obtains oily matter behind the reclaim under reduced pressure chloroform, adds methyl alcohol, separates out solid after the stirring, dry behind the suction filtration bullion, obtain cis bromo ester 260g, yield 58%, mp:117-120 ℃ with recrystallizing methanol again.
(4) cis-alcohol is synthetic
In the 1000mL four-hole boiling flask, add DMF, cis bromo ester 446g, 1,2; 4-triazole 69g, yellow soda ash 53g, stirring heating refluxes, and adds entry, 30% alkali lye then; Be incubated after 2 hours, be cooled to 30 ℃, stirred 1 hour, centrifugal, washing dries and obtains the cis-alcohol bullion.Bullion gets cis-alcohol elaboration 205g, yield 62%, mp:135-140 ℃ with toluene and recrystallizing methanol after filtering, drying.
(5) methanesulfonic acid active ester is synthetic
In the 1000mL four-hole boiling flask, add triethylamine, add cis-alcohol then, stirring and dissolving is cooled to 5 ℃; Drip Methanesulfonyl chloride then, be warming up to 25 ℃ after adding, be incubated and reclaim solvent after 5 hours; Add suitable quantity of water and stir 5 hours after-filtration, washing, drying, recrystallization gets the 359g methanesulfonic acid active ester again, is white or off-white color solid; Yield 88%, mp:96-100 ℃.
Claims (2)
1. the preparation method of cis-2-(2,4 dichloro benzene base)-2-([1,2,4] triazole-1-methyl)-[1,3] dioxolane-4-methylmethanesulfonate ester is characterized in that comprising the steps: that (1) is raw material with the Meta Dichlorobenzene, carries out friedel-crafts reaction with bromoacetyl bromide; (2) at heteropolyacid TiSiW
12O
40/ SiO
2Following and the glycerine condensation of catalysis; (3) with the Benzoyl chloride 99min. esterification; (4) under yellow soda ash catalysis with 1,2, the condensation of 4-triazole, behind the hydrolysis recrystallization cis-alcohol; (5) obtain product with the methylsulfonyl chloride esterification.
2. preparation method according to claim 1 is characterized in that wherein said yellow soda ash is acid binding agent.
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| CN2008101380055A CN101302213B (en) | 2008-06-30 | 2008-06-30 | Preparation of cis-2-(2,4- dichlorophenyl)-2-([1,2,4]- triazole-1-methyl )-[1,3] dioxolane -4-Methyl methanesulfonate |
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| CN2008101380055A CN101302213B (en) | 2008-06-30 | 2008-06-30 | Preparation of cis-2-(2,4- dichlorophenyl)-2-([1,2,4]- triazole-1-methyl )-[1,3] dioxolane -4-Methyl methanesulfonate |
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| CN101302213B true CN101302213B (en) | 2012-07-25 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0052905A1 (en) * | 1980-11-24 | 1982-06-02 | Janssen Pharmaceutica N.V. | Novel (2-aryl-4-phenylthioalkyl-1,3-dioxolan-2-yl-methyl)azole derivatives |
| US4338327A (en) * | 1978-10-06 | 1982-07-06 | Janssen Pharmaceutica, N.V. | Substituted 1-(2-aryl-1,3-dioxolan-2-ylmethyl)-1H-1,2,4-triazoles |
| US4358449A (en) * | 1977-01-31 | 1982-11-09 | Janssen Pharmaceutica, N.V. | 1-(1,3-Dioxolan-2-ylmethyl)-1H-1,2,4-triazoles and compositions |
-
2008
- 2008-06-30 CN CN2008101380055A patent/CN101302213B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4358449A (en) * | 1977-01-31 | 1982-11-09 | Janssen Pharmaceutica, N.V. | 1-(1,3-Dioxolan-2-ylmethyl)-1H-1,2,4-triazoles and compositions |
| US4338327A (en) * | 1978-10-06 | 1982-07-06 | Janssen Pharmaceutica, N.V. | Substituted 1-(2-aryl-1,3-dioxolan-2-ylmethyl)-1H-1,2,4-triazoles |
| EP0052905A1 (en) * | 1980-11-24 | 1982-06-02 | Janssen Pharmaceutica N.V. | Novel (2-aryl-4-phenylthioalkyl-1,3-dioxolan-2-yl-methyl)azole derivatives |
Non-Patent Citations (1)
| Title |
|---|
| J.Heeres et al..Antimycotic Azoles.6.Synthesis and Antifungal Properties of Terconazole,a Novel Triazole Ketal.《J.Med.Chem.》.1983,第26卷 * |
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