CN105777539A - Synthesis method of 2-[2-(2,4-diflurophenyl)propenyl]-1,3-diethyl malonate - Google Patents
Synthesis method of 2-[2-(2,4-diflurophenyl)propenyl]-1,3-diethyl malonate Download PDFInfo
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- CN105777539A CN105777539A CN201610190074.5A CN201610190074A CN105777539A CN 105777539 A CN105777539 A CN 105777539A CN 201610190074 A CN201610190074 A CN 201610190074A CN 105777539 A CN105777539 A CN 105777539A
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- difluorobenzene
- diethyl malonate
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- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
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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
- C07C67/343—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 by increase in the number of carbon atoms
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Abstract
The invention relates to a synthesis method of 2-[2-(2,4-diflurophenyl)propenyl]-1,3-diethyl malonate. The synthesis method of 2-[2-(2,4-diflurophenyl)propenyl]-1,3-diethyl malonate is characterized in that the synthesis method comprises the following steps: (1) mixing 2-chloromethyl epoxy propane with 1,3-difluorobenzene to perform reaction under an effect of catalyst to obtain 2-(2,4-diflurophenyl)-1-chloro-3-propanol; (2) mixing 2-(2,4-diflurophenyl)-1-chloro-3-propanol obtained in step (1) with potassium hydrogen sulfate and chlorobenzene to perform reaction to obtain 1-(1-chloromethylvinyl)-2,4-difluorobenzene; (3) enabling 1-(1-chloromethylvinyl)-2,4-difluorobenzene obtained in step (2) to react with diethyl malonate to obtain a target product 2-[2-(2,4-diflurophenyl)propenyl]-1,3-diethyl malonate; a specific synthesis route is as shown in the accompanying drawing.
Description
Technical field
The present invention relates to the synthetic method of posaconazole intermediate, be specifically related to a kind of 2-[2-(2,4 difluorobenzene base) alkene
Propyl group]-1, the synthetic method of 3-diethyl malonate.
Background technology
Posaconazole (chemical name: 4-[4-[4-[4-[[(3R, 5R)-5-(2,4 difluorobenzene base)-5-(1,2,4-triazole-
1-ylmethyl) oxa-penta ring-3-base] methoxyl group] phenyl] piperazine-1-base] phenyl]-2-[(2S, 3S)-2-hydroxyl amyl-3-yl]-
1,2,4-triazole-3-ketone, English name: Posaconazole), structural formula is as follows:
Being developed by Schering Plough company of the U.S., in JIUYUE, 2006 U.S. FDA 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 aspergillosis and monilial infection, and treat pars oralis pharyngis monilial infection and to fluconazol and the mouth of voriconazole drug resistance
Pharyngeal monilial infection.
2-[2-(2,4 difluorobenzene base) pi-allyl]-1,3-diethyl malonate is the intermediate of synthesis posaconazole, its
Structural formula is as follows:
European patent EP 2789610 (A1), world patent WO 2011144653 (A1), WO 2011144656 (A1) with
And WO 2011144657 (A1) all discloses by 1,3-difluorobenzene synthesizes the method for this intermediate, as follows:
Said method to use expensive trimethyl chloromethyl base silane class material, causes 2-[2-(2,4 difluorobenzene
Base) pi-allyl]-1,3-diethyl malonate production cost height significantly raises.It addition, what is more important the method is also used
To grignard reaction, this reaction needs anhydrous and oxygen-free condition, it is difficult to operation, is difficult to realize industrialized production；Additionally, this course of reaction
The compound chloracetyl chloride of intense stimulus to be used, pollutes relatively big, and has a strong impact on the healthy of experimenter.
Summary of the invention
The present invention is directed to above-mentioned the deficiencies in the prior art, it is provided that one does not use expensive trimethyl chloromethyl base silicon
Alkane, preparation cost are low, do not use grignard reaction, without anhydrous and oxygen-free condition, easily operated, easily realize industrialized production, and after
Process simple, 2-[2-(2,4 difluorobenzene base) pi-allyl]-1 easy and simple to handle, the synthetic method of 3-diethyl malonate.
In order to solve above-mentioned technical problem, the technical solution used in the present invention is: a kind of 2-[2-(2,4 difluorobenzene base) alkene
Propyl group]-1, the synthetic method of 3-diethyl malonate, the step of this synthetic method is as follows:
(1) by 2-chloromethyl expoxy propane (epoxychloropropane) and 1,3-difluorobenzene mixes, and enters under the effect of catalyst
Row reaction, it is thus achieved that 2-(2,4 difluorobenzene base)-1-chloro-3-propanol；
(2) step (1) is obtained 2-(2,4 difluorobenzene base)-1-chloro-3-propanol and potassium acid sulfate and chlorobenzene hybrid reaction,
Obtain 1-(1-chloromethyl vinyl base)-2,4 difluorobenzene；
(3) 1-(1-chloromethyl vinyl base)-2,4 difluorobenzene step (2) obtained and diethyl malonate are carried out instead
Should, it is thus achieved that target product 2-[2-(2,4 difluorobenzene base) pi-allyl]-1,3-diethyl malonate.
The 2-[2-(2,4 difluorobenzene base) pi-allyl]-1 that the present invention is above-mentioned, the synthetic method of 3-diethyl malonate, tool
The synthesis path of body is:
The above-mentioned 2-of the present invention [2-(2,4 difluorobenzene base) pi-allyl]-1, the synthetic method of 3-diethyl malonate, step
(1) particularly as follows: by 2-chloromethyl expoxy propane and 1,3-difluorobenzene is mix homogeneously at 4～-5 DEG C, the most in batches
Add catalyst, add and react 5-12 hour under rear room temperature；Then reaction system is warmed up to 45-70 DEG C of continuation reaction 2-4 hour；
After completion of the reaction, at 4～-5 DEG C, reaction system mixture is joined in hydrochloric acid solution, make with dichloromethane after stirring
Extract 2-4 time for extractant, merge the dichloromethane layer of extraction every time, use saturated NaHCO the most successively3Solution, water, saturated food
Saline washs；The organic layer (dichloromethane layer) obtained uses anhydrous Na2SO4Dried filtration, obtains oily after removing dichloromethane and produces
Thing 2-(2,4 difluorobenzene base)-1-chloro-3-propanol.
2-chloromethyl expoxy propane in step of the present invention (1), 1, the mol ratio of 3-difluorobenzene and catalyst is: 1～1.2:
1:1～1.2；It is preferably 1:1:1；Catalyst can be the one in the lewis acids such as aluminum chloride, zinc chloride, ferric chloride,
It can also be concentrated sulphuric acid.
Being dividedly in some parts catalyst 3-6 can be divided into criticize addition described in concrete steps of the present invention (1), this operation can have
Effect prevents reactant mixture excessively thickness, it is difficult to the appearance of the problems such as stirring.
In concrete steps of the present invention (1), hydrochloric acid solution is the hydrochloric acid solution of 2mol/l concentration, and the consumption of hydrochloric acid solution is with 2-
Chloromethyl expoxy propane meter, 2-chloromethyl expoxy propane molar concentration in hydrochloric acid solution be 0.05-0.2mol/100ml (i.e.
The 2-chloromethyl expoxy propane of 100ml hydrochloric acid solution correspondence 0.05-0.2mol), preferably 0.1mol/100ml.
In concrete steps of the present invention (1), each extraction quantity of dichloromethane and the volume ratio of hydrochloric acid solution are 1.5-2.5:3,
It is preferably 2:3, such as, if having employed the hydrochloric acid solution of 300ml, 2mol/l concentration, the extraction that follow-up dichloromethane is each
Amount is 200ml.
The above-mentioned 2-of the present invention [2-(2,4 difluorobenzene base) pi-allyl]-1, the synthetic method of 3-diethyl malonate, step
(2) particularly as follows: 2-(2,4 difluorobenzene base)-1-chloro-3-propanol step (1) prepared and potassium acid sulfate join in chlorobenzene,
It is heated to reflux 8-15 hour；Chlorobenzene layer is washed to neutrality after completion of the reaction, then uses anhydrous Na2SO4Dried filtration, filtrate is removed
Oil product 1-(1-chloromethyl vinyl base)-2,4 difluorobenzene is obtained after falling (such as decompression distillation) chlorobenzene.
In concrete steps of the present invention (2), 2-(2,4 difluorobenzene base)-1-chloro-3-propanol with the mol ratio of potassium acid sulfate is
1:1-1.5, preferably 1:1.1.
In concrete steps of the present invention (2), 2-(2,4 difluorobenzene base)-1-chloro-3-propanol molar concentration in chlorobenzene is
0.15-0.30mol/300ml (i.e. 2-(2,4 difluorobenzene base) the chloro-3-of-1-of 300ml chlorobenzene correspondence addition 0.15-0.30mol
Propanol)；It is preferably 0.2mol/300ml.
The above-mentioned 2-of the present invention [2-(2,4 difluorobenzene base) pi-allyl]-1, the synthetic method of 3-diethyl malonate, step
(3) particularly as follows: 1-step (2) prepared (1-chloromethyl vinyl base)-2,4 difluorobenzene takes is dissolved in DMSO (dimethyl Asia
Sulfone) in, it is subsequently adding diethyl malonate and hydroxide, stirring reaction 4-10 hour at 15-35 DEG C；It is subsequently adding water,
And gained mixture is stirred 0.5-1.5 hour, by thus obtained solution extractant, extract first at 25-30 DEG C；
After extraction separate water layer extractant, 25-30 DEG C carry out second time extract；The organic layer merging twice extraction (i.e. extracts
Agent place layer), then wash with sodium hydrate aqueous solution, then wash with water, after washing, the solvent under reduced pressure of organic layer is distilled
Obtain oily target product 2-[2-(2,4 difluorobenzene base) pi-allyl]-1,3-diethyl malonate.
In step of the present invention (3), 1-(1-chloromethyl vinyl base)-2,4 difluorobenzene and DMSO amount ratio are 30-75g:
100ml；1-(1-chloromethyl vinyl base)-2,4 difluorobenzene: hydroxide: the mol ratio of diethyl malonate is 1.0:1.5-
3.0:1.0-4.0, preferred 1.0:2-2.5:3-4.0.
In step of the present invention (3), at 25-30 DEG C, stirring is reacted 4-6 hour；It is subsequently adding water, the addition of water now
It is 2-6:1 with DMSO volume ratio, is preferably: 3:1.
In step of the present invention (3), hydroxide can be the one in potassium hydroxide, Cesium hydrate., Lithium hydrate etc..
In step of the present invention (3), extractant can be dichloromethane, (60-90 DEG C, wherein 60-90 DEG C refers to petroleum ether
The specification of petroleum ether), chloroform, one in normal hexane or hexamethylene etc..
Extractant, the extractant of second time extraction and DMSO volume ratio that step of the present invention (3) extracts first are 2:1:1.
The sodium hydrate aqueous solution concentration of step of the present invention (3) is 5% (weight/volume)；Sodium hydrate aqueous solution and
DMSO volume ratio is 1-3:1.
Advantages of the present invention and beneficial effect:
1. the employing that the present invention is creative first is by 2-chloromethyl expoxy propane and 1, and 3-difluorobenzene is as raw material, in two steps
Prepare 1-(1-chloromethyl vinyl base)-2,4 difluorobenzene；Then target product is obtained by simple substitution reaction；This is prepared
Process neither uses expensive trimethyl chloromethyl base silane class material, thus sufficiently lower production cost；And prepare
Technique is the gentleest, easily operated, does not has the anhydrous and oxygen-free condition that traditional handicraft grignard reaction needs, more easily operates, and holds
Easily realize industrialized production；Additionally, this preparation process does not the most use the compound chloracetyl chloride of intense stimulus, thus reduce ring
Environment pollution compared with and the healthy impact of experimenter is effectively reduced.
2. the product that prepared by the present invention, post processing is simple, it is thus only necessary to extracts, wash, distillation of reducing pressure, and can obtain final
Product, yield is high；And the material such as the extractant of use and hydroxide is easy to get, low price, applied widely.
Detailed description of the invention
Below by embodiment, the present invention is described in further detail, but the present invention is not limited solely to following example.
Embodiment 1
1, by 2-chloromethyl expoxy propane (27.60g, 0.30mol) and 1,3-difluorobenzene (34.23g, 0.30mol) is at 0 DEG C
Divide 5 batches to add aluminum chloride (40.00g, 0.30mol) altogether after lower mix homogeneously while stirring, add reaction 7.5 under rear room temperature little
Time, then it is warmed up to 58 DEG C and continues reaction 3 hours.At 0 DEG C, mixture is carefully added into 300ml concentration after completion of the reaction
For in the hydrochloric acid solution of 2mol/l, extract three times with dichloromethane after stirring, each 200ml, combined dichloromethane layer, two
Chloromethanes layer uses saturated NaHCO successively3Solution, water, saturated aqueous common salt washed once respectively.Dichloromethane layer nothing after washing
Water Na2SO4Dried filtration, rotary evaporation obtains oil product 2-(2,4 difluorobenzene base) the chloro-3-of-1-third after removing dichloromethane
Alcohol 51.65g (0.25mol), productivity 83%.
2, by 2-(2,4 difluorobenzene base)-1-chloro-3-propanol 41.32g (0.20mol), potassium acid sulfate 29.96g
(0.22mol) join in 300ml chlorobenzene, be heated to reflux 14 hours.Chlorobenzene layer is washed to neutrality after completion of the reaction, anhydrous
Na2SO4Dried filtration, decompression distillation obtains oil product 1-(1-chloromethyl vinyl base)-2,4 difluorobenzene after removing chlorobenzene
32.06g (0.17mol), productivity 85%.
3, take 1-(1-chloromethyl vinyl base)-2,4 difluorobenzene 37.72g (0.20mol) and be dissolved in 100ml dimethyl sulfoxide,
Being subsequently added into 12.00g (0.30mol) sodium hydroxide and 90.5ml (0.60mol) diethyl malonate, reactant mixture is in room temperature
Under (15-35 degree Celsius) stir 8 hours.Add 300ml water after completion of the reaction, continue stirring 1 hour.Gained solution is used respectively
200ml and 100ml hexamethylene is extracted twice (second time is the water layer obtained after extraction extracts for the first time), merges twice extraction and obtains
The hexamethylene layer (i.e. extractant place layer) obtained, washed once with 150ml 5% (w/v) sodium hydroxide solution, then uses
150ml water washed once, anhydrous Na2SO4Dried filtration, rotary evaporation is removed hexamethylene and is obtained oil product 2-[2-(2,4-bis-
Fluorophenyl) pi-allyl]-1,3-diethyl malonate 56.22g (0.18mol), productivity 90%.
Embodiment 2
1, by 2-chloromethyl expoxy propane (22.08g, 0.24mol) and 1,3-difluorobenzene (22.82g, 0.20mol) is at 0 DEG C
Divide 4 batches to add ferric chloride (0.24mol) altogether after lower mix homogeneously while stirring, add and react 8 hours under rear room temperature, then rise
Temperature to 60 DEG C continues reaction 3 hours.It is 2mol/l's that mixture is carefully added at 0 DEG C 200ml concentration after completion of the reaction
In hydrochloric acid solution, extract three times with dichloromethane after stirring, each 130ml, combined dichloromethane layer, use saturated NaHCO3
Solution, water, saturated aqueous common salt washed once respectively.Organic layer anhydrous Na2SO4Dried filtration, rotary evaporation removes dichloromethane
Oil product 2-(2,4 difluorobenzene base)-1-chloro-3-propanol 33.06g, (0.16mol), productivity 80% is obtained after alkane.
2, by 2-(2,4 difluorobenzene base)-1-chloro-3-propanol 41.32g (0.20mol), potassium acid sulfate 29.96g
(0.22mol), join in 200ml chlorobenzene, be heated to reflux 14 hours.Chlorobenzene layer is washed to neutrality after completion of the reaction, anhydrous
Na2SO4Dried filtration, decompression distillation obtains oil product 1-(1-chloromethyl vinyl base)-2,4 difluorobenzene after removing chlorobenzene
32.06g (0.17mol), productivity 85%.
3,1-(1-chloromethyl vinyl base)-2,4 difluorobenzene 37.72g (0.20mol) is dissolved in 100ml dimethyl sulfoxide,
Being subsequently added into Lithium hydrate and 90.5ml (0.60mol) diethyl malonate of 0.30mol, reactant mixture is stirred at room temperature
8 hours.Add 300ml water after completion of the reaction, continue stirring 1 hour.Gained solution is respectively with 200ml and 100ml petroleum ether
(60-90 DEG C) is extracted twice, and merges petroleum ether layer, washed once with 150ml 5% (w/v) sodium hydroxide solution, then
Washed once with 150ml water, anhydrous Na2SO4Dried filtration, rotary evaporation is removed petroleum ether and is obtained oil product 2-[2-(2,4-
Difluorophenyl) pi-allyl]-1,3-diethyl malonate 56.21g (0.18mol), productivity 90%.
Knowable to above-described embodiment, the method product of the present invention is easily operated, and post processing is simple, it is easy to industry metaplasia
Produce.
Claims (10)
1. a 2-[2-(2,4 difluorobenzene base) pi-allyl]-1, the synthetic method of 3-diethyl malonate, it is characterised in that: step
Suddenly include:
(1) by 2-chloromethyl expoxy propane and 1,3-difluorobenzene mixes, and reacts under the effect of catalyst, it is thus achieved that 2-(2,
4-difluorophenyl)-1-chloro-3-propanol；
(2) step (1) is obtained 2-(2,4 difluorobenzene base)-1-chloro-3-propanol and potassium acid sulfate and chlorobenzene hybrid reaction, it is thus achieved that
1-(1-chloromethyl vinyl base)-2,4 difluorobenzene；
(3) 1-(1-chloromethyl vinyl base)-2,4 difluorobenzene step (2) obtained reacts with diethyl malonate, obtains
Obtain target product 2-[2-(2,4 difluorobenzene base) pi-allyl]-1,3-diethyl malonate.
2-the most according to claim 1 [2-(2,4 difluorobenzene base) pi-allyl]-1, the synthesis side of 3-diethyl malonate
Method, it is characterised in that: concrete synthesis path is:
2-the most according to claim 1 [2-(2,4 difluorobenzene base) pi-allyl]-1, the synthesis side of 3-diethyl malonate
Method, it is characterised in that: step (1) is particularly as follows: by 2-chloromethyl expoxy propane and 1,3-difluorobenzene mixes all at 4～-5 DEG C
Even, it is dividedly in some parts catalyst the most while stirring, adds and react 5-12 hour under rear room temperature；Then reaction system is warmed up to 45-
70 DEG C are continued reaction 2-4 hour；After completion of the reaction, at 4～-5 DEG C, reaction system mixture is joined in hydrochloric acid solution, stir
Mix uniformly rear dichloromethane to extract 2-4 time as extractant, merge the dichloromethane layer of extraction every time, the most successively with saturated
NaHCO3Solution, water, saturated aqueous common salt wash；The organic layer anhydrous Na obtained2SO4Dried filtration, after removing dichloromethane
Obtain oil product 2-(2,4 difluorobenzene base)-1-chloro-3-propanol.
2-the most according to claim 3 [2-(2,4 difluorobenzene base) pi-allyl]-1, the synthesis side of 3-diethyl malonate
Method, it is characterised in that: 2-chloromethyl expoxy propane in step (1), 1, the mol ratio of 3-difluorobenzene and catalyst is 1～1.2:1:
1～1.2；Catalyst is divided into 3-6 to criticize addition, and catalyst is aluminum chloride, zinc chloride, ferric chloride or concentrated sulphuric acid.
2-the most according to claim 3 [2-(2,4 difluorobenzene base) pi-allyl]-1, the synthesis side of 3-diethyl malonate
Method, it is characterised in that: in step (1), hydrochloric acid solution is the hydrochloric acid solution of 2mol/l concentration, and the consumption of hydrochloric acid solution is with 2-chloromethane
Basic ring Ethylene Oxide meter, 2-chloromethyl expoxy propane molar concentration in hydrochloric acid solution is 0.05-0.2mol/100ml；Step
(1) in, each extraction quantity of dichloromethane and the volume ratio of hydrochloric acid solution are 1.5-2.5:3.
2-the most according to claim 1 [2-(2,4 difluorobenzene base) pi-allyl]-1, the synthesis side of 3-diethyl malonate
Method, it is characterised in that: step (2) is particularly as follows: 2-(2,4 difluorobenzene the base)-1-chloro-3-propanol step (1) prepared and sulphuric acid
Hydrogen potassium joins in chlorobenzene, is heated to reflux 8-15 hour；Chlorobenzene layer is washed to neutrality after completion of the reaction, then uses anhydrous Na2SO4
Dried filtration, filtrate obtains oil product 1-(1-chloromethyl vinyl base)-2,4 difluorobenzene after removing chlorobenzene.
2-the most according to claim 6 [2-(2,4 difluorobenzene base) pi-allyl]-1, the synthesis side of 3-diethyl malonate
Method, it is characterised in that: in step (2), 2-(2,4 difluorobenzene base)-1-chloro-3-propanol is 1:1-with the mol ratio of potassium acid sulfate
1.5；In step (2), 2-(2,4 difluorobenzene base)-1-chloro-3-propanol molar concentration in chlorobenzene is 0.15-0.30mol/
300ml。
2-the most according to claim 1 [2-(2,4 difluorobenzene base) pi-allyl]-1, the synthesis side of 3-diethyl malonate
Method, it is characterised in that: step (3) is particularly as follows: 1-(1-chloromethyl vinyl base)-2,4 difluorobenzene step (2) prepared takes molten
Solution, in dimethyl sulfoxide, is subsequently adding diethyl malonate and hydroxide, stirring reaction 4-10 hour at 15-35 DEG C；
It is subsequently adding water, and gained mixture is stirred 0.5-1.5 hour, by thus obtained solution extractant, enter at 25-30 DEG C
Row extracts first；After extraction separate water layer extractant, 25-30 DEG C carry out second time extract；Merge twice extraction has
Machine layer, then washs with sodium hydrate aqueous solution, then washes with water, is distilled by the solvent under reduced pressure of organic layer and obtain oil after washing
Shape target product 2-[2-(2,4 difluorobenzene base) pi-allyl]-1,3-diethyl malonate.
2-the most according to claim 8 [2-(2,4 difluorobenzene base) pi-allyl]-1, the synthesis side of 3-diethyl malonate
Method, it is characterised in that: in step (3), 1-(1-chloromethyl vinyl base)-2,4 difluorobenzene and dimethyl sulfoxide amount ratio are 30-
75g:100ml；1-(1-chloromethyl vinyl base)-2,4 difluorobenzene: hydroxide: the mol ratio of diethyl malonate is 1.0:
1.5-3.0:1.0-4.0.
2-the most according to claim 9 [2-(2,4 difluorobenzene base) pi-allyl]-1, the synthesis side of 3-diethyl malonate
Method, it is characterised in that: in step (3), at 25-30 DEG C, stirring is reacted 4-6 hour, is subsequently adding water, the addition of water now
It is 2-6:1 with dimethyl sulfoxide volume ratio；In step (3), hydroxide is in potassium hydroxide, Cesium hydrate., Lithium hydrate
Kind；In step (3), extractant is the one in dichloromethane, petroleum ether, chloroform, normal hexane or hexamethylene；Step (3)
Sodium hydrate aqueous solution concentration is 5% (weight/volume)；Sodium hydrate aqueous solution and DMSO volume ratio are 1-3:1.
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| CN114409505A (en) * | 2022-01-26 | 2022-04-29 | 山东金城医药研究院有限公司 | Preparation method of posaconazole intermediate |
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| WO1995016658A1 (en) * | 1993-12-13 | 1995-06-22 | Schering Corporation | Process for preparing intermediates for the synthesis of antifungal agents |
| CN1147807A (en) * | 1994-05-09 | 1997-04-16 | 先灵公司 | Process for preparing intermediates for the synthesis of antifungal agents |
| CN105622413A (en) * | 2016-01-14 | 2016-06-01 | 宁波新凯生物科技有限公司 | Synthesis method of diethyl 2-[2-(2,4-difluorophenyl)allyl]-1,3-malonate |
| CN105755060A (en) * | 2016-03-30 | 2016-07-13 | 浙江大学宁波理工学院 | Synthesis method for 2-methylpropionate-[(2S)-4-(2,4-difluorophenyl)-2-hydroxymethyl-4-pentene-1-yl]ester |
| CN105777486A (en) * | 2016-03-30 | 2016-07-20 | 浙江大学宁波理工学院 | Synthesis method of 2-[2-(2,4-diflurophenyl)-2-propen-1-yl)-1,3-propanediol |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114409505A (en) * | 2022-01-26 | 2022-04-29 | 山东金城医药研究院有限公司 | Preparation method of posaconazole intermediate |
| CN114409505B (en) * | 2022-01-26 | 2023-10-17 | 山东金城医药研究院有限公司 | Preparation method of posaconazole intermediate |
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