CN105755060B - A kind of synthetic method of 2 Methylpropionic acid-[(2S) -4- (2,4- difluorophenyl) -2- methylol -4- amylene -1- base] ester - Google Patents

A kind of synthetic method of 2 Methylpropionic acid-[(2S) -4- (2,4- difluorophenyl) -2- methylol -4- amylene -1- base] ester Download PDF

Info

Publication number
CN105755060B
CN105755060B CN201610191035.7A CN201610191035A CN105755060B CN 105755060 B CN105755060 B CN 105755060B CN 201610191035 A CN201610191035 A CN 201610191035A CN 105755060 B CN105755060 B CN 105755060B
Authority
CN
China
Prior art keywords
difluorophenyl
base
amylene
reaction
methylol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CN201610191035.7A
Other languages
Chinese (zh)
Other versions
CN105755060A (en
Inventor
骆成才
郑培灿
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ningbo Institute of Technology of ZJU
Original Assignee
Ningbo Institute of Technology of ZJU
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ningbo Institute of Technology of ZJU filed Critical Ningbo Institute of Technology of ZJU
Priority to CN201610191035.7A priority Critical patent/CN105755060B/en
Publication of CN105755060A publication Critical patent/CN105755060A/en
Application granted granted Critical
Publication of CN105755060B publication Critical patent/CN105755060B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/62—Carboxylic acid esters

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Microbiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biotechnology (AREA)
  • Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

A kind of 2 Methylpropionic acid-[(2S) -4- (2,4- difluorophenyl) -2- methylol -4- amylene -1- base] ester synthetic method, it include: by 2- chloromethyl propylene oxide and 1,3- difluorobenzene mixes, and reacts under catalyst, obtains 2- (2,4- difluorophenyl) the chloro- 3- propyl alcohol of -1-, by itself and potassium acid sulfate and chlorobenzene hybrid reaction, 1- (1- chloromethyl vinyl base) -2,4- difluorobenzene is obtained；1- (1- chloromethyl vinyl base) -2,4- difluorobenzene is reacted with diethyl malonate, obtains 2- [2- (2,4- difluorophenyl) allyl] -1,3- diethyl malonate；2- [2- (2,4- difluorophenyl) -2- propylene -1- base] -1,3- diethyl malonate is dissolved in the in the mixed solvent of isopropyl alcohol and water, then it is reacted with boron hydride, obtain product 2- [2- (2,4- difluorophenyl) -2- propylene -1- base] -1,3-PD；By 2- [2- (2,4- difluorophenyl) -2- propylene -1- base] -1,3-PD and Esterified Enzyme, isobutyric anhydride hybrid reaction, target product is obtained；Specific synthesis path are as follows:

Description

A kind of 2 Methylpropionic acid-[(2S) -4- (2,4- difluorophenyl) -2- methylol -4- penta Alkene -1- base] ester synthetic method
Technical field
The present invention relates to posaconazole intermediate synthesis technical fields, and in particular to a kind of 2 Methylpropionic acid-[(2S) -4- (2,4- difluorophenyl) -2- methylol -4- amylene -1- base] ester synthetic method.
Background technique
Posaconazole (chemical name: 4- [4- [4- [4- [[(3R, 5R) -5- (2,4 difluorobenzene base) -5- (1,2,4- triazole - 1- ylmethyl) penta ring -3- base of oxa-] methoxyl group] phenyl] piperazine -1- base] phenyl] -2- [the amyl- 3- of (2S, 3S) -2- hydroxyl Base] -1,2,4- triazole -3- ketone, English name: Posaconazole), structural formula is as shown below:
It is 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 are mainly used for preventing 13 years old and the above patient Intrusive Aspergillus and monilial infection, and treatment pars oralis pharyngis monilial infection and to Fluconazole and the drug resistant mouth of voriconazole Pharyngeal monilial infection.
2 Methylpropionic acid-[(2S) -4- (2,4- difluorophenyl) -2- methylol -4- amylene -1- base] ester is that husky health is moored in synthesis The intermediate of azoles, structural formula are as shown below:
European patent EP 2789610 (A1), world patent WO2011144653 (A1), WO2011144656 (A1) and WO2011144657 (A1) discloses the method for synthesizing the intermediate by 1,3- difluorobenzene, as shown below:
The above method will use expensive trimethyl chloromethyl base silane substance, lead to 2 Methylpropionic acid-[(2S)- 4- (2,4- difluorophenyl) -2- methylol -4- amylene -1- base] ester high production cost is sharply increased.In addition, more importantly Grignard reaction is also used in this method, which needs anhydrous and oxygen-free condition, it is difficult to operate, not be easy to realize industrial production； In addition, the reaction process will also use the compound chloracetyl chloride of intense irritation, pollution is larger, and seriously affects experimenter Health.
Summary of the invention
The present invention in view of the above shortcomings of the prior art, provides a kind of without using expensive trimethyl chloromethyl base silicon It is alkane, low without using compound chloracetyl chloride, the preparation cost of strong and stimulating, do not use grignard reaction, without anhydrous and oxygen-free condition, It is easily operated, be easy to realize industrial production, and it is simple not have to the compound chloracetyl chloride of intense irritation, post-processing, operation letter The synthetic method of 2 Methylpropionic acid-[(2S) -4- (2,4- difluorophenyl) -2- methylol -4- amylene -1- base] ester just.
In order to solve the above-mentioned technical problem, a kind of the technical solution adopted by the present invention are as follows: 2 Methylpropionic acid-[(2S) -4- (2,4- difluorophenyl) -2- methylol -4- amylene -1- base] ester synthetic method, step includes:
(1) 2- chloromethyl propylene oxide (epoxychloropropane) and 1,3- difluorobenzene are mixed, under the effect of the catalyst into Row reaction, obtains the chloro- 3- propyl alcohol of 2- (2,4- difluorophenyl) -1-；
(2) step (1) is obtained into the chloro- 3- propyl alcohol of 2- (2,4- difluorophenyl) -1- and potassium acid sulfate and chlorobenzene hybrid reaction, Obtain 1- (1- chloromethyl vinyl base) -2,4- difluorobenzene；
(3) 1- (1- chloromethyl vinyl base) -2, the 4- difluorobenzene and diethyl malonate obtained step (2) carries out anti- It answers, obtains product 2- [2- (2,4- difluorophenyl) allyl] -1,3- diethyl malonate；
(4) 2- [2- (2,4- difluorophenyl) -2- propylene -1- base] -1, the 3- diethyl malonate obtained step (3) is molten It is formed by the mixed solvent in isopropyl alcohol and water, is then reacted with boron hydride, product 2- [2- (2,4- difluorobenzenes are obtained Base) -2- propylene -1- base] -1,3-PD；
(5) 2- [2- (2,4- difluorophenyl) -2- propylene -1- the base] -1,3-PD and Esterified Enzyme for obtaining step (4) (Novo435 enzyme), isobutyric anhydride hybrid reaction obtain target product 2 Methylpropionic acid-[(2S) -4- (2,4- difluorophenyl) -2- Methylol -4- amylene -1- base] ester.
Above-mentioned 2 Methylpropionic acid-[(2S) -4- (2,4- the difluorophenyl) -2- methylol -4- amylene -1- base] ester of the present invention Synthetic method, specific synthesis path are as follows:
Above-mentioned 2 Methylpropionic acid-[(2S) -4- (2,4- the difluorophenyl) -2- methylol -4- amylene -1- base] ester of the present invention Synthetic method, step (1) specifically: by 2- chloromethyl propylene oxide and 1,3- difluorobenzene is uniformly mixed at 4~-5 DEG C, then Catalyst is added portionwise while stirring, is reacted at room temperature after adding 5-12 hours；Then reaction system be warming up to 45-70 DEG C after Continuous reaction 2-4 hours；After completion of the reaction, reaction system mixture is added in hydrochloric acid solution at 4~-5 DEG C, is stirred evenly It uses methylene chloride to extract 2-4 times as extractant afterwards, merges the dichloromethane layer extracted every time, then successively with saturation NaHCO3 Solution, water, saturated common salt water washing；The organic layer (dichloromethane layer) of acquisition uses anhydrous Na2SO4It is filtered after drying, removes dichloro The chloro- 3- propyl alcohol of oil product 2- (2,4- difluorophenyl) -1- is obtained after methane.
The molar ratio of 2- chloromethyl propylene oxide, 1,3- difluorobenzene and catalyst in step (1) of the present invention are as follows: 1~1.2: 1:1~1.2；Preferably 1:1:1；Catalyst can be one of lewis acids such as alchlor, zinc chloride, ferric trichloride, It is also possible to the concentrated sulfuric acid.
Catalyst is added portionwise described in specific steps (1) of the present invention can be divided into 3-6 batches of additions, which can have Effect prevents reaction mixture excessively 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 specific steps (1) of the present invention, and the dosage of hydrochloric acid solution is with 2- Chloromethyl propylene oxide meter, molar concentration of the 2- chloromethyl propylene oxide in hydrochloric acid solution be 0.05-0.2mol/100ml (i.e. 100ml hydrochloric acid solution corresponds to the 2- chloromethyl propylene oxide of 0.05-0.2mol), preferably 0.1mol/100ml.
The volume ratio of the extraction quantity of each methylene chloride and hydrochloric acid solution is 1.5-2.5:3 in specific steps (1) of the present invention, Preferably 2:3, for example, if using the hydrochloric acid solution of 300ml, 2mol/l concentration, each extraction of subsequent methylene chloride Amount is 200ml.
Above-mentioned 2 Methylpropionic acid-[(2S) -4- (2,4- the difluorophenyl) -2- methylol -4- amylene -1- base] ester of the present invention Synthetic method, step (2) specifically: the chloro- 3- propyl alcohol of 2- (2,4- difluorophenyl) -1- and potassium acid sulfate for preparing step (1) It is added in chlorobenzene, is heated to reflux 8-15 hours；Chlorobenzene layer is washed to neutrality after completion of the reaction, then uses anhydrous Na2SO4It is dry After filter, filtrate removes after (as be evaporated under reduced pressure) chlorobenzene to obtain oil product 1- (1- chloromethyl vinyl base) -2,4- difluorobenzene.
In specific steps (2) of the present invention, the molar ratio of the chloro- 3- propyl alcohol of 2- (2,4- difluorophenyl) -1- and potassium acid sulfate is 1:1-1.5 preferably 1:1.1.
In specific steps (2) of the present invention, molar concentration of the chloro- 3- propyl alcohol of 2- (2,4- difluorophenyl) -1- in chlorobenzene is 0.15-0.30mol/300ml (the i.e. corresponding chloro- 3- of 2- (2,4- difluorophenyl) -1- that 0.15-0.30mol is added of 300ml chlorobenzene Propyl alcohol)；Preferably 0.2mol/300ml.
Above-mentioned 2 Methylpropionic acid-[(2S) -4- (2,4- the difluorophenyl) -2- methylol -4- amylene -1- base] ester of the present invention Synthetic method, step (3) specifically: 1- (1- chloromethyl vinyl base) -2,4- difluorobenzene prepared by step (2) is taken and is dissolved in In DMSO (dimethyl sulfoxide), diethyl malonate and hydroxide is then added, it is small to be stirred to react 4-10 at 15-35 DEG C When；Then water is added, and gained mixture is stirred 0.5-1.5 hours, by thus obtained solution extractant, in 25-30 It DEG C is extracted for the first time；The water layer separated after extraction extractant carries out second of extraction at 25-30 DEG C；Merging extracts twice Organic layer (i.e. extractant where layer), then washed with sodium hydrate aqueous solution, be then washed with water, by organic layer after washing Solvent under reduced pressure distill to obtain oily target product 2- [2- (2,4- difluorophenyl) allyl] -1,3- diethyl malonate.
1- (1- chloromethyl vinyl base) -2,4- difluorobenzene and DMSO amount ratio are 30-75g in step (3) of the present invention: 100ml；1- (1- chloromethyl vinyl base) -2,4- difluorobenzene: hydroxide: the molar ratio of diethyl malonate is 1.0:1.5- 3.0:1.0-4.0 preferred 1.0:2-2.5:3-4.0.
It is stirred to react at 25-30 DEG C 4-6 hours in step (3) of the present invention；Then water is added, the additive amount of water at this time It is 2-6:1 with DMSO volume ratio, preferably are as follows: 3:1.
Hydroxide can be one of potassium hydroxide, cesium hydroxide, lithium hydroxide etc. in step (3) of the present invention.
Extractant can be methylene chloride in step (3) of the present invention, (60-90 DEG C, wherein refer to for 60-90 DEG C petroleum ether The specification of petroleum ether), chloroform, one of n-hexane or hexamethylene etc..
The extractant and DMSO volume ratio of extractant, second of extraction that step (3) of the present invention extracts for the first time 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 ratio is 1-3:1.
Above-mentioned 2 Methylpropionic acid-[(2S) -4- (2,4- the difluorophenyl) -2- methylol -4- amylene -1- base] ester of the present invention Synthetic method, step (4) specifically: the 2- [2- (2,4- difluorophenyl) -2- propylene -1- base] -1,3- for preparing step (3) Diethyl malonate is dissolved in isopropyl alcohol and water and is formed by the mixed solvent, and lithium chloride, boron hydrogen are added after being cooled to -10~0 DEG C Reaction 15-30 hours is stirred at room temperature in compound, reaction mixture；The pH=1-3 of reaction solution is first adjusted after completion of the reaction； The pH=9-11 of reaction solution is adjusted again；Organic layer is separated after then proceeding to stirring 0.5-2 hours, rotary evaporation removes isopropyl Alcohol；Toluene and water is added in gained grease, and stirring stands and separates toluene layer, by the toluene removal of toluene layer up to target product.
2- [2- (2,4- difluorophenyl) -2- propylene -1- base] -1,3- diethyl malonate in step (4) of the present invention: chlorination Lithium: the molar ratio of boron hydride is 1:2-4:2-4；Preferably 1:2:2.
Boron hydride is sodium borohydride or potassium borohydride in step (4) of the present invention；The volume ratio of isopropyl alcohol and water is 8-12: 1。
Above-mentioned 2 Methylpropionic acid-[(2S) -4- (2,4- the difluorophenyl) -2- methylol -4- amylene -1- base] ester of the present invention Synthetic method, step (5) specifically: the 2- [2- (2,4- difluorophenyl) -2- propylene -1- base] -1,3- for preparing step (4) Propylene glycol is dissolved in toluene, and sodium bicarbonate, 435 Esterified Enzyme of Novo SP (Novo435 enzyme), isobutyric anhydride is added at -15~-5 DEG C； Then insulated and stirred is reacted 20-40 hours；Solid is filtered after completion of the reaction, and filtrate successively uses sodium bicarbonate solution, water washing, so After remove toluene and obtain oily crude product；The crude product is dissolved in normal heptane at 50-60 DEG C, and gained clear liquid progressively cools to 10 DEG C, 10-15 hours are stood at this temperature, crystal is filtered out, up to product 2- methylpropanoic acid-[(2S) -4- (2,4- bis- after crystal is dry Fluorophenyl) -2- methylol -4- amylene -1- base] ester.
2- [2- (2,4- difluorophenyl) -2- propylene -1- base] -1,3-PD in step (5) of the present invention: sodium bicarbonate: The molar ratio of isobutyric anhydride is 1:2:1；435 Esterified Enzyme of Novo SP and 2- [2- (2,4- difluorophenyl) -2- propylene -1- base] - The weight ratio of 1,3-PD is 1:20-25；Preferably, 435 Esterified Enzyme of Novo SP and 2- [2- (2,4- difluorophenyl) -2- Propylene -1- base] -1,3-PD weight ratio be 1:20.
The advantages of the present invention:
1. present invention use creative for the first time is by 2- chloromethyl propylene oxide and 1,3- 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；The preparation Process neither uses expensive trimethyl chloromethyl base silane substance, to sufficiently lower production cost；And it prepares Technique is more mild, easily operated, without the anhydrous and oxygen-free condition that traditional handicraft grignard reaction needs, more easily operates, holds It is easy to realize industrial production；In addition, the preparation process does not use the compound chloracetyl chloride of intense irritation yet, to reduce ring Border pollution compared with and by experimenter health influence be effectively reduced.
2. the present invention cleverly uses 1- (1- chloromethyl vinyl base) -2,4- difluorobenzene and takes and be dissolved in DMSO (dimethyl Sulfoxide) in, diethyl malonate and hydroxide is then added, is stirred to react 4-10 hours and is reacted at 15-35 DEG C, instead Mild condition, small toxicity are answered, low energy consumption；Then using stablize under normal temperature and pressure, in air aqueous vapor and oxygen it is more stable, operation Easy boron hydride is handled as reducing agent, obtains 2- [2- (2,4- difluorophenyl) -2- propylene -1- base] -1,3- the third two Alcohol；It is then dissolved in toluene, sodium bicarbonate, 435 Esterified Enzyme of Novo SP (Novo435 enzyme), isobutyric acid is added at -15~-5 DEG C Anhydride reactant, simple washing, are dried acquisition target product at crystallization；It is simple with post-processing, it is thus only necessary to extract, wash, Vacuum distillation, can be obtained final product, high income；And the substances such as the extractant used and hydroxide are easy to get, are cheap, It is applied widely.
Specific embodiment
The present invention is described in further detail below by embodiment, but the present invention is not limited solely to following embodiment.
Embodiment 1
1, by 2- chloromethyl propylene oxide (27.60g, 0.30mol) and 1,3- difluorobenzene (34.23g, 0.30mol) 0 Divide 5 batches alchlor (40.00g, 0.30mol) is added altogether at DEG C while stirring after mixing, reacts 7.5 after adding at room temperature Hour, being then warming up to 58 DEG C, the reaction was continued 3 hours.Mixture is carefully added into 300ml concentration at 0 DEG C after completion of the reaction In the hydrochloric acid solution of 2mol/l, to be extracted with dichloromethane after mixing evenly three times, each 200ml, merging dichloromethane layer, two Chloromethanes layer is successively with saturation NaHCO3Solution, water, saturated salt solution washed once respectively.Dichloromethane layer nothing after washing Water Na2SO4It is filtered after drying, rotary evaporation obtains the chloro- 3- third of oil product 2- (2,4- difluorophenyl) -1- after removing methylene chloride Alcohol 51.65g (0.25mol), yield 83%.
2, by the chloro- 3- propyl alcohol 41.32g (0.20mol) of 2- (2,4- difluorophenyl) -1-, potassium acid sulfate 29.96g (0.22mol) is added in 300ml chlorobenzene, is heated to reflux 14 hours.Chlorobenzene layer is washed to neutrality after completion of the reaction, anhydrous Na2SO4It is filtered after drying, vacuum distillation obtains oil product 1- (1- chloromethyl vinyl base) -2,4- difluorobenzene after removing chlorobenzene 32.06g (0.17mol), yield 85%.
3,1- (1- chloromethyl vinyl base) -2,4- difluorobenzene 37.72g (0.20mol) is taken to be dissolved in 100ml dimethyl sulfoxide, It is subsequently added into 12.00g (0.30mol) sodium hydroxide and 90.5ml (0.60mol) diethyl malonate, reaction mixture is in room temperature Under (15-35 degrees Celsius) stir 8 hours.300ml water is added after completion of the reaction, continues stirring 1 hour.Acquired solution is used respectively 200ml and 100ml hexamethylene is extracted twice (being the water layer obtained after extraction extracts for the first time for the second time), merges extraction twice and obtains The hexamethylene layer (i.e. layer where extractant) obtained, washed once with 150ml 5% (w/v) sodium hydroxide solution, then Primary, the anhydrous Na with 150ml water washing2SO4It is filtered after drying, rotary evaporation removes hexamethylene and obtains oil product 2- [2- (2,4- Difluorophenyl) allyl] -1,3- diethyl malonate 56.21g (0.18mol), yield 90%.
4, by 2- [2- (2,4- difluorophenyl) -2- propylene -1- base] -1,3- diethyl malonate 12.48g (0.04mol) It is dissolved in 100ml isopropanol and 10ml water is formed by the mixed solvent, lithium chloride 3.36g is added after being cooled to -5 DEG C Reaction 20 hours is stirred at room temperature in (0.08mol), sodium borohydride 3.04g (0.08mol), reaction mixture.After completion of the reaction PH value of solution=1 is adjusted to 4.0mol/l hydrochloric acid.Then (contain 20g hydrogen-oxygen in w/v, that is, 100ml solution with 20% again Change sodium, embodiment 2 is same) sodium hydroxide solution is adjusted to pH=10.Organic layer is separated after continuing stirring 1 hour, rotary evaporation removes Fall isopropanol.100ml toluene and 100ml water are added in gained grease, separates toluene layer, rotary evaporation removes toluene up to oil Shape product 2- [2- (2,4- difluorophenyl) -2- propylene -1- base] -1,3-PD 7.30g (0.032mol), yield 80%.
5,2- [2- (2,4- difluorophenyl) -2- propylene -1- base] -1,3-PD 22.80g (0.10mol) is dissolved in Sodium bicarbonate 16.8g (0.20mol) is added at -15 DEG C in 150ml toluene, 435 Esterified Enzyme 1.0g of Novo SP, isobutyric anhydride 15.8ml (0.10mol), mixture is stirred to react 24 hours at same temperature.Solid is filtered after completion of the reaction, and filtrate is successively used Each 100ml washing of the sodium bicarbonate solution and water of 5% (w/v), rotary evaporation obtain oily crude product after removing toluene. The 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 this temperature, Crystal is filtered out, up to product 2 Methylpropionic acid-[(2S) -4- (2,4- difluorophenyl) -2- methylol -4- penta after drying at 40 DEG C Alkene -1- base] ester 22.37g (0.075mol), yield 75%.
Embodiment 2
1, by 2- chloromethyl propylene oxide (22.08g, 0.24mol) and 1,3- difluorobenzene (22.82g, 0.20mol) at 0 DEG C Under divide while stirring after mixing 4 batches altogether be added ferric trichloride (0.24mol), react after adding 8 hours, then rise at room temperature The reaction was continued 3 hours to 60 DEG C for temperature.It is 2mol/l's that mixture, which is carefully added into 200ml concentration, at 0 DEG C after completion of the reaction It in hydrochloric acid solution, is extracted with dichloromethane after mixing evenly three times, each 130ml, merges dichloromethane layer, with saturation NaHCO3 Solution, water, saturated salt solution washed once respectively.Organic layer anhydrous Na2SO4It is filtered after drying, rotary evaporation removes dichloromethane The chloro- 3- propyl alcohol 33.06g of oil product 2- (2,4- difluorophenyl) -1-, (0.16mol), yield 80% are obtained after alkane.
2, by the chloro- 3- propyl alcohol 41.32g (0.20mol) of 2- (2,4- difluorophenyl) -1-, potassium acid sulfate 29.96g (0.22mol) is added in 200ml chlorobenzene, is heated to reflux 14 hours.Chlorobenzene layer is washed to neutrality after completion of the reaction, anhydrous Na2SO4It is filtered after drying, vacuum distillation obtains oil product 1- (1- chloromethyl vinyl base) -2,4- difluorobenzene after removing chlorobenzene 32.06g (0.17mol), yield 85%.
3,1- (1- chloromethyl vinyl base) -2,4- difluorobenzene 37.72g (0.20mol) is dissolved in 100ml dimethyl sulfoxide, The lithium hydroxide and 90.5ml (0.60mol) diethyl malonate, reaction mixture for being subsequently added into 0.30mol are stirred at room temperature 8 hours.300ml water is added after completion of the reaction, continues stirring 1 hour.Acquired solution uses 200ml and 100ml petroleum ether respectively (60-90 DEG C) is extracted twice, and is merged petroleum ether layer, be washed once with 150ml 5% (w/v) sodium hydroxide solution, then Primary, the anhydrous Na with 150ml water washing2SO4It is filtered after drying, rotary evaporation removes petroleum ether and obtains oil product 2- [2- (2,4- Difluorophenyl) allyl] -1,3- diethyl malonate 56.21g (0.18mol), yield 90%.
4, by 2- [2- (2,4- difluorophenyl) -2- propylene -1- base] -1,3- diethyl malonate 12.48g (0.04mol) It is dissolved in 200ml isopropanol and 20ml water is formed by the mixed solvent, lithium chloride 5.04g is added after being cooled to -5 DEG C Reaction 25 hours is stirred at room temperature in (0.12mol), lithium borohydride 0.12mol, reaction mixture.It uses after completion of the reaction 4.0mol/l hydrochloric acid is adjusted to pH value of solution=1.Then pH=10 is adjusted to 20% (w/v) sodium hydroxide solution again. Organic layer is separated after continuing stirring 1 hour, rotary evaporation removes isopropanol.Be added in gained grease 150 ml toluene and 150ml water, separates toluene layer, and rotary evaporation removes toluene up to oil product 2- [2- (2,4- difluorophenyl) -2- propylene -1- Base] -1,3-PD 7.53g (0.033mol), yield 82%.
5,2- [2- (2,4- difluorophenyl) -2- propylene -1- base] -1,3-PD 34.2g (0.15mol) is dissolved in Sodium bicarbonate 25.2g (0.30mol) is added at -15 DEG C in 150ml toluene, 435 Esterified Enzyme 1.0g of Novo SP, isobutyric anhydride 23.4ml (0.15mol), mixture is stirred to react 30 hours at same temperature.Solid is filtered after completion of the reaction, and filtrate is successively used Each 150ml washing of the sodium bicarbonate solution and water of 5% (w/v), rotary evaporation obtain oily crude product after removing toluene. The 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 this temperature, Crystal is filtered out, up to product 2 Methylpropionic acid-[(2S) -4- (2,4- difluorophenyl) -2- methylol -4- penta after drying at 40 DEG C Alkene -1- base] ester 32.82g (0.11mol), yield 74%.
From above-described embodiment it is found that method reaction product of the invention is easily operated, post-processing is simple, is easy to industrial metaplasia It produces.

Claims (10)

  1. The synthesis side of [(2S) -4-(2,4- difluorophenyl) -2- methylol -4- amylene -1- base] ester 1. a kind of 2 Methylpropionic acid - Method, it is characterised in that: step includes:
    (1) by 2- chloromethyl propylene oxide and 1, the mixing of 3- difluorobenzene is reacted under the effect of the catalyst, obtains 2-(2, 4- difluorophenyl) the chloro- 3- propyl alcohol of -1-；
    (2) step (1) is obtained into 2-(2,4- difluorophenyl) the chloro- 3- propyl alcohol of -1- and potassium acid sulfate and chlorobenzene hybrid reaction, it obtains 1-(1- chloromethyl vinyl base) -2,4- difluorobenzene；
    (3) the 1-(1- chloromethyl vinyl base for obtaining step (2)) -2,4- difluorobenzene and diethyl malonate and sodium hydroxide into Row reaction, and acquisition product 2- [2-(2,4- difluorophenyl) allyl] -1,3- diethyl malonate；
    (4) 2- [2-(2,4- difluorophenyl) -2- propylene -1- base] -1,3- diethyl malonate that step (3) obtain is dissolved in different Third alcohol and water is formed by the mixed solvent, then reacts with boron hydride, and acquisition product 2- [2-(2,4- difluorophenyl) -2- Propylene -1- base] -1,3-PD；
    (5) 2- [2-(2,4- difluorophenyl) -2- propylene -1- the base] -1,3-PD and Novo SP obtained step (4) 435 Esterified Enzymes, isobutyric anhydride hybrid reaction, and acquisition target product 2 Methylpropionic acid-[(2S) -4-(2,4- difluorophenyl) -2- hydroxyl Methyl -4- amylene -1- base] ester；
    Catalyst as described in step (1) is alchlor or ferric trichloride.
  2. 2. 2 Methylpropionic acid-according to claim 1 [(2S) -4-(2,4- difluorophenyl) -2- methylol -4- amylene -1- Base] ester synthetic method, it is characterised in that: step (1) specifically: by 2- chloromethyl propylene oxide and 1,3- difluorobenzene is -5 ~ 4 It is uniformly mixed at DEG C, catalyst is then added portionwise while stirring, is reacted at room temperature after adding 5-12 hours；Then reaction system Being warming up to 45-70 DEG C, the reaction was continued 2-4 hours；After completion of the reaction, reaction system mixture is added to hydrochloric acid at -5 ~ 4 DEG C In solution, methylene chloride is used to extract 2-4 times as extractant after mixing evenly, merges the dichloromethane layer extracted every time, then Successively with saturation NaHCO3Solution, water, saturated common salt water washing；The organic layer anhydrous Na of acquisition2SO4It filters, removes after drying Oil product 2-(2,4- difluorophenyl are obtained after methylene chloride) the chloro- 3- propyl alcohol of -1-；Step (2) specifically: prepare step (1) 2-(2,4- difluorophenyl) the chloro- 3- propyl alcohol of -1- and potassium acid sulfate be added in chlorobenzene, be heated to reflux 8-15 hours；It has reacted Chlorobenzene layer is washed to neutrality after finishing, and then uses anhydrous Na2SO4It is filtered after drying, filtrate obtains oil product 1-(1- after removing chlorobenzene Chloromethyl vinyl base) -2,4- difluorobenzene.
  3. 3. 2 Methylpropionic acid-according to claim 2 [(2S) -4-(2,4- difluorophenyl) -2- methylol -4- amylene -1- Base] ester synthetic method, it is characterised in that: mole of 2- chloromethyl propylene oxide, 1,3- difluorobenzene and catalyst in step (1) Than are as follows: 1 ~ 1.2:1:1 ~ 1.2；Catalyst is divided into 3-6 batches and is added；Hydrochloric acid solution is that the hydrochloric acid of 2mol/l concentration is molten in step (1) Liquid, the dosage of hydrochloric acid solution is in terms of 2- chloromethyl propylene oxide, molar concentration of the 2- chloromethyl propylene oxide in hydrochloric acid solution For 0.05-0.2mol/100ml；The volume ratio of the extraction quantity of each methylene chloride and hydrochloric acid solution is 1.5-2.5 in step (1): 3。
  4. 4. 2 Methylpropionic acid-according to claim 2 [(2S) -4-(2,4- difluorophenyl) -2- methylol -4- amylene -1- Base] ester synthetic method, it is characterised in that: 2-(2 in step (2), 4- difluorophenyl) the chloro- 3- propyl alcohol of -1- and potassium acid sulfate Molar ratio is 1:1-1.5；2-(2 in step (2), 4- difluorophenyl) molar concentration of the chloro- 3- propyl alcohol of -1- in chlorobenzene be 0.15-0.30mol/300ml。
  5. 5. 2 Methylpropionic acid-according to claim 1 [(2S) -4-(2,4- difluorophenyl) -2- methylol -4- amylene -1- Base] ester synthetic method, it is characterised in that: step (3) specifically: by step (2) prepare 1-(1- chloromethyl vinyl base) -2, 4- difluorobenzene, which takes, to be dissolved in dimethyl sulfoxide, and diethyl malonate and hydroxide is then added, and is stirred at 15-35 DEG C anti- It answers 4-10 hours；Then be added water, and gained mixture stirred 0.5-1.5 hours, by thus obtained solution extractant, It is extracted for the first time at 25-30 DEG C；The water layer separated after extraction extractant carries out second of extraction at 25-30 DEG C；Merge two The organic layer of secondary extraction, is then washed with sodium hydrate aqueous solution, is then washed with water, by the solvent under reduced pressure of organic layer after washing Distillation obtains oil product 2- [2-(2,4- difluorophenyl) allyl] -1,3- diethyl malonate.
  6. 6. 2 Methylpropionic acid-according to claim 5 [(2S) -4-(2,4- difluorophenyl) -2- methylol -4- amylene -1- Base] ester synthetic method, it is characterised in that: 1-(1- chloromethyl vinyl base in step (3)) -2,4- difluorobenzene and dimethyl sulfoxide Amount ratio is 30-75g:100ml；1-(1- chloromethyl vinyl base) -2,4- difluorobenzene: hydroxide: diethyl malonate rubs You are than being 1.0:1.5-3.0:1.0-4.0；It is stirred to react at 25-30 DEG C in step (3) 4-6 hours, water is then added, at this time Water additive amount and dimethyl sulfoxide volume ratio be 2-6:1；Hydroxide is potassium hydroxide, cesium hydroxide, hydrogen in step (3) One of lithia；Extractant is one in methylene chloride, petroleum ether, chloroform, n-hexane or hexamethylene in step (3) Kind；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。
  7. 7. 2 Methylpropionic acid-according to claim 1 [(2S) -4-(2,4- difluorophenyl) -2- methylol -4- amylene -1- Base] ester synthetic method, it is characterised in that: step (4) specifically: by step (3) preparation 2- [2-(2,4- difluorophenyl)- 2- propylene -1- base] -1,3- diethyl malonate is dissolved in isopropyl alcohol and water and is formed by the mixed solvent, after being cooled to -10 ~ 0 DEG C Lithium chloride, boron hydride is added, reaction 15-30 hours is stirred at room temperature in reaction mixture；Reaction is first adjusted after completion of the reaction PH=1-3 of solution；PH=9-11 of reaction solution is adjusted again；Organic layer is separated after then proceeding to stirring 0.5-2 hours, rotation is steamed Hair removes isopropanol；Toluene and water is added in gained grease, and stirring stands and separates toluene layer, by the toluene removal of toluene layer to obtain the final product Target product.
  8. 8. 2 Methylpropionic acid-according to claim 7 [(2S) -4-(2,4- difluorophenyl) -2- methylol -4- amylene -1- Base] ester synthetic method, it is characterised in that: 2- in step (4) [2-(2,4- difluorophenyl) -2- propylene -1- base] -1,3- the third two Diethyl phthalate: lithium chloride: the molar ratio of boron hydride is 1:2-4:2-4；Boron hydride is sodium borohydride or boron hydrogen in step (4) Change potassium；The volume ratio of isopropyl alcohol and water is 8-12:1.
  9. 9. 2 Methylpropionic acid-according to claim 1 [(2S) -4-(2,4- difluorophenyl) -2- methylol -4- amylene -1- Base] ester synthetic method, it is characterised in that: step (5) specifically: by step (4) preparation 2- [2-(2,4- difluorophenyl)- 2- propylene -1- base] -1,3-PD is dissolved in toluene, sodium bicarbonate, 435 Esterified Enzyme of Novo SP, different is added at -15 ~ -5 DEG C Butyric anhydride；Then insulated and stirred is reacted 20-40 hours；Solid is filtered after completion of the reaction, and filtrate successively uses sodium bicarbonate solution, water Washing, then removes toluene and obtains oily crude product；The crude product is dissolved in normal heptane, gained clear liquid Slow cooling at 50-60 DEG C To 10 DEG C, 10-15 hours are stood at this temperature, crystal is filtered out, up to product 2 Methylpropionic acid-[(2S) -4- after crystal is dry (2,4- difluorophenyl) -2- methylol -4- amylene -1- base] ester.
  10. 10. 2 Methylpropionic acid-according to claim 9 [(2S) -4-(2,4- difluorophenyl) -2- methylol -4- amylene - 1- yl] ester synthetic method, it is characterised in that: 2- in step (5) [2-(2,4- difluorophenyl) -2- propylene -1- base] -1,3- third Glycol: sodium bicarbonate: the molar ratio of isobutyric anhydride is 1:2:1；435 Esterified Enzyme of Novo SP and 2- [2-(2,4- difluorobenzene Base) -2- propylene -1- base] -1,3-PD weight ratio be 1:20-25.
CN201610191035.7A 2016-03-30 2016-03-30 A kind of synthetic method of 2 Methylpropionic acid-[(2S) -4- (2,4- difluorophenyl) -2- methylol -4- amylene -1- base] ester Expired - Fee Related CN105755060B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201610191035.7A CN105755060B (en) 2016-03-30 2016-03-30 A kind of synthetic method of 2 Methylpropionic acid-[(2S) -4- (2,4- difluorophenyl) -2- methylol -4- amylene -1- base] ester

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201610191035.7A CN105755060B (en) 2016-03-30 2016-03-30 A kind of synthetic method of 2 Methylpropionic acid-[(2S) -4- (2,4- difluorophenyl) -2- methylol -4- amylene -1- base] ester

Publications (2)

Publication Number Publication Date
CN105755060A CN105755060A (en) 2016-07-13
CN105755060B true CN105755060B (en) 2019-01-04

Family

ID=56346772

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201610191035.7A Expired - Fee Related CN105755060B (en) 2016-03-30 2016-03-30 A kind of synthetic method of 2 Methylpropionic acid-[(2S) -4- (2,4- difluorophenyl) -2- methylol -4- amylene -1- base] ester

Country Status (1)

Country Link
CN (1) CN105755060B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105777539B (en) * 2016-03-30 2018-04-10 浙江大学宁波理工学院 One kind 2 [2（2,4 difluorophenyls）Pi-allyl] 1,3 diethyl malonates synthetic method

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH09188637A (en) * 1996-01-09 1997-07-22 Mitsubishi Chem Corp Production of 3-bromo-2-(substituted)-1-propene

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

Also Published As

Publication number Publication date
CN105755060A (en) 2016-07-13

Similar Documents

Publication Publication Date Title
CN104945299B (en) A kind of high-efficiency synthesis method of vildagliptin
CN104428296A (en) Processes for the preparation of 3,5-disubstituted-1,2,4-oxadiazoles
CN102190628B (en) Preparation method of 5-fluoro-6-ethyl-4-hydroxypyrimidine intermediate and Voriconazole
CN106554347A (en) Egfr kinase inhibitor and its preparation method and application
CN105755060B (en) A kind of synthetic method of 2 Methylpropionic acid-[(2S) -4- (2,4- difluorophenyl) -2- methylol -4- amylene -1- base] ester
CN108358900A (en) A kind of preparation method of Afatinib and its maleate
CN101786963B (en) Synthesis method of Azasetron intermediate
CN105777486B (en) A kind of synthetic method of 2- [2- (2,4- difluorophenyl) -2- propylene -1- bases] -1,3-PD
CN104876920A (en) Isooxazole compounds and intermediates thereof, and preparation method and application thereof
CN104744390A (en) Preparation method of ezetimibe internmediate ketone
CN105622413B (en) The synthetic method of 2 [2 (2,4 difluorophenyl) pi-allyl] 1,3 diethyl malonates
CN105777539B (en) One kind 2 [2（2,4 difluorophenyls）Pi-allyl] 1,3 diethyl malonates synthetic method
CN106916147A (en) Compound and its production and use
CN105753693B (en) The synthetic method of 2 methylpropanoic acids [base of 4 amylene of (2S) 4 (2,4 difluorophenyl) 2 methylol 1] ester
CN105001235B (en) Substituted thiophene benzoquinone isoxazole compound and preparation method and application thereof
CN109666019B (en) Deuterated azolol compound and preparation method and application thereof
CN105732310B (en) The synthetic method of 2 [base of 2 (2,4 difluorophenyl) 2 propylene 1] 1,3 propane diols
CN107266442A (en) The preparation method of piperidines with antitumor activity and pyridine compounds and their
CN105777482B (en) A kind of 1-（1- chloromethyl vinyl bases）The synthetic method of -2,4- difluorobenzene
CN105753692B (en) One kind 2 methylpropanoic acids of synthesis [(2S) 4（2,4 difluorophenyls）The base of 2 methylol, 4 amylene 1] ester method
CN103910695B (en) A kind of synthetic method of Febuxostat
CN107312000A (en) The preparation method of new farnesyl transferase inhibitor with the triazole structure of 4,5 dihydro 1,2,3
EP2699560B1 (en) 5-carbamoyl-adamantan-2-yl amide derivatives, pharmaceutically acceptable salts thereof and preparation process thereof
CN104230836A (en) Phenyloxazole compounds and application thereof to preparation of medicament for treating cancers
CN105646137B (en) The method of one kind 1 (1 chloromethyl vinyl base) 2,4 difluorobenzenes of synthesis

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant
CF01 Termination of patent right due to non-payment of annual fee
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20190104

Termination date: 20200330