CN106279280A - A kind of compound and its preparation method and application - Google Patents
A kind of compound and its preparation method and application Download PDFInfo
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- CN106279280A CN106279280A CN201510266987.6A CN201510266987A CN106279280A CN 106279280 A CN106279280 A CN 106279280A CN 201510266987 A CN201510266987 A CN 201510266987A CN 106279280 A CN106279280 A CN 106279280A
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- fluconazol
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- 0 CCCC(*CN(C#C)N)=C(**)C=*(C)F Chemical compound CCCC(*CN(C#C)N)=C(**)C=*(C)F 0.000 description 1
- DOLWNAUAYNRIOA-UHFFFAOYSA-N CN(CCO)/N=C\N Chemical compound CN(CCO)/N=C\N DOLWNAUAYNRIOA-UHFFFAOYSA-N 0.000 description 1
Abstract
The present invention is compound 2 (2; 4 difluorophenyls) 1; 3 couples of (1H 1; 2; 4 triazole 1 bases) 2 propyl group di(2-ethylhexyl)phosphate tertiary butyl ester and preparation method thereof; and 2 (2; 4 difluorophenyls) 1; 3 pairs of (1H 1,2,4 triazole 1 base) 2 propyl group di(2-ethylhexyl)phosphate tertiary butyl ester are preparing compound 2; 4 difluoro α α bis-(1 hydrogen 1; 2,4 triazole 1 ylmethyls) application in benzyl alcohol dihydrogen phosphate, there is the reaction condition of milder and more preferable environmental protection property.
Description
Technical field
The present invention relates to a kind of compound, specially compound 2-(2,4 difluorobenzene base)-1,3-double (1H-1,2,4-triazole-1-
Base)-2-propyl group di(2-ethylhexyl)phosphate tertiary butyl ester and preparation method thereof, and 2-(2,4 difluorobenzene base)-1,3-double (1H-1,2,4-triazole-1-
Base) application in the preparing compound good fortune department fluconazol of-2-propyl group di(2-ethylhexyl)phosphate tertiary butyl ester.
Background technology
Good fortune department fluconazol is the phosphate ester prod-drug of fluconazol, has good water solublity, can reduce amount of infusion, alleviate cyclic system
System burden.After intravenously administrable, it is hydrolyzed into fluconazol and phosphoric acid by alkaline phosphatase in vivo.Therefore find safe and efficient
Anti-fungal infection medicine has great importance on clinical treatment.
Good fortune department fluconazol (Fosfluconazole), chemistry is entitled: 2,4-bis-fluoro-alpha α-two (1 hydrogen-1,2,4-triazol-1-yl first
Base) benzyl alcohol dihydrogen phosphate is to the fungemia caused by Candida and Cryptococcus, respiratory apparatus fungus disease, fungus
Property peritonitis, digestive tube fungus disease, urinary tract fungus disease, fungoid meningitis etc. have good efficacy.Good fortune department fluconazol structural formula is:
Good fortune department fluconazol was listed, at present in Japan's approval by the institute exploitation of central authorities of Hui Duan company of Britain, on October 16th, 2003
Document reports that the synthetic method of good fortune department fluconazol has following several: open the reporting with fluconazol of patent WO1997028169 is former
Material and tetrazolium, dibenzyl diisopropyl amido phosphine generation esterification prepare fluconazol phosphate ester, remove benzyl with palladium carbon hydrogenation
Prepare good fortune department fluconazol, as shown in route one.Route one:
The raw materials used tetrazolium of this route and dibenzyl diisopropyl amido phosphine expensive, supply is less, it is difficult to carry out industry
Metaplasia is produced；Final step is to remove benzyl by palladium carbon catalytic hydrogenation in methanol solvate, owing to good fortune department fluconazol is in methanol
Insoluble, therefore route has following weak point: catalyst poisoning, end-product easily separate out, equipment operation requires higher, tool
There is potential safety hazard etc., be not suitable for industrialized production.
Patent WO1997028169 is open to be reported with fluconazol for raw material and Phosphorous chloride., benzyl alcohol and hydrogen peroxide generation ester
Change reaction and prepare fluconazol phosphate ester, remove benzyl with palladium carbon hydrogenation and prepare good fortune department fluconazol, as shown in route two.Route two:
Route two is raw material initially with Phosphorous chloride., benzyl alcohol and hydrogen peroxide, low price, and supply is sufficient, although literary composition
Offering productivity is 63.0%, and reaction controllability is poor, but can carry out industrialized production, and this route still uses palladium carbon hydrogenation to take off
Except benzyl, difference is solvent to change sodium hydrate aqueous solution into, and product is solvable and stable in sodium hydrate aqueous solution,
But in hydrogenation process, raw material fluconazol phosphate ester is not dissolved in sodium hydrate aqueous solution, causes reaction efficiency relatively low, during reaction
Between extend, be easily caused fluconazol phosphate fire-resistant oil is fluconazol simultaneously so that product quality is difficult to control to.
Patent CN1262551 is announced route as follows:
This route is used patent WO1997028169 route two method to prepare, through palladium carbon and first by formula 2 compound in route
Acid ammonium hydrogenation and removing benzyl, becomes ammonium salt acidified, prepares good fortune department fluconazol, in hydrogenation subtractive process, owing to ammonium formate easily rises
China, it is easy to blocking reflux condensing tube, causes pressure in reactor process to increase, and danger is higher, making it difficult to carry out industry
Metaplasia is produced.Therefore route has following weak point: catalyst poisoning, end-product easily separate out, potential safety hazard is bigger, no
It is suitable for industrialized production.
Though above-mentioned all technical schemes respectively have its own advantage, but it is poor to there is reaction controllability, and severe reaction conditions and danger are higher,
Relatively costly, it is unfavorable for the defect of industrialized production.
Summary of the invention
It is an object of the invention to overcome initiation material in above-mentioned prior art expensive, harsh to equipment requirements, it is difficult to industrialization
Etc. shortcoming, it is provided that a kind of reactions steps is brief, reaction condition is gentle, the conjunction of good fortune department easy and simple to handle, environment amenable fluconazol
One-tenth method.
Indication of the present invention if formula (2), formula (3) are to be appointed as standard in summary of the invention, the correlation related in above-mentioned background technology
It is intended merely to be better described the background of this technology, described in the correlation related in present invention and above-mentioned background technology
That specifies has difference, as different from formula of the present invention (2) compound for the formula (2) described in CN1262551.
According to the reaction equation of the present invention, the invention provides the compound of a kind of formula (2):
Formula (2)
Wherein R is the tert-butyl group.
The compound of formula (2) is as intermediate application in formula (3) compound good fortune department fluconazol, formula (3)
The preparation method of formula (2) compound of the present invention, by formula (1) compound fluconazol and Phosphorous chloride., the tert-butyl alcohol and mistake
Prepared by hydrogen oxide generation esterification,
Formula (1)
The preparation method of formula (2) compound of the present invention, for adding to organic solvent by formula (1) compound fluconazol and organic base
In, add Phosphorous chloride. and make reaction, continuously add the tert-butyl alcohol and make reaction, add hydrogenperoxide steam generator, make reaction, remove aqueous phase
Solution, washs organic facies with sodium metabisulfite solution and water, boils off solvent, and solvent crystallization, filter, be dried, to obtain final product；Institute
The organic base stated selected from pyridine, 3-picoline, 2,6-lutidines, organic solvent be selected from ethers, esters, halo alkanes,
Ether solvent is selected from oxolane, methyltetrahydrofuran, and esters solvent is selected from ethyl acetate, Ethyl formate, butyl acetate,
Alkyl halide kind solvent be selected from dichloromethane, chloroform, 1,2-dichloroethanes, 1,1-dichloroethanes.
The preparation method of formula (2) compound of the present invention, adds Phosphorous chloride. and makes reaction and continuously add the tert-butyl alcohol and make the anti-of reaction
Answering temperature to control as-15～30 DEG C, the response time can be 0.5～24 hour.
The preparation method of formula (2) compound of the present invention, the mole dosage ratio of described formula (1) compound fluconazol and organic base
It is 1: (1.0～5.0)；Described formula (1) compound fluconazol is 1 with the mole dosage ratio of Phosphorous chloride.: (1.0～2.0).
The compound of the formula (2) of the present invention is as intermediate application in formula (3) compound good fortune department fluconazol, preparation
Method is that the compound of formula (2) occurs hydrolysis to obtain formula (3) compound in organic solvent；Acid used by hydrolysis can
Think mineral acid, as being selected from hydrochloric acid, hydrochloric acid, sulphuric acid, nitric acid, phosphoric acid.
The compound of the formula (2) of the present invention is as intermediate application in formula (3) compound good fortune department fluconazol, preparation
In method, organic solvent is preferably alcohols, esters or ethers selected from solvent for use, and wherein alcohols is selected from ethanol, methanol, isopropyl
Alcohol, n-butyl alcohol, ether solvent is selected from oxolane, methyltetrahydrofuran, dioxane, and esters solvent is selected from acetic acid second
Ester, methyl acetate, butyl acetate.
The compound preparation of the formula (2) of the present invention and obtain compound good fortune department fluconazol reaction equation as intermediate generation hydrolysis
It is exemplified below:
The new technology of the present invention is given synthesis good fortune department fluconazol, has the beneficial effect that the operating process of the present invention is without more low temperature and nothing
The harsh conditions such as water, anaerobic, effectively raise reaction yield, and in the present invention, used in each step reaction, reagent is little point
Sub-alkali, it is easy to purification, therefore, it is gentle, easy and simple to handle, to ring that the preparation method of good fortune department of the present invention fluconazol has reaction condition
The advantages such as border is friendly, production cost is low, are suitable for industrialized production.
Detailed description of the invention
The present invention is more specifically illustrated by following embodiment.But, described embodiment is not intended to limit the scope of the present invention.
Embodiment 1
Double (1H-1,2,4-the triazol-1-yls)-2-propyl group di(2-ethylhexyl)phosphate tertiary butyl ester [formula (2)] of 2-(2,4 difluorobenzene base)-1,3-
Synthesis: fluconazol (765g, 2.5mol) and pyridine (593.2g, 7.5mol) are added to the ethyl acetate (3431g) of stirring
In, then it being cooled to-5～0 DEG C, dropping Phosphorous chloride. (357.1,2.62mol) is in reactant mixture, and maintains the reaction temperature to be
-5～0 DEG C are reacted 1 hour, are added dropwise to wherein, finish by the tert-butyl alcohol (518.0g, 7.0mol), in-5～0 DEG C at-5～0 DEG C
Lower stirring reaction 2 hours；Then drip hydrogen peroxide (27.5%w/w aqueous solution, 932.5g), and maintain same temperature, in-5～0 DEG C
Lower stirring reaction 12 hours, removes aqueous phase, washs organic facies with sodium metabisulfite solution, dilute hydrochloric acid and water, removes solvent under reduced pressure,
It is placed in ethyl acetate (765g) and petroleum ether (625g), 20 DEG C of stirring and crystallizing 1 hour, little 0 DEG C of stirring and crystallizing 1
Shi Hou, filters, and washs with ethyl acetate (76.5g) and petroleum ether (62.5g), is then vacuum dried 18 hours in 50 DEG C,
Obtain target product (896.8g, 72.0%).
Embodiment 2
The conjunction of double (1H-1,2,4-the triazol-1-yls)-2-propyl group di(2-ethylhexyl)phosphate tertiary butyl ester [formula (2)] of 2-(2,4 difluorobenzene base)-1,3-
Become: fluconazol (306g, 1.0mol) and pyridine (237.3g, 3.0mol) are added in the dichloromethane (1789g) of stirring,
Then being cooled to-5～0 DEG C, dropping Phosphorous chloride. (144.2,1.05mol) is in reactant mixture, and to maintain reaction temperature be-5～0 DEG C
Reacting 1 hour, be added dropwise to wherein, finish by the tert-butyl alcohol (207.2g, 2.8mol) at-5～0 DEG C, at-5～0 DEG C, stirring is anti-
Answer 2 hours；Then drip hydrogen peroxide (27.5%w/w aqueous solution, 373g), and maintain same temperature, stir at-5～0 DEG C
Mix reaction 12 hours, remove aqueous phase, wash organic facies with sodium metabisulfite solution, dilute hydrochloric acid and water, remove solvent under reduced pressure,
To target product (333.3g, 66.9%).
Embodiment 3
Double (1H-1,2,4-the triazol-1-yls)-2-propyl group di(2-ethylhexyl)phosphate tertiary butyl ester [formula (2)] of 2-(2,4 difluorobenzene base)-1,3-
Synthesis: fluconazol (306g, 1.0mol) and 3-picoline (279.4g, 3.0mol) are added to stirring ethyl acetate (1372g)
In, then it being cooled to-5～0 DEG C, dropping Phosphorous chloride. (144.2,1.05mol) is in reactant mixture, and maintains the reaction temperature to be
-5～0 DEG C are reacted 1 hour, are added dropwise to wherein, finish by the tert-butyl alcohol (207.2g, 2.8mol), in-5～0 DEG C at temperature control-5～0 DEG C
Lower stirring reaction 2 hours；Then drip hydrogen peroxide (27.5%w/w aqueous solution, 373g), and maintain same temperature, in-5～0 DEG C
Lower stirring reaction 12 hours, removes aqueous phase, washs organic facies with sodium metabisulfite solution, dilute hydrochloric acid and water, removes solvent under reduced pressure,
It is placed in ethyl acetate (306g) and petroleum ether (250g).20 DEG C of stirring and crystallizing 1 hour, little 0 DEG C of stirring and crystallizing 1
Shi Hou, filters, and washs with ethyl acetate (30.6g) and petroleum ether (25g), is then vacuum dried 18 hours at 50 DEG C,
To target product (343.3g, 68.9%).
Embodiment 4
The synthesis of good fortune department fluconazol: in reaction bulb, adds 2-(2,4 difluorobenzene base)-1,3-double (1H-1,2,4-triazole-1-
Base)-2-propyl group di(2-ethylhexyl)phosphate tertiary butyl ester (820g, 1.64mol), ethanol (4100g), dropping concentrated hydrochloric acid (332.6g, 3.28mol),
Finish, be heated to backflow, stirring reaction 2 hours.Reaction is finished, and decompression steams solvent, adds purified water (1640g),
Stirring reaction 2 hours at 15～30 DEG C, sucking filtration, dehydrated alcohol (150g) washs 3 times, then 50 DEG C of vacuum drying
18 hours, obtain target product (580.9g, 91.7%).Fusing point 223～224 DEG C, consistent with document through Structural Identification.
Embodiment 5
The synthesis of good fortune department fluconazol: in reaction bulb, adds 2-(2,4 difluorobenzene base)-1,3-double (1H-1,2,4-triazole-1-
Base)-2-propyl group di(2-ethylhexyl)phosphate tertiary butyl ester (160.0g, 0.32mol), dioxane (800g), dropping concentrated hydrochloric acid (65.1g, 0.64mol),
Finish, be heated to backflow, stirring reaction 2 hours.Reaction is finished, and decompression steams solvent, adds purified water (300g),
Stirring reaction 2 hours at 15～30 DEG C, sucking filtration, dehydrated alcohol (50g) washs 3 times, then little 50 DEG C of vacuum drying 18
Time, obtain target product (115.9g, 93.8%).Fusing point 223～224 DEG C, consistent with document through Structural Identification.
Embodiment 6
The synthesis of good fortune department fluconazol: in reaction bulb, adds 2-(2,4 difluorobenzene base)-1,3-double (1H-1,2,4-triazole-1-
Base)-2-propyl group di(2-ethylhexyl)phosphate tertiary butyl ester (160.0g, 0.32mol), ethyl acetate (1.2L), drip 30% sulphuric acid (88.2g,
0.32mol), finish, be heated to backflow, stirring reaction 2 hours.Reaction is finished, and decompression steams solvent, adds purified water
(300g), stirring reaction 2 hours at 15～30 DEG C, sucking filtration, dehydrated alcohol (50g) washs 3 times, then true at 50 DEG C
Empty dry 18 hours, obtain target product (111.2g, 90.0%).Fusing point 223～224 DEG C, consistent with document through Structural Identification.
Embodiment 7
By double to formula (2) the compound 2-(2,4 difluorobenzene base)-1 of the present invention, 3-(1H-1,2,4-triazol-1-yls)-2-propyl group
Di(2-ethylhexyl)phosphate tertiary butyl ester carries out structural analysis, is specifically shown in Fig. 1, Fig. 2 and Fig. 3, resolves as follows:
1H-NMR (500MHz, DMSO) δ=1.29ppm (9H, 6 ×-CH3), 5.02～5.05ppm (2H ,-CH2-)、
5.13～5.16ppm (2H ,-CH2-), 6.95～6.98ppm (1H ,-CH=), 7.24～7.29ppm (2H ,-CH=),
7.89ppm (2H, 2 ×-CH=), 8.53～8.54ppm (2H, 2 ×-CH=).
13C-NMR (500MHz, DMSO) δ=23.93ppm (2C, quaternary carbon), 29.17～29.40ppm (6C, primary carbon),
51.82～52.24ppm (2C, secondary carbon), 83.49～83.56ppm (1C, quaternary carbon), 104.41～104.84ppm (1C, uncle
Carbon), 110.80～110.94ppm (1C, tertiary carbon), 119.91～120.03ppm (1C, quaternary carbon), 129.48～129.60ppm
(1C, tertiary carbon), 145.31～145.79ppm (2C, tertiary carbon), 151.02～151.36ppm (2C, tertiary carbon), 159.61～
159.71ppm (1C, quaternary carbon), 161.62～161.84ppm (1C, quaternary carbon).
MS:521.2 (M+Na+), 443.1 [M-C4H9+H]+, 387.1 [M-2C4H9+H]+。
Accompanying drawing explanation
Fig. 1 is embodiment of the present invention formula (2) compound1H-NMR collection of illustrative plates.
Fig. 2 is embodiment of the present invention formula (2) compound13C-NMR collection of illustrative plates.
Fig. 3 is embodiment of the present invention formula (2) compound MS collection of illustrative plates.
Claims (12)
1. the compound of a formula (2):
Wherein R is the tert-butyl group.
2. the preparation method of formula (2) compound, by formula (1) compound fluconazol and Phosphorous chloride., the tert-butyl alcohol and hydrogen peroxide
Esterification is occurred to prepare,
The preparation method of formula the most according to claim 2 (2) compound, adds to formula (1) compound fluconazol and organic base
In organic solvent, add Phosphorous chloride. and make reaction, continuously add the tert-butyl alcohol and make reaction, add hydrogenperoxide steam generator, make reaction,
Remove aqueous phase solution, wash organic facies with sodium metabisulfite solution and water, boil off solvent, and solvent crystallization, filter, be dried,
Obtain.
The preparation method of formula the most according to claim 3 (2) compound, it is characterised in that: organic base is selected from pyridine, 3-first
Yl pyridines, 2,6-lutidines, organic solvent be selected from ethers, esters, halo alkanes, ether solvent be selected from oxolane,
Methyltetrahydrofuran, esters solvent is selected from ethyl acetate, Ethyl formate, butyl acetate, and alkyl halide kind solvent is selected from dichloro
Methane, chloroform, 1,2-dichloroethanes, 1,1-dichloroethanes.
The preparation method of formula the most according to claim 3 (2) compound, it is characterised in that: add Phosphorous chloride. make reaction and
Continuously adding the tert-butyl alcohol makes the reaction temperature of reaction control as-15～30 DEG C.
The preparation method of formula the most according to claim 3 (2) compound, it is characterised in that: described formula (1) compound fluorine health
Azoles is 1 with the mole dosage ratio of organic base: (1.0～5.0).
The preparation method of formula the most according to claim 3 (2) compound, it is characterised in that: described formula (1) compound fluorine health
Azoles is 1 with the mole dosage ratio of Phosphorous chloride.: (1.0～2.0).
8. the compound of formula (2) is as intermediate application in formula (3) compound good fortune department fluconazol,
The compound of formula the most according to claim 8 (2) as intermediate at formula (3) compound good fortune department fluconazol
In application, preparation method is that the compound of formula (2) occurs hydrolysis to obtain formula (3) compound in organic solvent.
The compound of formula the most according to claim 9 (2) as intermediate in formula (3) compound good fortune department fluorine health
Application in azoles, in preparation method, used by hydrolysis, acid is mineral acid.
The compound of 11. formulas according to claim 10 (2) as intermediate in formula (3) compound good fortune department fluorine health
Application in azoles, in preparation method, acid used by hydrolysis is selected from hydrochloric acid, hydrochloric acid, sulphuric acid, nitric acid, phosphoric acid.
The compound of 12. formulas according to claim 8 (2) as intermediate in formula (3) compound good fortune department fluorine health
Application in azoles, in preparation method, organic solvent is preferably alcohols, esters or ethers selected from solvent for use, and wherein alcohols is selected from
Ethanol, methanol, isopropanol, n-butyl alcohol, ether solvent is selected from oxolane, methyltetrahydrofuran, dioxane, esters
Solvent is selected from ethyl acetate, methyl acetate, butyl acetate.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510266987.6A CN106279280A (en) | 2015-05-25 | 2015-05-25 | A kind of compound and its preparation method and application |
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| CN201510266987.6A CN106279280A (en) | 2015-05-25 | 2015-05-25 | A kind of compound and its preparation method and application |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111171075A (en) * | 2020-04-03 | 2020-05-19 | 北京四环生物制药有限公司 | Preparation method of fosfluconazole |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1210540A (en) * | 1996-02-02 | 1999-03-10 | 辉瑞研究开发公司 | Triazole derivatives useful in therapy |
| WO2005006860A2 (en) * | 2003-07-18 | 2005-01-27 | The Board Of Governors For Higher Education State Of Rhode Island And Providence Plantations | Azole derivatives and methods for making the same |
| WO2010105910A1 (en) * | 2009-03-19 | 2010-09-23 | Seps Pharma N.V. | Fosfluconazole derivatives, synthesis, and use in long acting formulations |
-
2015
- 2015-05-25 CN CN201510266987.6A patent/CN106279280A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1210540A (en) * | 1996-02-02 | 1999-03-10 | 辉瑞研究开发公司 | Triazole derivatives useful in therapy |
| WO2005006860A2 (en) * | 2003-07-18 | 2005-01-27 | The Board Of Governors For Higher Education State Of Rhode Island And Providence Plantations | Azole derivatives and methods for making the same |
| WO2010105910A1 (en) * | 2009-03-19 | 2010-09-23 | Seps Pharma N.V. | Fosfluconazole derivatives, synthesis, and use in long acting formulations |
| CN102439018A (en) * | 2009-03-19 | 2012-05-02 | 塞普斯制药有限公司 | Fosfluconazole derivatives, synthesis, and use in long acting formulations |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111171075A (en) * | 2020-04-03 | 2020-05-19 | 北京四环生物制药有限公司 | Preparation method of fosfluconazole |
| CN111171075B (en) * | 2020-04-03 | 2022-07-12 | 北京四环生物制药有限公司 | Preparation method of fosfluconazole |
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