CN105777486A - Synthesis method of 2-[2-(2,4-diflurophenyl)-2-propen-1-yl)-1,3-propanediol - Google Patents

Synthesis method of 2-[2-(2,4-diflurophenyl)-2-propen-1-yl)-1,3-propanediol Download PDF

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CN105777486A
CN105777486A CN201610191032.3A CN201610191032A CN105777486A CN 105777486 A CN105777486 A CN 105777486A CN 201610191032 A CN201610191032 A CN 201610191032A CN 105777486 A CN105777486 A CN 105777486A
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base
difluorobenzene
propylene
chloromethyl
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CN105777486B (en
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骆成才
郑培灿
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Ningbo Institute of Technology of ZJU
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/35—Preparation of halogenated hydrocarbons by reactions not affecting the number of carbon or of halogen atoms in the reaction
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
    • C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
    • C07C29/147—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of carboxylic acids or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • 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)-2-propen-1-yl)-1,3-propanediol. The synthesis method comprises the following steps: 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; mixing 2-(2,4-diflurophenyl)-1-chloro-3-propanol with potassium hydrogen sulfate and chlorobenzene to perform reaction to obtain 1-(1-chloromethylvinyl)-2,4-difluorobenzene; enabling 1-(1-chloromethylvinyl)-2,4-difluorobenzene to react with diethyl malonate to obtain a product 2-[2-(2,4-diflurophenyl)propenyl]-1,3-diethyl malonate; dissolving 2-[2-(2,4-diflurophenyl)-2-propen-1-yl]-1,3-diethyl malonate in mixed solvent formed by isopropanol and water to react with borohydride to obtain a target product 2-[2-(2,4-diflurophenyl)-2-propen-1-yl)-1,3-propanediol; a synthesis route is as shown in the accompanying drawing.

Description

A kind of conjunction of 2-[2-(2,4 difluorobenzene base)-2-propylene-1-base]-1,3-PD One-tenth method
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)-2- Propylene-1-base] synthetic method of-1,3-PD.
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 shown below:
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)-2-propylene-1-base]-1,3-PD is the intermediate of synthesis 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) all discloses by 1,3-difluorobenzene synthesizes the method for this intermediate, is shown below:
Said method to use expensive trimethyl chloromethyl base silane class material, causes 2-[2-(2,4 difluorobenzene Base)-2-propylene-1-base]-1,3-PD 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, do not use the compound chloracetyl chloride of strong and stimulating, preparation cost low, do not use grignard reaction, without anhydrous and oxygen-free condition, Easily operated, easily realize industrialized production, and compound chloracetyl chloride, the post processing without intense stimulus is simple, operation letter The synthetic method of 2-[2-(2,4 difluorobenzene base)-2-propylene-1-base]-1,3-PD just.
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)- 2-propylene-1-base] synthetic method of-1,3-PD, step includes:
(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 product 2-[2-(2,4 difluorobenzene base) pi-allyl]-1,3-diethyl malonate；
(4) 2-[2-(2,4 difluorobenzene base)-2-propylene-1-base]-1 step (3) obtained, 3-diethyl malonate is molten In the mixed solvent that isopropyl alcohol and water is formed, then react with boron hydride, it is thus achieved that target product 2-[2-(2,4-difluoros Phenyl)-2-propylene-1-base]-1,3-PD.
The synthetic method of 2-[2-(2,4 difluorobenzene base)-2-propylene-1-the base]-1,3-PD that the present invention is above-mentioned, tool The synthesis path of body is:
The synthetic method of the above-mentioned 2-of the present invention [2-(2,4 difluorobenzene base)-2-propylene-1-base]-1,3-PD, 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 synthetic method of the above-mentioned 2-of the present invention [2-(2,4 difluorobenzene base)-2-propylene-1-base]-1,3-PD, 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 synthetic method of the above-mentioned 2-of the present invention [2-(2,4 difluorobenzene base)-2-propylene-1-base]-1,3-PD, 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.
The synthetic method of the above-mentioned 2-of the present invention [2-(2,4 difluorobenzene base)-2-propylene-1-base]-1,3-PD, step (4) particularly as follows: 2-step (3) prepared [2-(2,4 difluorobenzene base)-2-propylene-1-base]-1,3-diethyl malonate is molten In the mixed solvent that isopropyl alcohol and water is formed, after being cooled to-10～0 DEG C, add lithium chloride, boron hydride, reactant mixture It is stirred at room temperature reaction 15-30 hour；The most first regulate the pH=1-3 of reaction solution；Regulate reaction solution again PH=9-11；Separating organic layer after then proceeding to stirring 0.5-2 hour, rotary evaporation removes isopropanol；Gained grease adds Toluene and water, stirring standing separates toluene layer, the toluene removal of toluene layer is i.e. obtained target product.
2-[2-(2,4 difluorobenzene base)-2-propylene-1-base]-1,3-diethyl malonate: chlorination in step of the present invention (4) Lithium: the mol ratio of boron hydride is 1:2-4:2-4；It is preferably 1:2:2.
In step of the present invention (4), boron hydride is sodium borohydride or potassium borohydride；The volume ratio of isopropyl alcohol and water is 8-12: 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 present invention have employed 1-(1-chloromethyl vinyl base)-2,4 difluorobenzene cleverly and takes and be dissolved in DMSO (dimethyl Sulfoxide) in, it is subsequently adding diethyl malonate and hydroxide, at 15-35 DEG C, stirring reaction is reacted, instead for 4-10 hour Answering mild condition, toxicity little, energy consumption is low；Then use under normal temperature and pressure stable, more stable to the aqueous vapor in air and oxygen, operation Process easy boron hydride as reducing agent, it is thus achieved that final goal product.And the target product of preparation, post processing is simple, Need only to extract, wash, distillation of reducing pressure, end product can be obtained, yield is high；And the extractant of use and hydroxide etc. Material 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.Mixture is carefully added at 0 DEG C 300ml concentration after completion of the reaction is In the hydrochloric acid solution of 2mol/l, extract three times with dichloromethane after stirring, each 200ml, combined dichloromethane layer, dichloro Methane layer uses saturated NaHCO successively3Solution, water, saturated aqueous common salt washed once respectively.Dichloromethane layer after washing is with anhydrous Na2SO4Dried filtration, rotary evaporation obtains oil product 2-(2,4 difluorobenzene base)-1-chloro-3-propanol after removing dichloromethane 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 56.21g (0.18mol), productivity 90%.
4, by 2-[2-(2,4 difluorobenzene base)-2-propylene-1-base]-1,3-diethyl malonate 12.48g (0.04mol) It is dissolved in 100ml isopropanol and in mixed solvent that 10ml water is formed, after being cooled to-5 DEG C, adds lithium chloride 3.36g (0.08mol), sodium borohydride 3.04g (0.08mol), reactant mixture is stirred at room temperature reaction 20 hours.After completion of the reaction Regulate to pH value of solution=1 with 4.0mol/l hydrochloric acid.The most again with 20% (containing 20g hydrogen-oxygen in w/v i.e. 100ml solution Change sodium, embodiment 2 with) sodium hydroxide solution regulation is to pH=10.Separating organic layer after continuing stirring 1 hour, rotary evaporation removes Fall isopropanol.Adding 100ml toluene and 100ml water in gained grease, separate toluene layer, rotary evaporation is removed toluene and is i.e. obtained oily Shape product 2-[2-(2,4 difluorobenzene base)-2-propylene-1-base]-1,3-PD 7.31g (0.032mol), productivity 80%.
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 57.46g (0.18mol), productivity 92%.
4, by 2-[2-(2,4 difluorobenzene base)-2-propylene-1-base]-1,3-diethyl malonate 12.48g (0.04mol) It is dissolved in 200ml isopropanol and in mixed solvent that 20ml water is formed, after being cooled to-5 DEG C, adds lithium chloride 5.04g (0.12mol), lithium borohydride 0.12mol, reactant mixture is stirred at room temperature reaction 25 hours.Use after completion of the reaction 4.0mol/l hydrochloric acid regulates to pH value of solution=1.The most again with 20% (w/v) sodium hydroxide solution regulation to pH=10. Separating organic layer after continuing stirring 1 hour, rotary evaporation removes isopropanol.Gained grease adds 150ml toluene and 150ml Water, separates toluene layer, and rotary evaporation is removed toluene and i.e. obtained oil product 2-[2-(2,4 difluorobenzene base)-2-propylene-1-base]-1, Ammediol 7.53g (0.033mol), productivity 82%.
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. the synthetic method of 2-[2-(2,4 difluorobenzene base)-2-propylene-1-base]-1,3-PD, 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 product 2-[2-(2,4 difluorobenzene base) pi-allyl]-1,3-diethyl malonate；
(4) 2-[2-(2,4 difluorobenzene base)-2-propylene-1-base]-1 step (3) obtained, 3-diethyl malonate is dissolved in different In the mixed solvent that third alcohol and water is formed, then react with boron hydride, it is thus achieved that target product 2-[2-(2,4 difluorobenzene Base)-2-propylene-1-base]-1,3-PD.
The synthesis side of 2-the most according to claim 1 [2-(2,4 difluorobenzene base)-2-propylene-1-base]-1,3-PD Method, it is characterised in that: concrete synthesis path is:
The synthesis side of 2-the most according to claim 1 [2-(2,4 difluorobenzene base)-2-propylene-1-base]-1,3-PD 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.
The synthesis side of 2-the most according to claim 3 [2-(2,4 difluorobenzene base)-2-propylene-1-base]-1,3-PD 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 aluminum chloride, zinc chloride, ferric chloride or concentrated sulphuric acid, and catalyst is divided into 3-6 to criticize addition；Step (1) Middle hydrochloric acid solution is the hydrochloric acid solution of 2mol/l concentration, the consumption of hydrochloric acid solution in terms of 2-chloromethyl expoxy propane, 2-chloromethyl Expoxy propane molar concentration in hydrochloric acid solution is 0.05-0.2mol/100ml；The extraction of each dichloromethane in step (1) Amount is 1.5-2.5:3 with the volume ratio of hydrochloric acid solution.
The synthesis side of 2-the most according to claim 1 [2-(2,4 difluorobenzene base)-2-propylene-1-base]-1,3-PD 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.
The synthesis side of 2-the most according to claim 5 [2-(2,4 difluorobenzene base)-2-propylene-1-base]-1,3-PD 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。
The synthesis side of 2-the most according to claim 1 [2-(2,4 difluorobenzene base)-2-propylene-1-base]-1,3-PD 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 product 2-[2-(2,4 difluorobenzene base) pi-allyl]-1,3-diethyl malonate.
The synthesis side of 2-the most according to claim 7 [2-(2,4 difluorobenzene base)-2-propylene-1-base]-1,3-PD 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；In step (3), at 25-30 DEG C, stirring is reacted 4-6 hour, is subsequently adding water, the interpolation of water now Amount and dimethyl sulfoxide volume ratio are 2-6:1；In step (3), hydroxide is in potassium hydroxide, Cesium hydrate., Lithium hydrate A kind of；In step (3), extractant is the one in dichloromethane, petroleum ether, chloroform, normal hexane or hexamethylene；Step (3) Sodium hydrate aqueous solution concentration be 5% (weight/volume)；Sodium hydrate aqueous solution and DMSO volume ratio are 1-3:1.
The synthesis side of 2-the most according to claim 1 [2-(2,4 difluorobenzene base)-2-propylene-1-base]-1,3-PD Method, it is characterised in that: step (4) particularly as follows: prepared by step (3) 2-[2-(2,4 difluorobenzene base)-2-propylene-1-base]- 1,3-diethyl malonate is dissolved in the mixed solvent that isopropyl alcohol and water is formed, after being cooled to-10～0 DEG C add lithium chloride, Boron hydride, reactant mixture is stirred at room temperature reaction 15-30 hour；The most first regulate the pH=1-of reaction solution 3；Regulate the pH=9-11 of reaction solution again；Separating organic layer after then proceeding to stirring 0.5-2 hour, rotary evaporation removes isopropyl Alcohol；Gained grease adds toluene and water, and stirring standing separates toluene layer, the toluene removal of toluene layer is i.e. obtained target product.
The synthesis side of 2-the most according to claim 9 [2-(2,4 difluorobenzene base)-2-propylene-1-base]-1,3-PD Method, it is characterised in that: 2-[2-(2,4 difluorobenzene base)-2-propylene-1-base]-1,3-diethyl malonate: chlorination in step (4) Lithium: the mol ratio of boron hydride is 1:2-4:2-4；In step (4), boron hydride is sodium borohydride or potassium borohydride；Isopropanol and The volume ratio of water is 8-12:1.
CN201610191032.3A 2016-03-30 2016-03-30 A kind of synthetic method of 2- [2- (2,4- difluorophenyl) -2- propylene -1- bases] -1,3-PD Expired - Fee Related CN105777486B (en)

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