CN106632223B - 2- (the bromo- 4- of 3- (3- fluorine benzyloxy) phenyl) -1,3- dioxolanes and preparation method thereof - Google Patents
2- (the bromo- 4- of 3- (3- fluorine benzyloxy) phenyl) -1,3- dioxolanes and preparation method thereof Download PDFInfo
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- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
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Abstract
The present invention relates to a kind of noval chemical compound 2- (the bromo- 4- of 3- (3- fluorine benzyloxy) phenyl) -1,3- dioxolanes and preparation method thereof, this method first prepares the bromo- 4- of 3- (3- fluorine benzyloxy) benzaldehyde and 4- toluenesulfonic acid pyridine respectively, it reacts the bromo- 4- of 3- (3- fluorine benzyloxy) benzaldehyde with 4- toluenesulfonic acid pyridine and generates 2- (the bromo- 4- of 3- (3- fluorine benzyloxy) phenyl) -1,3-dioxolane.Noval chemical compound 2- (the bromo- 4- of 3- (3- fluorine benzyloxy) phenyl) -1 provided by the invention, 3- dioxolanes, it can be used for directly preparing 3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzaldehyde, and 3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzaldehyde yield of preparation is up to 64.85%, the purity that high performance liquid chromatography measures reaches 98.92%.
Description
Technical field
The present invention relates to a kind of noval chemical compound 2- (the bromo- 4- of 3- (3- fluorine benzyloxy) phenyl) -1,3-dioxolane, the present invention
Further relate to the preparation method of the compound.
Background technique
Safinamide (Safinamide), entitled (S) -2- [4- (the 3- fluorine benzyloxy) benzyl amino] propionamide (Formulas I) of chemistry,
It is Newron Pharmaceuticals Inc.'s research and development for a kind of for treating the newtype drug of Parkinson's disease.
Currently, the method for synthesis safinamide: parahydroxyben-zaldehyde reacts under certain reaction condition with fluorobenzyl chloride, obtains
To intermediate product 4- (3- fluorine benzyloxy) benzaldehyde (intermediate -1)；Then, L- alanimamides hydrochloride and intermediate -1 react
Generate (S) -2- [4- (3- fluorine benzyloxy) benzyl amino] propionamide (intermediate -2)；Finally, reduction intermediate -2 obtains husky fragrant acyl
Amine.
In the technique of published preparation safinamide, 3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzaldehyde (formula 9) knot
Structure formula is as follows.The impurity is a kind of potential key intermediate impurity, on the one hand research earlier, control impurity improve sand
On the other hand the quality standard of fragrant amide ensures to prepare the product met the quality standard, have for the research of safinamide
Important meaning.
In published preparation process, parahydroxyben-zaldehyde and it is excessive between fluorobenzyl chloride in the presence of potassium carbonate, toluene, it is high
The warm reaction time is 5 days, and the gas chromatographic analysis of reaction mass is shown, reaction mass at this time is by 4- (3- fluorine benzyloxy)
Benzaldehyde (intermediate -1) and 3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzaldehyde (formula 9) are with 91.4:8.6 (area ratio) ratio
Example mixing；Impurity 9 is obtained by fractionation from the mixed material, yield is down to 3.6%.
There is no the methods for directly preparing impurity 9 in currently available technology, only will during preparing safinamide
It is separated, and yield is extremely low.
To solve the above-mentioned problems, the present invention provides a kind of noval chemical compound 2- (the bromo- 4- of 3- (3- fluorine benzyloxy) phenyl)-
1,3-dioxolane, the compound can be used for preparing 3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzaldehyde, and obtain ideal
Yield.
Summary of the invention
The technical problem to be solved by the invention for the present situation of prior art is to provide a kind of noval chemical compound 2-, (3- is bromo-
4- (3- fluorine benzyloxy) phenyl) -1,3-dioxolane, which can be used for preparing 3- (3- luorobenzyl) -4- (3- fluorine benzyloxy
Base) benzaldehyde, and significantly improve yield.
Another technical problem to be solved by this invention is the status for the prior art, provides a kind of 2- (bromo- 4- of 3-
(3- fluorine benzyloxy) phenyl) -1,3- dioxolanes preparation method.
The technical scheme of the invention to solve the technical problem is: a kind of noval chemical compound 2- (3- bromo- 4- (3- fluorine
Benzyloxy) phenyl) -1,3-dioxolane, it is characterised in that structural formula is as follows:
A kind of preparation method of above-mentioned noval chemical compound 2- (the bromo- 4- of 3- (3- fluorine benzyloxy) phenyl) -1,3-dioxolane,
Be characterized in that the following steps are included:
(1) the bromo- 4- of 3- (3- fluorine benzyloxy) benzaldehyde is prepared
In the presence of potassium carbonate, tetrabutylammonium bromide, (the change of following formula 1 of the bromo- 4- hydroxy benzaldehyde of 3- is added into organic solvent
Close object) and fluorine bromobenzyl (2 compound of following formula), after reaction, obtain the bromo- 4- of 3- (3- fluorine benzyloxy) benzaldehyde (3 chemical combination of following formula
Object)；
(2) 4- toluenesulfonic acid pyridine is prepared
Under nitrogen protection, reaction generates 4- methyl for p-methyl benzenesulfonic acid (4 compound of following formula) and pyridine (5 compound of following formula)
Benzene sulfonic acid pyridine (6 compound of following formula)；
(3) 2- (the bromo- 4- of 3- (3- fluorine benzyloxy) phenyl) -1,3- dioxolanes is synthesized
4- methylbenzene obtained by 3- bromo- 4- (3- fluorine benzyloxy) benzaldehyde (3 compound of formula) and step (2) obtained by step (1)
Sulfonic acid pyridine (6 compound of formula) reaction, obtains 2- (the bromo- 4- of 3- (3- fluorine benzyloxy) phenyl) -1,3-dioxolane (following formula 7
Compound).
Preferably, step (1) carries out under nitrogen protection, reaction temperature is 70~90 DEG C.
Further preferably, after completion of the reaction, reactant is cooled to room temperature, is filtered, remove inorganic salts, organic solvent washing
Filtrate is concentrated under reduced pressure in residue, obtains the bromo- 4- of 3- (3- fluorine benzyloxy) benzaldehyde, purifies spare.
Preferably, step (2) carries out under nitrogen protection, and reaction temperature is 0~5 DEG C, after completion of the reaction, is dried under reduced pressure,
Obtain 4- toluenesulfonic acid pyridine.
Preferably, for step (3) in the presence of ethylene glycol solvent, reaction temperature is 90 DEG C or more；It cools down, wash after completion of the reaction
It washs, be dried under reduced pressure to obtain 2- (the bromo- 4- of 3- (3- fluorine benzyloxy) phenyl) -1,3- dioxolanes.
Compared with the prior art, the advantages of the present invention are as follows: the present invention provides a kind of noval chemical compound 2- (bromo- 4- (3- of 3-
Fluorine benzyloxy) phenyl) -1,3-dioxolane, which can be used for directly preparing 3- (3- luorobenzyl) -4- (3- fluorine benzyloxy
Base) benzaldehyde, and 3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) the benzaldehyde yield prepared is up to 64.85%, high-efficient liquid phase color
It composes the purity measured and reaches 98.92%.
Detailed description of the invention
Fig. 1 is the HPLC map of step (1) product in the embodiment of the present invention；
Fig. 2 is the GC map of step (1) product in the embodiment of the present invention；
Fig. 3 is the TIC map of step (1) product in the embodiment of the present invention；
Fig. 4 is the UV map of step (1) product in the embodiment of the present invention；
Fig. 5 is the Mass map of step (1) product in the embodiment of the present invention；
Fig. 6 is the IR map of step (1) product in the embodiment of the present invention；
Fig. 7 is the HPLC map of step (2) product in the embodiment of the present invention；
Fig. 8 is the TIC map of step (2) product in the embodiment of the present invention；
Fig. 9 is the UV map of step (2) product in the embodiment of the present invention；
Figure 10 is the Mass map (pyridine) of step (2) product in the embodiment of the present invention；
Figure 11 is the Mass map (p- toluenesulfonic acid) of step (2) product in the embodiment of the present invention；
Figure 12 is the GC map of step (3) product in the embodiment of the present invention；
Figure 13 is the TIC map of step (3) product in the embodiment of the present invention；
Figure 14 is the UV map of step (3) product in the embodiment of the present invention；
Figure 15 is the Mass map of step (3) product in the embodiment of the present invention；
Figure 16 is the IR map of step (3) product in the embodiment of the present invention；
Figure 17 is the HPLC map of step (a) product in the embodiment of the present invention；
Figure 18 is the TIC map of step (a) product in the embodiment of the present invention；
Figure 19 is the UV map of step (a) product in the embodiment of the present invention；
Figure 20 is the Mass map of step (a) product in the embodiment of the present invention；
Figure 21 is the IR map of step (a) product in inventive embodiments；
Figure 22 is the HPLC map of step (b) product in the embodiment of the present invention；
Figure 23 is the TIC map of step (b) product in the embodiment of the present invention；
Figure 24 is the UV map of step (b) product in the embodiment of the present invention；
Figure 25 is the Mass map of step (b) product in the embodiment of the present invention；
Figure 26 is the IR map of step (b) product in inventive embodiments.
Specific embodiment
The present invention will be described in further detail below with reference to the embodiments of the drawings.
Noval chemical compound 2- (the bromo- 4- of 3- (3- fluorine benzyloxy) phenyl) -1,3- dioxolane structure formula of the present embodiment is as follows:
The characteristic of above compound is as follows:
IR(KBr；cm-1): 2886 (C-H), 1591 (C=C), 1086 (C-O-C-O), 1043 (Ar-O-C), 552 (C-
Br)；
1H NMR(400MHz,DMSO-d6,δppm):7.61-7.62(d,1H,Ar-H),7.39-7.45(m,1H,Ar-H),
7.36-7.39(dd,1H,Ar-H),7.26-7.39(m,2H,Ar-H),7.17-7.24(d,1H,Ar-H),7.11-7.16(m,
1H,Ar-H),5.65(s,1H,O-CH-O),5.22(s,2H,O-CH2),3.99-4.02(m,2H,O-CH2-CH2-O),3.87-
3.90(m,2H,O-CH2-CH2-O)；
13C NMR(400MHz,DMSO-d6,δppm):163.83,155.13,139.85,132.74,131.56,
131.00,127.86,123.55,115.10,114.40,114.14,111.36,102.19,69.65,65.25；
MS (ESI+ve, m/z, Exact mass=352.01): 352.9 (M+H), 307,289,273,124.
The preparation method of noval chemical compound 2- (the bromo- 4- of 3- (3- fluorine benzyloxy) phenyl) -1,3- dioxolanes of the present embodiment
The following steps are included:
Step 1: be successively added into reactor the bromo- 4- hydroxy benzaldehyde (25g, 0.12mol) of 3-, toluene (250mL),
Potassium carbonate (22.2g, 0.161mol), tetrabutylammonium bromide (20g, 0.062mol), then pass to nitrogen, gained mixture is in room
The lower stirring of temperature；
Under nitrogen protection, fluorine bromobenzyl (23.5g, 0.124mol) between being added dropwise in Xiang Shangshu reaction mixture, is added dropwise
Afterwards, which is heated slowly to 70~90 DEG C, insulation reaction 6 hours；It is detected in reaction process by thin layer chromatography
(mobile phase is the ethyl acetate of n-hexane and 10%, under 254nm ultraviolet lamp), if thin-layer chromatography reaction is unobvious, then plus
Enter a fluorine bromobenzyl (4.5g, 0.023mol), until reaction proceeds to thin-layer chromatography colour developing well；
After completion of the reaction, reactant being cooled to room temperature, is filtered to remove inorganic salts, residual solid phase is washed with 25mL toluene,
Filtrate is concentrated under 50~55 DEG C of reduced pressure, obtains the bromo- 4- of 3- (3- fluorine benzyloxy) benzaldehyde crude product；
Purification: toluene (25mL) stirring and dissolving is added in the bromo- 4- of 3- (3- fluorine benzyloxy) benzaldehyde crude product at 25~30 DEG C,
Under stiring, n-hexane (50mL) is added dropwise into solution, obtained suspension is cooled to 0~5 DEG C and places 1 hour；Filtering is solid
Body, filter cake wash (25mL) with n-hexane, and wet filter cake is placed on to drying 4 hours in 45~50 DEG C of decompression baking oven, obtains 3-
Bromo- 4- (3- fluorine benzyloxy) benzaldehyde.
As shown in figs. 1 to 6, the quality of the bromo- 4- of gained 3- (3- fluorine benzyloxy) benzaldehyde is 31g, yield 80.6%, GC
It is that measure purity be 99.34% to 99.66%, HPLC that chromatography, which measures purity,.
Step 2: p-methyl benzenesulfonic acid (5g, 0.029mol) is added into reactor and continuously adds four under nitrogen protection
Hydrogen furans (40mL), room temperature reaction；Reaction solution is cooled to 0~5 DEG C, then, into solution be added dropwise pyridine (2.75g,
0.035mol), and guarantee to drip in 20~30 minutes, then stir 30 minutes；
It filters under nitrogen protection, gained filter cake is washed with 5mL tetrahydrofuran, places it in 45~50 DEG C of decompression baking oven
Middle drying 4 hours obtains 4- toluenesulfonic acid pyridine.
As shown in Fig. 7~11, gained 4- toluenesulfonic acid pyridine quality is 6g, yield 82.19%, HPLC detection purity
100%.
Step 3: the bromo- 4- of 3- (3- fluorine benzyloxy) benzaldehyde (25g, 0.081mol) is added into reactor, is stirring
Under, toluene (500mL), ethylene glycol (10g, 0.161mol), 4- toluenesulfonic acid pyridine (1g, 0.04mol) is added；It will reaction
Mixture is slowly heated to flow back, and steams solvent, reaction solution at a reflux temperature distill 5 hours by azeotrope with water, gas-chromatography
Detection reaction adds ethylene glycol (5g, 0.081mol) and guarantees that reaction continues if reaction does not carry out according to plan；Reaction terminates
Afterwards, cooling, 50mL NaHCO3Solution washing；Product after washing is dry in 5.0g sodium sulphate, at a temperature of 25~30 DEG C,
It is concentrated under reduced pressure to give 2- (the bromo- 4- of 3- (3- fluorine benzyloxy) phenyl) -1,3- dioxolanes.
As shown in Figure 12~16,7 mass of gained compound is 27.5g, and yield 96.3%, gas chromatographic detection purity is
98.89%.
3- is prepared using noval chemical compound 2- (the bromo- 4- of 3- (3- fluorine benzyloxy) the phenyl) -1,3- dioxolanes of the present embodiment
The step of (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzaldehyde, is as follows:
(a) compound 7 (25g, 0.071mol) is added into reactor, tetrahydrofuran (375mL) and boric acid is then added
Three isopropyl esters (24g, 0.127mol), under nitrogen protection normal-temperature reaction；Mixture is cooled to -78 DEG C, at such a temperature slowly
It is added dropwise n-BuLi-hexane mixture (11.3g, 0.176mol), reacts 1 hour, stirred after being added dropwise under nitrogen protection
Mix reaction 4 hours；Thin-layer chromatography chromatography (TLC) detects extent of reaction, if detecting that reaction is undesirable, adds normal-butyl
Lithium-hexane mixture (1g, 0.015mol) maintains reaction to continue；
After reaction, pH to 1~2 is adjusted with dilute hydrochloric acid (1:1), reaction mixture is heated to 25~30 DEG C, adds
25ml water stirs 30 minutes；Ethyl acetate extracts (3 × 75mL), and sodium sulphate is dry organic phase (10g), subtracts at 50~55 DEG C
Pressure concentration, obtains crude product 2- (3- fluorine benzyloxy) -5- formylphenylboronic acid.
Purification: at room temperature, being added methylene chloride (50mL) in 2- (3- fluorine benzyloxy) -5- formylphenylboronic acid crude product,
Stirring is lower to be added dropwise n-hexane (250mL), and obtained suspension is cooled to 0~5 DEG C and places 1 hour；Filtering, n-hexane washing filter
Wet filter cake is placed into decompression baking oven drying 4 hours, obtains 2- (3- fluorine benzyloxy) -5- formoxyl benzene boron by cake (25mL)
Acid.
As shown in Figure 17~21, gained 2- (3- fluorine benzyloxy) -5- formylphenylboronic acid quality is 13.8g, yield
71.13%, HPLC detect purity 96.19%.
(b) 2- (3- fluorine benzyloxy) -5- formylphenylboronic acid (25g, 0.91mol) is added into reactor, in room temperature, nitrogen
Under the conditions of gas, Isosorbide-5-Nitrae-dioxanes (250mL), water (25mL), fluorine bromobenzyl (25.8g, 0.136mol) is added, then, leads to 30 points
Clock nitrogen；Add Pd2(dba)3(1.75g, 0.002mol) is to slowly warm up to 70 DEG C, is stirred to react two hours, passes through thin layer
Chromatography detection reaction；
After reaction, mixture is cooled to room temperature, and is filtered with diatomite, and Isosorbide-5-Nitrae-dioxanes (25mL) washs filter cake；So
Vacuum distillation obtains oily phase at 60~65 DEG C of Rotary Evaporators afterwards；Remaining oil is added to water (100ml), then uses ethyl acetate
It extracts (3 × 100mL), the dry organic phase of sodium sulphate (10g) is dried under reduced pressure crude product at 50~55 DEG C, obtains 3- (3- luorobenzyl)-
4- (3- fluorine benzyloxy) benzaldehyde；
Purification: 3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzaldehyde crude product (is washed through silica gel column chromatography (mesh-20)
De- liquid: n-hexane: ethyl acetate (9.8:0.2)) purifying.
As shown in Figure 22~26, gained 3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzaldehyde quality is 20g, and yield is
It is 97.82% that 64.85%, HPLC, which detect purity,.
As it can be seen that compared with the method for preparing 3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzaldehyde in the prior art, this reality
It applies example and 3- (3- luorobenzyl) -4- is prepared using noval chemical compound 2- (the bromo- 4- of 3- (3- fluorine benzyloxy) phenyl) -1,3- dioxolanes
The yield of (3- fluorine benzyloxy) benzaldehyde is significantly improved.
Claims (6)
1. a kind of noval chemical compound 2- (the bromo- 4- of 3- (3- fluorine benzyloxy) phenyl) -1,3-dioxolane, it is characterised in that structural formula is such as
Under:
The preparation of noval chemical compound 2- described in a kind of claim 1 2. (the bromo- 4- of 3- (3- fluorine benzyloxy) phenyl) -1,3- dioxolanes
Method, it is characterised in that the following steps are included:
(1) the bromo- 4- of 3- (3- fluorine benzyloxy) benzaldehyde is prepared
In the presence of potassium carbonate, tetrabutylammonium bromide, the bromo- 4- hydroxy benzaldehyde of 3- (1 chemical combination of following formula is added into organic solvent
Object) and fluorine bromobenzyl (2 compound of following formula), after reaction, obtain the bromo- 4- of 3- (3- fluorine benzyloxy) benzaldehyde (3 compound of following formula)；
(2) 4- toluenesulfonic acid pyridine is prepared
Under nitrogen protection, reaction generates 4- methylbenzene sulphur for p-methyl benzenesulfonic acid (4 compound of following formula) and pyridine (5 compound of following formula)
Sour pyridine (6 compound of following formula)；
(3) 2- (the bromo- 4- of 3- (3- fluorine benzyloxy) phenyl) -1,3- dioxolanes is synthesized
4- toluenesulfonic acid obtained by 3- bromo- 4- (3- fluorine benzyloxy) benzaldehyde (3 compound of formula) and step (2) obtained by step (1)
Pyridine (6 compound of formula) reaction, obtains 2- (the bromo- 4- of 3- (3- fluorine benzyloxy) phenyl) -1,3-dioxolane (7 chemical combination of following formula
Object).
3. the preparation of noval chemical compound 2- (the bromo- 4- of 3- (3- fluorine benzyloxy) phenyl) -1,3- dioxolanes according to claim 2
Method, it is characterised in that: step (1) carries out under nitrogen protection, and reaction temperature is 70~90 DEG C.
4. the preparation of noval chemical compound 2- (the bromo- 4- of 3- (3- fluorine benzyloxy) phenyl) -1,3- dioxolanes according to claim 3
Method, it is characterised in that: after completion of the reaction, reactant is cooled to room temperature, is filtered, inorganic salts are removed, residual solid phase is with organic
Solvent washing, is then concentrated under reduced pressure filtrate, obtains the bromo- 4- of 3- (3- fluorine benzyloxy) benzaldehyde, purifies spare.
5. the preparation of noval chemical compound 2- (the bromo- 4- of 3- (3- fluorine benzyloxy) phenyl) -1,3- dioxolanes according to claim 2
Method, it is characterised in that: step (2) carries out under nitrogen protection, and reaction temperature is 0~5 DEG C, after completion of the reaction, is dried under reduced pressure,
Obtain 4- toluenesulfonic acid pyridine.
6. the preparation of noval chemical compound 2- (the bromo- 4- of 3- (3- fluorine benzyloxy) phenyl) -1,3- dioxolanes according to claim 2
Method, it is characterised in that: for step (3) in the presence of ethylene glycol solvent, reaction temperature is 90 DEG C or more；Cooling after completion of the reaction,
It washs, be dried under reduced pressure to obtain 2- (the bromo- 4- of 3- (3- fluorine benzyloxy) phenyl) -1,3- dioxolanes.
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| CN104523668A (en) * | 2007-12-11 | 2015-04-22 | 纽朗制药有限公司 | High purity 2-[4-(3- or 2-fluorobenzyloxy)benzylamino]propanamides and methods of use thereof |
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