CN105622412B - The method of one kind 2 [2 (2,4 difluorophenyl) pi-allyl] 1,3 diethyl malonates of synthesis - Google Patents
The method of one kind 2 [2 (2,4 difluorophenyl) pi-allyl] 1,3 diethyl malonates of synthesis Download PDFInfo
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- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
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Abstract
The method of one kind 2 [2 (2,4 difluorophenyl) pi-allyl] 1,3 diethyl malonates of synthesis, 1,2,3 trichloropropane is dripped to and adds alchlor in 1,3 difluorobenzenes, extraction, washing；Use anhydrous Na2SO4Dry filter, evaporate (2, the 4 difluorophenyl) propane of 1,3 dichloro 2 and being added to potassium hydroxide in alcohol flows back；Except alcohol water on the rocks, neutrality is neutralized with hydrochloric acid at 5~5 DEG C, is extracted in three times with dichloromethane, uses anhydrous Na2SO4Filtered after drying, obtain 1 chlorine 2 (2,4 difluorophenyl) 3 propyl alcohol and be added in chlorobenzene and be heated to reflux with potassium acid sulfate；It is washed to neutrality anhydrous Na2SO4Dry filter, obtains 1 (1 chloromethyl vinyl base) 2,4 difluorobenzenes, in molten DMSO, adds diethyl malonate and hydroxide reacts, extraction, washing are evaporated under reduced pressure to target product；Synthesis path is：
Description
Technical field
The present invention relates to the preparation method of posaconazole intermediate, is specially a kind of synthesis 2- [2- (2,4- difluorophenyl)
Pi-allyl] -1,3- diethyl malonates method.
Background technology
Posaconazole (chemical name：4- [4- [4- [4- [[(3R, 5R) -5- (2,4 difluorobenzene base) -5- (1,2,4- triazoles -
1- ylmethyls) penta ring -3- bases of oxa-] methoxyl group] phenyl] piperazine -1- bases] phenyl] -2- [the amyl- 3- yls of (2S, 3S) -2- hydroxyls] -
1,2,4- triazole -3- ketone, English name：Posaconazole), structural formula is shown below：
Developed by Schering Plough company of the U.S., the U.S. FDA of in September, 2006 approval listing, is a kind of highly lipophilic wide spectrum three
Triazole antifungal agent.Trade name Noxafil (promise section flies), oral suspensions, it is mainly used in preventing 13 years old and above patient
Intrusive mood Aspergillus and monilial infection, and treatment pars oralis pharyngis monilial infection and to Fluconazole and the mouth of voriconazole resistance
Pharyngeal monilial infection.
2- [2- (2,4- difluorophenyl) pi-allyl] -1,3- diethyl malonates are the intermediates for synthesizing posaconazole, its
Structural formula is shown below：
European patent EP 2789610 (A1), world patent WO 2011144653 (A1), WO 2011144656 (A1) with
And WO 2011144657 (A1) discloses the method that the intermediate is synthesized by 1,3- difluorobenzenes, is shown below：
This method will use expensive trimethyl chloromethyl base silane class material, cause 1- (1- chloromethyl vinyls base)-
2,4- difluorobenzene production costs are high.In addition, grignard reaction is also used in this method.The reaction needs anhydrous and oxygen-free condition, difficult
In operation, it is not easy to realize industrialized production.
The content of the invention
The present invention is directed to above-mentioned the deficiencies in the prior art, there is provided one kind is without using expensive trimethyl chloromethyl base silicon
Alkane, to prepare cost low, do not use grignard reaction, without anhydrous and oxygen-free condition, it is easily operated, easily realize industrialized production, and after
Processing is simple, the method for synthesizing 2- [2- (2,4- difluorophenyl) pi-allyl] -1,3- diethyl malonates easily to operate.
In order to solve the above-mentioned technical problem, the technical solution adopted by the present invention is：One kind synthesis 2- [2- (2,4- difluorobenzenes
Base) pi-allyl] -1,3- diethyl malonates method, include the step of the synthetic method：
(1) 1,2,3- trichloropropane is added drop-wise in 5~-5 DEG C of 1,3- difluorobenzenes dropwise, reactant mixture stirring 20-
Alchlor is added portionwise after 40min, has gas releasing after addition；0.5-1.5 hours are reacted after adding at 5~-5 DEG C,
Then 20-45 DEG C is warming up to continue to react 1.5-8 hours；Hydrochloric acid to be added mixture at 5~-5 DEG C molten after completion of the reaction
In liquid, extracted 3-5 times with dichloromethane after stirring, combined dichloromethane layer, then use saturation NaHCO successively3Solution,
Water, saturated aqueous common salt washed once respectively；The organic layer anhydrous Na of acquisition2SO4Filtered after drying, rotary evaporation removes dichloro
Oil product 1,3- bis- chloro- 2- (2,4- difluorophenyl) propane are obtained after methane；
(2) by 1,3-, bis- chloro- 2- (2,4- difluorophenyl) propane prepared by step (1) method and potassium hydroxide or hydroxide
Sodium is added in alcohol compound, is heated to reflux 3.5-6 hours；It is evaporated under reduced pressure after completion of the reaction and removes alcohol compound, gained
Remove and frozen water is added in the mixture of alcohol compound, neutrality is neutralized with hydrochloric acid at 5~-5 DEG C, extracted in three times with dichloromethane
Take, merge organic layer, then use anhydrous Na2SO4Filtered after drying, rotary evaporation obtains oil product 1- (1- after removing dichloromethane
Chloromethyl vinyl base) -2,4- difluorobenzenes；
(3) 1- (1- chloromethyl vinyls base) -2,4- difluorobenzenes prepared by step (2) are taken and are dissolved in DMSO, Ran Houjia
Enter diethyl malonate and hydroxide, the stirring reaction 4-10 hours at 15-35 DEG C；Then water is added, and gained is mixed
Thing stirs 0.5-1.5 hours, and thus obtained solution is extracted first with extractant, at 25-30 DEG C；Separated after extraction
Water layer carries out second with extractant, at 25-30 DEG C and extracted；Merge the organic layer (i.e. layer where extractant) extracted twice, so
Washed with sodium hydrate aqueous solution, be then washed with water afterwards, distill the solvent under reduced pressure of organic layer after washing to obtain oily target
Product 2- [2- (2,4- difluorophenyl) pi-allyl] -1,3- diethyl malonates.
The synthetic method such as following formula of 2- [2- (2,4- difluorophenyl) pi-allyl] -1,3- diethyl malonates of the present invention
It is shown：
The mol ratio of 1,2,3- trichloropropanes in step (1) of the present invention, 1,3- difluorobenzene and alchlor is 1~1.2:
1:1~1.2, preferably 1:1:1.
Alchlor is divided into 4-6 batches and added in step (1) of the present invention, and the operation can effectively prevent reactant mixture excessively
It is sticky, it is difficult to the appearance for the problems such as stirring.
Hydrochloric acid solution is the hydrochloric acid solution of 2mol/l concentration in step (1) of the present invention, and the dosage of hydrochloric acid solution is with 1,2,3-
Trichloropropane meter, concentration of 1,2, the 3- trichloropropane in hydrochloric acid solution are 0.05-0.2mol/100ml (i.e. using 0.05-
The 1 of 0.2mol, 2,3- trichloropropanes, the corresponding hydrochloric acid solution 100ml using 2mol/l concentration)；Preferably 0.1mol/100ml.
The dichloromethane and the volume ratio of hydrochloric acid solution extracted every time in step (1) of the present invention is 1:1, such as, if adopted
With the hydrochloric acid solution 200ml of 2mol/l concentration, then it is 200ml to extract the dichloromethane used every time.
1,3-, bis- chloro- 2- (2,4- difluorophenyl) propane and potassium hydroxide or sodium hydroxide rubs in step (2) of the present invention
You are than being 1:1-2, preferably 1:1.1.
The use ratio of 1,3-, bis- chloro- 2- (2,4- difluorophenyl) propane and alcohol compound is in step (2) of the present invention
0.15-0.25mol：150ml；Preferably 0.20mol：150ml.
The use ratio of 1,3-, bis- chloro- 2- (2,4- difluorophenyl) propane and frozen water is 0.15- in step (2) of the present invention
0.25mol：150ml；Preferably 0.20mol：150ml.
Concentration of hydrochloric acid is 5mol/l in step (2) of the present invention.
The use ratio of 1,3-, bis- chloro- 2- (2,4- difluorophenyl) propane and dichloromethane in step (2) of the present invention is
0.15-0.25mol：450ml；Preferably 0.20mol：450ml.
The alcohol compound of step (2) of the present invention is the tert-butyl alcohol, ethanol, propyl alcohol or isopropanol.
The mol ratio of 1- (1- chloromethyl vinyls base) -2,4- difluorobenzenes and diethyl malonate is in step (3) of the present invention
1:1-4；Preferably 1:3.
1- (1- chloromethyl vinyls base) -2,4- difluorobenzenes and DMSO amount ratios are 40-75g in step (3) of the present invention：
100ml；Diethyl malonate and NaOH amount ratio are 15:2.
In step (3) of the present invention at 25-30 DEG C stirring reaction 4-6 hours；Then water is added, the addition of water now
It is 2-6 with DMSO volume ratios：1, be preferably:3:1.
Hydroxide can be one kind in potassium hydroxide, cesium hydroxide, lithium hydroxide etc. in step (3) of the present invention.
Extractant can be dichloromethane in step (3) of the present invention, (60-90 DEG C, wherein 60-90 DEG C refers to petroleum ether
The specification of petroleum ether), chloroform, one kind in n-hexane or hexamethylene etc..
Extractant, the extractant of second of extraction and the DMSO volume ratios that step (3) of the present invention extracts first are 2:1:1.
The sodium hydrate aqueous solution concentration of step (3) of the present invention is 5% (weight/volume)；Sodium hydrate aqueous solution and
DMSO volume ratios are 1-3:1.
The advantages of the present invention：
1. the present invention is used 1,2,3- trichloropropane and 1,3- difluorobenzene as raw material first, synthesis is prepared in two steps
The intermediate of posaconazole --- 1- (1- chloromethyl vinyls base) -2,4- difluorobenzenes；Preparation process is neither using expensive
Trimethyl chloromethyl base silane class material, so as to constituent reduction production cost；And preparation technology is more gentle, easily operated,
The anhydrous and oxygen-free condition for not having traditional handicraft grignard reaction to need, more easily operates, easily realizes industrialized production.
2. product prepared by the present invention, post processing is simple, it is thus only necessary to washs, dries, is evaporated under reduced pressure, you can obtains final
Product, high income.
Embodiment
The present invention is described in further detail below by embodiment, but the present invention is not limited solely to following examples.
Embodiment 1
1st, by 1,2,3- trichloropropane (29.40g, 0.20mol) be added drop-wise to dropwise 0 DEG C 1,3- difluorobenzenes (22.82g,
In 0.20mol), reactant mixture continues to divide 5 batches to add alchlor (26.66g, 0.20mol) altogether after stirring 30min, adds
There is gas releasing afterwards.Reacted after adding at 0 DEG C 1 hour, then (20-35 degrees Celsius) continues reaction 6 hours at room temperature.Reaction
After at 0 DEG C by mixture be carefully added into 200ml concentration be 2mol/l hydrochloric acid solution in, use dichloro after stirring
Methane extracts three times, each 200ml, combined dichloromethane layer, with saturation NaHCO3Solution, water, saturated aqueous common salt wash respectively
Once.Organic layer anhydrous Na2SO4Filtered after drying, rotary evaporation obtains oil product 1, bis- chloro- 2- of 3- after removing dichloromethane
(2,4- difluorophenyl) propane 38.26g (0.17mol), yield 85%.
2nd, by 1,3-, bis- chloro- 2- (2,4- difluorophenyl) propane 45.01g (0.20mol) potassium hydroxide 12.34g
(0.22mol) is added in the 150ml tert-butyl alcohols, is heated to reflux 5 hours.It is evaporated under reduced pressure after completion of the reaction and removes the tert-butyl alcohol, gained
150ml frozen water is added in mixture, is neutralized to neutrality with 5mol/l hydrochloric acid at 0 DEG C, is extracted in three times with 450ml dichloromethane
Take, merge organic layer, anhydrous Na2SO4Filtered after drying, rotary evaporation obtains oil product 1- (1- chloromethyls after removing dichloromethane
Vinyl) -2,4- difluorobenzenes 33.95g (0.18mol), yield 90%.
3rd, 1- (1- chloromethyl vinyls base) -2,4- difluorobenzenes 37.72g (0.20mol) is dissolved in 100ml dimethyl sulfoxide (DMSO)s,
12.00g (0.30mol) sodium hydroxides and 90.5ml (0.60mol) diethyl malonate are subsequently added into, reactant mixture is in room temperature
Lower stirring 8 hours.300ml water is added after completion of the reaction, continues stirring 1 hour.Resulting solution uses 200ml and 100ml rings respectively
Hexane is extracted twice, and is merged hexamethylene layer, be washed once with 150ml 5% (w/v) sodium hydroxide solution, then use
150ml water washings once, anhydrous Na2SO4Filtered after drying, rotary evaporation removes hexamethylene and obtains oil product 2- [2- (2,4- bis-
Fluorophenyl) pi-allyl] -1,3- diethyl malonates 56.22g (0.18mol), yield 90%.
Embodiment 2
1st, by 1,2,3- trichloropropane (26.54g, 0.18mol) be added drop-wise to dropwise 0 DEG C 1,3- difluorobenzenes (17.11g,
In 0.15mol), reactant mixture continues to divide 4 batches to add alchlor (24.00g, 0.18) altogether after stirring 30min, after addition i.e.
There is gas releasing.Reacted 1 hour at 0 DEG C after adding, then continue reaction 6 hours at room temperature.After completion of the reaction will be mixed at 0 DEG C
Compound is carefully added into the hydrochloric acid solution that 150ml concentration is 2mol/l, after stirring with dichloromethane extraction three times, every time
150ml, combined dichloromethane layer, with saturation NaHCO3Solution, water, saturated aqueous common salt washed once respectively.Organic layer is with anhydrous
Na2SO4Filtered after drying, rotary evaporation obtains oil product 1,3- bis- chloro- 2- (2,4- difluorophenyl) propane after removing dichloromethane
29.37g (0.13mol), yield 87%.
2nd, by 1,3- bis- chloro- 2- (2,4- difluorophenyl) propane (33.76g, 0.15mol), sodium hydroxide (6.8g,
0.17mol) it is added in 100ml isopropanols, is heated to reflux 5 hours.It is evaporated under reduced pressure after completion of the reaction and removes the tert-butyl alcohol, gained mixes
100ml frozen water is added in compound, is neutralized to neutrality with 5mol/l hydrochloric acid at 0 DEG C, is extracted in three times with 300ml dichloromethane,
Merge organic layer, anhydrous Na2SO4Filtered after drying, rotary evaporation obtains oil product 1- (1- chloromethyl second after removing dichloromethane
Alkenyl) -2,4- difluorobenzenes 24.05g (0.13mol), yield 85%.
3rd, 1- (1- chloromethyl vinyls base) -2,4- difluorobenzenes 37.72g (0.20mol) is dissolved in 100ml dimethyl sulfoxide (DMSO)s,
16.83g (0.30mol) potassium hydroxide and 90.5ml (0.60mol) diethyl malonate are subsequently added into, reactant mixture is in room temperature
Lower stirring 8 hours.300ml water is added after completion of the reaction, continues stirring 1 hour.Resulting solution uses 200ml and 100ml stones respectively
Oily ether (60-90 DEG C) is extracted twice, and merges petroleum ether layer, one is washed with 150ml 5% (w/v) sodium hydroxide solution
It is secondary, then with 150ml water washings once, anhydrous Na2SO4Filtered after drying, rotary evaporation removes petroleum ether and obtains oil product 2- [2-
(2,4- difluorophenyl) pi-allyl] -1,3- diethyl malonates 57.47g (0.18mol), yield 92%.
It was found from above-described embodiment, method reaction product of the invention is easily operated, and post processing is simple, is easy to industrial metaplasia
Production.
Claims (9)
1. one kind synthesis 2- [2-（2,4- difluorophenyls）Pi-allyl] -1,3- diethyl malonates method, it is characterised in that：Should
The step of synthetic method, includes：
（1）1,2,3- trichloropropane is added drop-wise in 5 ~ -5 DEG C of 1,3- difluorobenzenes dropwise, reactant mixture stirring 20-40min
After alchlor is added portionwise, after addition i.e. have gas releasing；0.5-1.5 hours, Ran Housheng are reacted after adding at 5 ~ -5 DEG C
Temperature continues to react 1.5-3 hours to 35-45 DEG C；Add mixture in hydrochloric acid solution, stir at 5 ~ -5 DEG C after completion of the reaction
Extracted 3-5 times with dichloromethane after mixing uniformly, combined dichloromethane layer, then use saturation NaHCO successively3Solution, water, saturation food
Salt solution washed once respectively；The organic layer anhydrous Na of acquisition2SO4Filtered after drying, rotary evaporation must be oily after removing dichloromethane
Shape product 1, bis- chloro- 2- of 3-（2,4- difluorophenyls）Propane；
（2）By step（1）1,3-, bis- chloro- 2- prepared by method（2,4- difluorophenyls）Propane adds with potassium hydroxide or sodium hydroxide
Enter into alcohol compound, be heated to reflux 3.5-6 hours；It is evaporated under reduced pressure after completion of the reaction and removes alcohol compound, gained mixing
Frozen water is added in thing, neutrality is neutralized with hydrochloric acid at 5 ~ -5 DEG C, is extracted in three times with dichloromethane, merges organic layer, Ran Houyong
Anhydrous Na 2SO4 is filtered after drying, and rotary evaporation obtains oil product 1- after removing dichloromethane（1- chloromethyl vinyl bases）- 2,4-
Difluorobenzene；
（3）By step（2）The 1- of preparation（1- chloromethyl vinyl bases）- 2,4- difluorobenzene, which take, to be dissolved in DMSO, then adds third
Diethyl adipate and hydroxide, the stirring reaction 4-10 hours at 15-35 DEG C；Then water is added, and gained mixture is stirred
0.5-1.5 hours are mixed, thus obtained solution is extracted first with extractant, at 25-30 DEG C；The water layer separated after extraction
Second is carried out with extractant, at 25-30 DEG C to extract；Merge the organic layer extracted twice, then washed with sodium hydrate aqueous solution
Wash, be then washed with water, distill the solvent under reduced pressure of organic layer after washing to obtain oily target product 2- [2-（2,4- difluorobenzenes
Base）Pi-allyl] -1,3- diethyl malonates.
2. synthesis 2- [2- according to claim 1（2,4- difluorophenyls）Pi-allyl] -1,3- diethyl malonates side
Method, it is characterised in that：Step（1）In 1,2,3- trichloropropanes, the mol ratio of 1,3- difluorobenzene and alchlor is 1 ~ 1.2:
1:1~1.2；Alchlor is divided into 4-6 batches and added.
3. synthesis 2- [2- according to claim 1（2,4- difluorophenyls）Pi-allyl] -1,3- diethyl malonates side
Method, it is characterised in that：Step（1）Middle hydrochloric acid solution is the hydrochloric acid solution of 2mol/l concentration, and the dosage of hydrochloric acid solution is with 1,2,3-
Trichloropropane meter, concentration of 1,2, the 3- trichloropropane in hydrochloric acid solution are 0.05-0.2mol/100ml.
4. synthesis 2- [2- according to claim 3（2,4- difluorophenyls）Pi-allyl] -1,3- diethyl malonates side
Method, it is characterised in that：Step（1）In concentration of 1,2, the 3- trichloropropanes in hydrochloric acid solution be 0.1mol/100ml.
5. synthesis 1- according to claim 1（1- chloromethyl vinyl bases）The method of -2,4- difluorobenzene, it is characterised in that：
Step（1）In the volume ratio of the dichloromethane that extracts every time and hydrochloric acid solution be 1:1.
6. synthesis 2- [2- according to claim 1（2,4- difluorophenyls）Pi-allyl] -1,3- diethyl malonates side
Method, it is characterised in that：Step（2）In 1,3-, bis- chloro- 2-（2,4- difluorophenyls）Propane and potassium hydroxide or sodium hydroxide rub
You are than being 1:1-2；1,3- bis- chloro- 2-（2,4- difluorophenyls）The use ratio of propane and alcohol compound is 0.15-
0.25mol：150ml；Bis- chloro- 2- of 3-（2,4- difluorophenyls）The use ratio of propane and frozen water is 0.15-0.25mol：
150ml；Concentration of hydrochloric acid is 5mol/L.
7. synthesis 2- [2- according to claim 1（2,4- difluorophenyls）Pi-allyl] -1,3- diethyl malonates side
Method, it is characterised in that：Step（2）Middle alcohol compound is the tert-butyl alcohol, ethanol, propyl alcohol or isopropanol.
8. synthesis 2- [2- according to claim 1（2,4- difluorophenyls）Pi-allyl] -1,3- diethyl malonates side
Method, it is characterised in that：Step（2）In 1,3-, bis- chloro- 2-（2,4- difluorophenyls）The use ratio of propane and dichloromethane is
0.15-0.25mol：450ml.
9. synthesis 2- [2- according to claim 1（2,4- difluorophenyls）Pi-allyl] -1,3- diethyl malonates side
Method, it is characterised in that：Step（3）Middle 1-（1- chloromethyl vinyl bases）The mol ratio of -2,4- difluorobenzene and diethyl malonate is
1:1-1.5； 1-（1- chloromethyl vinyl bases）- 2,4- difluorobenzene and DMSO amount ratios are 40-75g：100ml；Diethyl malonate
Amount ratio with hydroxide is 15:2；The addition of water and DMSO volume ratios are 5-8:1；Extractant is dichloromethane, oil
One kind in ether, chloroform, n-hexane or hexamethylene；Extractant, the extractant and DMSO of second of extraction extracted first
Volume ratio is 2:1:1；Sodium hydrate aqueous solution concentration is 5%（Weight/volume）.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5349099A (en) * | 1993-12-13 | 1994-09-20 | Schering Corporation | Process for preparing intermediates for the synthesis of antifungal agents |
| CN102906087A (en) * | 2010-05-19 | 2013-01-30 | 桑多斯股份公司 | Process for the preparation of chiral triazolones |
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| JPH09188637A (en) * | 1996-01-09 | 1997-07-22 | Mitsubishi Chem Corp | Production of 3-bromo-2-(substituted)-1-propene |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5349099A (en) * | 1993-12-13 | 1994-09-20 | Schering Corporation | Process for preparing intermediates for the synthesis of antifungal agents |
| CN102906087A (en) * | 2010-05-19 | 2013-01-30 | 桑多斯股份公司 | Process for the preparation of chiral triazolones |
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