CN105753693A - synthetic method for 2-methyl propioric-[(2S)-4-(2,4-diflurophenyl)-2-hydroxymethyl-4-pentene-1-yl] ester - Google Patents

synthetic method for 2-methyl propioric-[(2S)-4-(2,4-diflurophenyl)-2-hydroxymethyl-4-pentene-1-yl] ester Download PDF

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CN105753693A
CN105753693A CN201610197191.4A CN201610197191A CN105753693A CN 105753693 A CN105753693 A CN 105753693A CN 201610197191 A CN201610197191 A CN 201610197191A CN 105753693 A CN105753693 A CN 105753693A
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base
difluorobenzene
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amylene
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CN105753693B (en
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库拉里
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Jiaxing Fucheng Chemical Technology Co., Ltd
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Ningbo Xinkai Biotechnology Co Ltd
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    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • 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
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    • 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
    • C07C29/32—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 without formation of -OH groups
    • C07C29/34—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 without formation of -OH groups by condensation involving hydroxy groups or the mineral ester groups derived therefrom, e.g. Guerbet reaction
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    • 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

A synthetic method for 2-methyl propioric-[(2S)-4-(2,4-diflurophenyl)-2-hydroxymethyl-4-pentene-1-yl] ester includes the steps that 3-chloro-1,2-propylene glycol and 1,3-difluorobenzene are mixed, react for 6-10 h after a catalyst is added and react for 2-4 h after being heated to the temperature of 50-70 DEG C; the product is added into a hydrochloric acid solution at the temperature of 5-minus 5 DEG C, dichloromethane is used as an extraction agent to conduct extraction for 3-5 times, and extract liquor is washed once with a NaHCO3 solution, water and saturated saline solution; anhydrous Na2SO4 is dried and filtered, and dichloromethane is evaporated to obtain 1-chloro-2-(2,4- diflurophenyl)-3-propyl alcohol; 1-chloro-2-(2,4- diflurophenyl)-3-propyl alcohol and potassium hydrogen sulfate are added into chlorobenzene, and heating reflux is conducted for 10-16 h; the product is washed to be neutral, dried with anhydrous Na2SO4 and then filtered, the distillation product is dissolved in DMSO, diethyl malonate and hydroxide are added for reacting, the obtained product reacts with lithium chloride and sodium borohydride to obtain a product, and the product is dissolved in methylbenzene, sodium bicarbonate, Novo SP 435 esterifying enzyme and isobutyric anhydride are added for reacting; the target product is obtained through washing, crystallizing and drying.The synthesis path is as follow (see the path in the description).

Description

2 Methylpropionic acid-[(2S)-4-(2,4 difluorobenzene base)-2-methylol-4-amylene-1- Base] synthetic method of ester
Technical field
The present invention relates to 2 Methylpropionic acid-[(2S)-4-(2,4 difluorobenzene base)-2-methylol-4-amylene-1-base] ester Synthetic method.
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 Methylpropionic acid-[(2S)-4-(2,4 difluorobenzene base)-2-methylol-4-amylene-1-base] ester is the husky health of synthesis pool The intermediate of azoles, 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:
The method to use expensive raw material trimethyl chloromethyl base silane class material and grignard reaction, causes 2-methyl Propanoic acid-[(2S)-4-(2,4 difluorobenzene base)-2-methylol-4-amylene-1-base] ester production cost is high, and is difficult to operate, no Easily realize industrialized production.It addition, the compound chloracetyl chloride of strong and stimulating to be used in the method, pollute bigger.
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 post processing is simple, 2 Methylpropionic acid easy and simple to handle-[(2S)-4-(2,4-difluoros Phenyl)-2-methylol-4-amylene-1-base] synthetic method of ester.
In order to solve above-mentioned technical problem, the technical solution used in the present invention is: 2 Methylpropionic acid-[(2S)-4-(2,4- Difluorophenyl)-2-methylol-4-amylene-1-base] synthetic method of ester, the step of this synthetic method is as follows:
(1) by 3-chlorine-1,2-propylene glycol and 1,3-difluorobenzene is mix homogeneously at 5～-5 DEG C, the most in batches Add catalyst, add and react 6-10 hour under rear room temperature；Then reaction system is warmed up to 50-70 DEG C of continuation reaction 2-4 hour； After completion of the reaction, at 5～-5 DEG C, reaction system mixture is joined in hydrochloric acid solution, make with dichloromethane after stirring Extract 3-5 time for extractant, merge the dichloromethane layer of extraction every time, use saturated NaHCO the most successively3Solution, water, saturated food Saline washs respectively；The organic layer (dichloromethane layer) obtained uses anhydrous Na2SO4Dried filtration, rotary evaporation removes dichloromethane The chloro-2-of oil product 1-(2,4 difluorobenzene base)-3-propanol is obtained after alkane；
(2) the chloro-2-of 1-(2,4 difluorobenzene base)-3-propanol step (1) prepared and potassium acid sulfate join in chlorobenzene, It is heated to reflux 10-16 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 (decompression distillation) chlorobenzene；
(3) 1-(1-chloromethyl vinyl base)-2,4 difluorobenzene step (2) prepared takes and 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, by organic layer (i.e. extractant place after washing Layer) solvent distillation obtain grease 2-[2-(2,4 difluorobenzene base)-2-propylene-1-base]-1,3-diethyl malonate；
(4) 2-[2-(2,4 difluorobenzene base)-2-propylene-1-base]-1 step (3) prepared, 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；Separate organic layer after then proceeding to stirring 0.5-2 hour, remove (rotary evaporation) isopropanol；Gained grease adds Entering toluene and water, stirring standing separates toluene layer, the toluene removal of toluene layer i.e. obtains 2-[2-(2,4 difluorobenzene base)-2-third Alkene-1-base]-1,3-PD；
(5) 2-[2-(2,4 difluorobenzene base)-2-propylene-1-base]-1,3-PD step (4) prepared is dissolved in first Benzene ,-15～-5 DEG C at add sodium bicarbonate, Novo SP 435 Esterified Enzyme (Novo435 enzyme), isobutyric anhydride；Then insulated and stirred React 20-40 hour；Filtering solid after completion of the reaction, filtrate with sodium bicarbonate solution, water washing, is then removed toluene and is obtained successively Oily crude product；This crude product is dissolved in normal heptane at 50-60 DEG C, and gained clear liquid progressively cools to 10 DEG C, stands at a temperature of being somebody's turn to do 10-15 hour, leaching crystal, crystal the most i.e. obtains product 2 Methylpropionic acid-[(2S)-4-(2,4 difluorobenzene base)-2-hydroxyl first Base-4-amylene-1-base] ester.
2 Methylpropionic acid of the present invention-[(2S)-4-(2,4 difluorobenzene base)-2-methylol-4-amylene-1-base] ester Synthesis path is as follows:
3-chlorine-1,2-propylene glycol 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, also It can be concentrated sulphuric acid.
Step of the present invention (1) is dividedly in some parts catalyst and 4-6 can be divided into criticize addition, and this operation can effectively prevent reaction mixed Compound excessively thickness, it is difficult to the appearance of the problems such as stirring.
In step of the present invention (1), hydrochloric acid solution is the hydrochloric acid solution of 2mol/l concentration, the consumption of hydrochloric acid solution with 3-chloro-1, 2-propylene glycol meter, 3-chlorine-1,2-propylene glycol molar concentration in hydrochloric acid solution is 0.05-0.2mol/100ml (i.e. 100ml salt The 3-chlorine-1,2-propylene glycol of acid solution correspondence 0.05-0.2mol), preferably 0.1mol/100ml.
In step of the present invention (1), each extraction quantity of dichloromethane and the volume ratio of hydrochloric acid solution are 1.5-2.5:3；Preferably For 2:3, such as, if having employed 300ml, the hydrochloric acid solution of 2mol/l concentration, each extraction quantity of follow-up dichloromethane is 200ml。
In step of the present invention (2), the chloro-2-of 1-(2,4 difluorobenzene base)-3-propanol is 1:1 with the mol ratio of potassium acid sulfate 1.5, preferably 1:1.1.
In step of the present invention (2), the chloro-2-of 1-(2,4 difluorobenzene base)-3-propanol molar concentration in chlorobenzene is 0.15- 0.30mol/300ml (i.e. the chloro-2-of 1-(2,4 difluorobenzene the base)-3-propanol of 300ml chlorobenzene correspondence addition 0.15-0.25mol)； It is preferably 0.2mol/300ml.
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%, and (weight/volume, i.e. containing 5g in 100ml solution Sodium hydroxide)；Sodium hydrate aqueous solution and DMSO volume ratio are 1-3:1.
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。
2-[2-(2,4 difluorobenzene base)-2-propylene-1-base]-1,3-PD in step of the present invention (5): sodium bicarbonate: The mol ratio of isobutyric anhydride is 1:2:1；Novo SP 435 Esterified Enzyme and 2-[2-(2,4 difluorobenzene base)-2-propylene-1-base]- The weight ratio of 1,3-PD is 1:20-25；Preferably, Novo SP 435 Esterified Enzyme and 2-[2-(2,4 difluorobenzene base)-2- Propylene-1-base] weight ratio of-1,3-PD is 1:20.
Advantages of the present invention and beneficial effect:
1. the present invention uses 3-chlorine-1,2-propylene glycol and 1 first, and 3-difluorobenzene, as raw material, is the most first prepared Synthesis 1-(1-chloromethyl vinyl base)-2,4 difluorobenzene, target product 2 Methylpropionic acid of then reentrying-[(2S)-4-(2,4- Difluorophenyl)-2-methylol-4-amylene-1-base] ester；Whole preparation process neither uses expensive trimethyl chloromethyl base Fluorosilane-type materials, thus sufficiently lower production cost；And preparation technology is the gentleest, easily operated, does not has traditional handicraft The anhydrous and oxygen-free condition that grignard reaction needs, more easily operates, easily realizes industrialized production.
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 2-[2-(2,4 difluorobenzene base)-2-propylene-1-base]-1,3-PD； Be then dissolved in toluene ,-15～-5 DEG C to add sodium bicarbonate, Novo SP 435 Esterified Enzyme (Novo435 enzyme), isobutyric anhydride anti- Should, simple washing, crystallization, dried obtain target product；There is post processing simple, it is thus only necessary to extract, wash, reduce pressure Distillation, can obtain end product, and yield is high；And the material such as the extractant of use and hydroxide is easy to get, low price, is suitable for Scope is wide.
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 3-chlorine-1,2-propylene glycol (33.16g, 0.30mol) and 1,3-difluorobenzene (34.23g, 0.30mol) is at 0 DEG C It is dividedly in some parts aluminum chloride (40.00g, 0.30mol) after lower mix homogeneously while stirring, adds reaction 8 hours under rear room temperature, so After be warmed up to 60 DEG C continue reaction 3 hours.It is 2mol/ that mixture is carefully added at 0 DEG C 300ml concentration after completion of the reaction In the hydrochloric acid solution of l, extracting three times with dichloromethane after stirring, each 200ml, combined dichloromethane layer, with saturated NaHCO3Solution, water, saturated aqueous common salt washed once respectively.Organic layer anhydrous Na2SO4Dried filtration, rotary evaporation is removed The chloro-2-of oil product 1-(2,4 difluorobenzene base)-3-propanol 51.65g (0.25mol), productivity 83% is obtained after dichloromethane.
2, by chloro-for 1-2-(2,4 difluorobenzene base)-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%.
3,1-(1-chloromethyl vinyl base)-2,4 difluorobenzene 37.72g (0.20mol) is 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, with 150ml 5%, (w/v, containing hydroxide in i.e. every 100ml solution Sodium 5g) sodium hydroxide solution washed once, then washed once with 150ml water, anhydrous Na2SO4Dried filtration, rotary evaporation removes Fall hexamethylene and obtain oil product 2-[2-(2,4 difluorobenzene base)-2-propylene-1-base]-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 7.30g (0.032mol), productivity 80%；
5,2-[2-(2,4 difluorobenzene base)-2-propylene-1-base]-1,3-PD 22.80g (0.10mol) is dissolved in 150ml toluene, adds sodium bicarbonate 16.8g (0.20mol), Novo SP 435 Esterified Enzyme 1.0g, isobutyric anhydride at-15 DEG C 15.8ml (0.10mol), mixture stirring reaction 24 hours at same temperature.Filtering solid after completion of the reaction, filtrate is used successively The sodium bicarbonate solution of 5% (w/v) and water each 100ml washing, rotary evaporation obtains oily crude product after removing toluene. This crude product is dissolved in 80ml normal heptane at 50-60 DEG C, and gained clear liquid progressively cools to 10 DEG C, stands 12 hours at a temperature of being somebody's turn to do, Leach crystal, at 40 DEG C, i.e. obtain product 2 Methylpropionic acid-[(2S)-4-(2,4 difluorobenzene base)-2-methylol-4-penta after drying Alkene-1-base] ester 22.37g (0.075mol), productivity 75%.
Embodiment 2
1, by 3-chlorine-1,2-propylene glycol (26.53g, 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 The chloro-2-of oil product 1-(2,4 difluorobenzene base)-3-propanol 33.06g, (0.16mol), productivity 80% is obtained after alkane.
2, by chloro-for 1-2-(2,4 difluorobenzene base)-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 50g (0.265mol) is dissolved in 150ml dimethyl sulfoxide, connects Lithium hydrate and the 1.06mol diethyl malonate adding 0.53mol, reactant mixture is stirred at room temperature 10 hours.Instead Add 450ml water after Ying, continue stirring 1.5 hours.Gained solution is respectively with 300ml and 150ml petroleum ether (60-90 DEG C) It is extracted twice, merges petroleum ether layer, washed once with 150ml 5% (w/v) sodium hydroxide solution, then use 200ml Water washed once, anhydrous Na2SO4Dried filtration, rotary evaporation is removed petroleum ether and is obtained oil product 2-[2-(2,4 difluorobenzene Base)-2-propylene-1-base]-1,3-diethyl malonate 76.20g (0.244mol), 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%.
5,2-[2-(2,4 difluorobenzene base)-2-propylene-1-base]-1,3-PD 34.2g (0.15mol) is dissolved in 150ml toluene, adds sodium bicarbonate 25.2g (0.30mol), Novo SP 435 Esterified Enzyme 1.0g, isobutyric anhydride at-15 DEG C 23.4ml (0.15mol), mixture stirring reaction 30 hours at same temperature.Filtering solid after completion of the reaction, filtrate is used successively The sodium bicarbonate solution of 5% (w/v) and water each 150ml washing, rotary evaporation obtains oily crude product after removing toluene. This crude product is dissolved in 120ml normal heptane at 50-60 DEG C, and gained clear liquid progressively cools to 10 DEG C, stands 15 hours at a temperature of being somebody's turn to do, Leach crystal, at 40 DEG C, i.e. obtain product 2 Methylpropionic acid-[(2S)-4-(2,4 difluorobenzene base)-2-methylol-4-penta after drying Alkene-1-base] ester 33.11g (0.111mol), productivity 74%.
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 synthesis side of 2 Methylpropionic acid-[(2S)-4-(2,4 difluorobenzene base)-2-methylol-4-amylene-1-base] ester Method, it is characterised in that: the step of this synthetic method is as follows:
(1) by 3-chlorine-1,2-propylene glycol and 1,3-difluorobenzene is mix homogeneously at 5～-5 DEG C, is dividedly in some parts the most while stirring Catalyst, adds and reacts 6-10 hour under rear room temperature；Then reaction system is warmed up to 50-70 DEG C of continuation reaction 2-4 hour；Reaction After, at 5～-5 DEG C, reaction system mixture is joined in hydrochloric acid solution, with dichloromethane as extraction after stirring Take agent to extract 3-5 time, merge the dichloromethane layer of extraction every time, use saturated NaHCO the most successively3Solution, water, saturated aqueous common salt Wash respectively；The organic layer anhydrous Na obtained2SO4Dried filtration, obtains 1-chloro-2-(2,4 difluorobenzene after removing dichloromethane Base)-3-propanol；
(2) the chloro-2-of 1-(2,4 difluorobenzene base)-3-propanol step (1) prepared and potassium acid sulfate join in chlorobenzene, heating Reflux 10-16 hour；Chlorobenzene layer is washed to neutrality after completion of the reaction, then uses anhydrous Na2SO4Dried filtration, filtrate removes chlorine 1-(1-chloromethyl vinyl base)-2,4 difluorobenzene is obtained after benzene；
(3) 1-(1-chloromethyl vinyl base)-2,4 difluorobenzene step (2) prepared takes and is dissolved in dimethyl sulfoxide, then Add diethyl malonate and hydroxide, stirring reaction 4-10 hour at 15-35 DEG C；It is subsequently adding water, and gained is mixed Compound stirs 0.5-1.5 hour, by thus obtained solution extractant, extracts first at 25-30 DEG C；Separate after extraction Water layer extractant, 25-30 DEG C carry out second time extract；Merge the organic layer of twice extraction, then use sodium hydroxide water Solution washs, and then washes with water, is distilled by the solvent under reduced pressure of organic layer and obtain 2-[2-(2,4 difluorobenzene base)-2-after washing Propylene-1-base]-1,3-diethyl malonate；
(4) 2-[2-(2,4 difluorobenzene base)-2-propylene-1-base]-1 step (3) prepared, 3-diethyl malonate is dissolved in different In the mixed solvent that third alcohol and water is formed, adding lithium chloride, boron hydride after being cooled to-10～0 DEG C, reactant mixture is in room Temperature lower stirring reaction 15-30 hour；Regulation reaction solution pH=1-3 after completion of the reaction；Regulate reaction solution again to pH=9-11； Separating organic layer after continuing stirring 0.5-2 hour, rotary evaporation removes isopropanol；Gained grease adds toluene and water, stirring Standing separates toluene layer, and the toluene removal of toluene layer obtains 2-[2-(2,4 difluorobenzene base)-2-propylene-1-base]-1,3-third Glycol；
(5) 2-[2-(2,4 difluorobenzene base)-2-propylene-1-base]-1,3-PD step (4) prepared is dissolved in toluene, and-15 ～at-5 DEG C, add sodium bicarbonate, Novo SP 435 Esterified Enzyme, isobutyric anhydride；Then insulated and stirred is reacted 20-40 hour；Instead Filtering solid after Ying, filtrate with sodium bicarbonate solution, water washing, is then removed toluene and is obtained oily crude product successively；This is thick Product is dissolved in normal heptane at 50-60 DEG C, and gained clear liquid progressively cools to 10 DEG C, stands 10-15 hour, leach crystalline substance at a temperature of being somebody's turn to do Body, crystal the most i.e. obtains product 2 Methylpropionic acid-[(2S)-4-(2,4 difluorobenzene base)-2-methylol-4-amylene-1-base] Ester.
2 Methylpropionic acid the most according to claim 1-[(2S)-4-(2,4 difluorobenzene base)-2-methylol-4-amylene-1- Base] synthetic method of ester, it is characterised in that: synthesis path is:
2 Methylpropionic acid the most according to claim 1-[(2S)-4-(2,4 difluorobenzene base)-2-methylol-4-amylene-1- Base] synthetic method of ester, it is characterised in that: 3-chlorine-1,2-propylene glycol in step (1), 1,3-difluorobenzene and catalyst mole Ratio is 1～1.2:1:1～1.2, and catalyst is divided into 4-6 to criticize addition；In step (1), concentration of hydrochloric acid solution is 2mol/l, and hydrochloric acid is molten The consumption of liquid is counted with 3-chlorine-1,2-propylene glycol, 3-chlorine-1,2-propylene glycol molar concentration in hydrochloric acid solution is as 0.05- 0.2mol/100ml。
2 Methylpropionic acid the most according to claim 1-[(2S)-4-(2,4 difluorobenzene base)-2-methylol-4-amylene-1- Base] synthetic method of ester, it is characterised in that: the catalyst in step (1) is aluminum chloride, zinc chloride, ferric chloride or dense sulfur One in acid；The extraction quantity of dichloromethane and the volume ratio of hydrochloric acid solution are 1.5-2.5:3 every time.
2 Methylpropionic acid the most according to claim 1-[(2S)-4-(2,4 difluorobenzene base)-2-methylol-4-amylene-1- Base] synthetic method of ester, it is characterised in that: the chloro-2-of 1-(2,4 difluorobenzene base)-3-propanol and potassium acid sulfate in step (2) Mol ratio is 1:1-1.5；In step (2), the chloro-2-of 1-(2,4 difluorobenzene base)-3-propanol molar concentration in chlorobenzene is 0.15-0.30mol/300ml；In step (2), the chloro-2-of 1-(2,4 difluorobenzene base)-3-propanol molar concentration in chlorobenzene is 0.2mol/300ml。
2 Methylpropionic acid the most according to claim 1-[(2S)-4-(2,4 difluorobenzene base)-2-methylol-4-amylene-1- Base] synthetic method of ester, it is characterised in that: 1-(1-chloromethyl vinyl base)-2,4 difluorobenzene and DMSO amount ratio in step (3) For 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 Methylpropionic acid the most according to claim 1-[(2S)-4-(2,4 difluorobenzene base)-2-methylol-4-amylene-1- Base] synthetic method of ester, it is characterised in that: in step (3) at 25-30 DEG C stirring reaction 4-6 hour；It is subsequently adding water, this Time addition and the DMSO volume ratio of water be 2-6:1；In step (3), hydroxide is potassium hydroxide, Cesium hydrate., hydroxide One in lithium.
2 Methylpropionic acid the most according to claim 1-[(2S)-4-(2,4 difluorobenzene base)-2-methylol-4-amylene-1- Base] synthetic method of ester, it is characterised in that: in step (3) extractant be dichloromethane, petroleum ether, chloroform, normal hexane or One in hexamethylene；Extractant, the extractant of second time extraction and DMSO volume ratio that step (3) extracts first are 2:1:1； The sodium hydrate aqueous solution concentration of step (3) is 5% (weight/volume)；Sodium hydrate aqueous solution and DMSO volume ratio are 1-3: 1。
2 Methylpropionic acid the most according to claim 1-[(2S)-4-(2,4 difluorobenzene base)-2-methylol-4-amylene-1- Base] synthetic method of ester, it is characterised in that: the 2-[2-(2,4 difluorobenzene base)-2-propylene-1-base]-1 described in step (4), 3-diethyl malonate: lithium chloride: the mol ratio of boron hydride is 1:2-4:2-4；Boron hydride described in step (4) is boron Sodium hydride or potassium borohydride；The volume ratio of isopropyl alcohol and water is 8-12:1.
2 Methylpropionic acid the most according to claim 1-[(2S)-4-(2,4 difluorobenzene base)-2-methylol-4-amylene- 1-yl] synthetic method of ester, it is characterised in that: 2-[2-(2,4 difluorobenzene base)-2-propylene-1-base]-1,3-third in step (5) Glycol: sodium bicarbonate: the mol ratio of isobutyric anhydride is 1:2:1；Novo SP 435 Esterified Enzyme and 2-[2-(2,4 difluorobenzene base)- 2-propylene-1-base] weight ratio of-1,3-PD is 1:20-25.
CN201610197191.4A 2016-03-30 2016-03-30 The synthetic method of 2 methylpropanoic acids [base of 4 amylene of (2S) 4 (2,4 difluorophenyl) 2 methylol 1] ester Active CN105753693B (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102892762A (en) * 2010-05-19 2013-01-23 桑多斯股份公司 Preparation of posaconazole intermediates
CN102906087A (en) * 2010-05-19 2013-01-30 桑多斯股份公司 Process for the preparation of chiral triazolones
EP2789610A1 (en) * 2013-04-10 2014-10-15 Sandoz Ag Purification of Posaconazole Intermediates

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102892762A (en) * 2010-05-19 2013-01-23 桑多斯股份公司 Preparation of posaconazole intermediates
CN102906087A (en) * 2010-05-19 2013-01-30 桑多斯股份公司 Process for the preparation of chiral triazolones
EP2789610A1 (en) * 2013-04-10 2014-10-15 Sandoz Ag Purification of Posaconazole Intermediates

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