CN106632223A - 2-(3-bromine-4-(3-fluorobenzyloxy)phenyl)-1,3-dioxolame and preparation method thereof - Google Patents
2-(3-bromine-4-(3-fluorobenzyloxy)phenyl)-1,3-dioxolame and preparation method thereof Download PDFInfo
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- C07C45/57—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom
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Abstract
The invention relates to a new compound 2-(3-bromine-4-(3-fluorobenzyloxy) phenyl)-1,3-dioxolame and a preparation method thereof. The preparation method includes: respectively preparing 3-bromine-4-(3-fluorobenzyloxy) benzaldehyde and 4-methyl benzenesulfonic acid pyridinium first, and allowing the 3-bromine-4-(3-fluorobenzyloxy) benzaldehyde to have reaction with the 4-methyl benzenesulfonic acid pyridinium to generate the 2-(3-bromine-4-(3-fluorobenzyloxy) phenyl)-1,3-dioxolame. The 2-(3-bromine-4-(3-fluorobenzyloxy) phenyl)-1,3-dioxolame prepared by the method can be directly used for preparing 3-(3-fluorobenzyl)-4-(3-fluorobenzyloxy) benzaldehyde, the yield of the prepared 3-(3-fluorobenzyl)-4-(3-fluorobenzyloxy) benzaldehyde reaches up to 64.85%, and the purity, measured by high performance liquid chromatography, of the 3-(3-fluorobenzyl)-4-(3-fluorobenzyloxy) benzaldehyde 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 benzyloxies) phenyl)-DOX, the present invention
Further relate to the preparation method of the compound.
Background technology
FCE-26743A (Safinamide), entitled (S) -2- [4- (the 3- fluorine benzyloxies) benzyl amino] propionic acid amide. (Formulas I) of chemistry,
Be Newron Pharmaceuticals Inc.'s research and development for a kind of for treating Parkinsonian newtype drug.
At present, the method for synthesizing FCE-26743A：Hydroxy benzaldehyde and a fluorobenzyl chloride react under certain reaction condition, obtain
To intermediate product 4- (3- fluorine benzyloxies) benzaldehyde (intermediate -1)；Then, L- aminopropanamide hydrochlorate and intermediate -1 react
Generate (S) -2- [4- (3- fluorine benzyloxies) benzyl amino] propionic acid amide. (intermediate -2)；Finally, reduce intermediate -2 and obtain husky sweet smell acyl
Amine.
In the published technique for preparing FCE-26743A, 3- (3- luorobenzyls) -4- (3- fluorine benzyloxies) benzaldehyde (formula 9) knot
Structure formula is as follows.The impurity is a kind of potential key intermediate impurity, research earlier, control impurity, on the one hand improves sand
The quality standard of fragrant amide, on the other hand guarantees to prepare the product for meeting quality standard, for the research of FCE-26743A has
Important meaning.
In published preparation technology, fluorobenzyl chloride is high in the presence of potassium carbonate, toluene between hydroxy benzaldehyde and excess
The warm response time is 5 days, and the gas chromatographic analysiss of reaction mass show, reaction mass now is by 4- (3- fluorine benzyloxies)
Benzaldehyde (intermediate -1) and 3- (3- luorobenzyls) -4- (3- fluorine benzyloxies) benzaldehyde (formula 9) are with 91.4:8.6 (area ratios) compare
Example mixing；Impurity 9, yield as little as 3.6% are obtained by fractional distillation from the mixed material.
The method for directly not preparing impurity 9 in currently available technology, simply will during FCE-26743A is prepared
It is separated, and yield is extremely low.
In order to solve the above problems, the invention provides a kind of noval chemical compound 2- (the bromo- 4- of 3- (3- fluorine benzyloxies) phenyl)-
DOX, the compound can be used to prepare 3- (3- luorobenzyls) -4- (3- fluorine benzyloxies) benzaldehyde, and obtain preferable
Yield.
The content of the invention
The technical problem to be solved is the present situation for prior art, there is provided (3- is bromo- for a kind of noval chemical compound 2-
4- (3- fluorine benzyloxies) phenyl)-DOX, the compound can be used for prepare 3- (3- luorobenzyls) -4- (3- fluorine benzyloxies
Base) benzaldehyde, and significantly improve yield.
Another technical problem to be solved by this invention is the present situation for prior art, there is provided a kind of 2- (bromo- 4- of 3-
(3- fluorine benzyloxies) phenyl) -1,3- dioxolanes preparation method.
The present invention solve the technical scheme that adopted of above-mentioned technical problem for：A kind of noval chemical compound 2- (3- bromo- 4- (3- fluorine
Benzyloxy) phenyl)-DOX, 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 benzyloxies) phenyl)-DOX, its
It is characterised by comprising the following steps：
(1) bromo- 4- (the 3- fluorine benzyloxies) benzaldehydes of 3- are prepared
In the presence of potassium carbonate, tetrabutyl ammonium bromide, the bromo- 4- hydroxy benzaldehydes of 3- are added in organic solvent, and (following formula 1 is changed
Compound) and a fluorine bromobenzyl (compound of following formula 2), after reaction, obtain the bromo- 4- of 3- (the 3- fluorine benzyloxies) benzaldehyde (chemical combination of following formula 3
Thing)；
(2) 4- toluene sulfonic acide pyridines are prepared
With pyridine (compound of following formula 5) under nitrogen protection, reaction generates 4- methyl to p-methyl benzenesulfonic acid (compound of following formula 4)
Benzenesulfonic acid pyridine (compound of following formula 6)；
(3) 2- (the bromo- 4- of 3- (3- fluorine benzyloxies) phenyl) -1,3- dioxolanes are synthesized
Bromo- 4- (the 3- fluorine benzyloxies) benzaldehydes (compound of formula 3) of step (1) gained 3- and step (2) gained 4- methylbenzene
Sulfonic acid pyridine (compound of formula 6) reacts, and obtains 2- (the bromo- 4- of 3- (3- fluorine benzyloxies) phenyl)-DOX (following formula 7
Compound).
Preferably, step (1) is carried out under nitrogen protection, reaction temperature is 70～90 DEG C.
Further preferably, after completion of the reaction, reactant is cooled to into room temperature, is filtered, remove inorganic salt, organic solvent washing
Residue, concentrating under reduced pressure filtrate obtains the bromo- 4- of 3- (3- fluorine benzyloxies) benzaldehyde, purifies standby.
Preferably, step (2) is carried out under nitrogen protection, and reaction temperature is 0～5 DEG C, after completion of the reaction, drying under reduced pressure,
Obtain 4- toluene sulfonic acide pyridines.
Preferably, in the presence of ethylene glycol solvent, reaction temperature is more than 90 DEG C to step (3)；Cool down after completion of the reaction, wash
Wash, drying under reduced pressure obtains 2- (the bromo- 4- of 3- (3- fluorine benzyloxies) phenyl) -1,3- dioxolanes.
Compared with prior art, it is an advantage of the current invention that：The invention provides a kind of noval chemical compound 2- (bromo- 4- (3- of 3-
Fluorine benzyloxy) phenyl)-DOX, the noval chemical compound can be used to directly prepare 3- (3- luorobenzyls) -4- (3- fluorine benzyloxies
Base) benzaldehyde, and 3- (3- luorobenzyls) -4- (3- fluorine benzyloxies) the benzaldehyde high incomes for preparing are up to 64.85%, high-efficient liquid phase color
The purity that spectrum is measured reaches 98.92%.
Description of the drawings
Fig. 1 is the HPLC collection of illustrative plates of step (1) product in the embodiment of the present invention；
Fig. 2 is the GC collection of illustrative plates of step (1) product in the embodiment of the present invention；
Fig. 3 is the TIC collection of illustrative plates of step (1) product in the embodiment of the present invention；
Fig. 4 is the UV collection of illustrative plates of step (1) product in the embodiment of the present invention；
Fig. 5 is the Mass collection of illustrative plates of step (1) product in the embodiment of the present invention；
Fig. 6 is the IR collection of illustrative plates of step (1) product in the embodiment of the present invention；
Fig. 7 is the HPLC collection of illustrative plates of step (2) product in the embodiment of the present invention；
Fig. 8 is the TIC collection of illustrative plates of step (2) product in the embodiment of the present invention；
Fig. 9 is the UV collection of illustrative plates of step (2) product in the embodiment of the present invention；
Figure 10 is the Mass collection of illustrative plates (pyridine) of step (2) product in the embodiment of the present invention；
Figure 11 is the Mass collection of illustrative plates (p- toluenesulfonic acid) of step (2) product in the embodiment of the present invention；
Figure 12 is the GC collection of illustrative plates of step (3) product in the embodiment of the present invention；
Figure 13 is the TIC collection of illustrative plates of step (3) product in the embodiment of the present invention；
Figure 14 is the UV collection of illustrative plates of step (3) product in the embodiment of the present invention；
Figure 15 is the Mass collection of illustrative plates of step (3) product in the embodiment of the present invention；
Figure 16 is the IR collection of illustrative plates of step (3) product in the embodiment of the present invention；
Figure 17 is the HPLC collection of illustrative plates of step (a) product in the embodiment of the present invention；
Figure 18 is the TIC collection of illustrative plates of step (a) product in the embodiment of the present invention；
Figure 19 is the UV collection of illustrative plates of step (a) product in the embodiment of the present invention；
Figure 20 is the Mass collection of illustrative plates of step (a) product in the embodiment of the present invention；
Figure 21 is the IR collection of illustrative plates of step (a) product in inventive embodiments；
Figure 22 is the HPLC collection of illustrative plates of step (b) product in the embodiment of the present invention；
Figure 23 is the TIC collection of illustrative plates of step (b) product in the embodiment of the present invention；
Figure 24 is the UV collection of illustrative plates of step (b) product in the embodiment of the present invention；
Figure 25 is the Mass collection of illustrative plates of step (b) product in the embodiment of the present invention；
Figure 26 is the IR collection of illustrative plates of step (b) product in inventive embodiments.
Specific embodiment
The present invention is described in further detail below in conjunction with accompanying drawing embodiment.
Noval chemical compound 2- (the bromo- 4- of 3- (3- fluorine benzyloxies) the phenyl) -1,3- dioxolane structure formulas of the present embodiment are as follows：
The characteristic of above-claimed cpd 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 benzyloxies) the phenyl) -1,3- dioxolanes of the present embodiment
Comprise the following steps：
Step one：Add in reactor successively the bromo- 4- hydroxy benzaldehydes (25g, 0.12mol) of 3-, toluene (250mL),
Potassium carbonate (22.2g, 0.161mol), tetrabutyl ammonium bromide (20g, 0.062mol), then pass to nitrogen, and gained mixture is in room
The lower stirring of temperature；
Under nitrogen protection, to fluorine bromobenzyl (23.5g, 0.124mol), completion of dropping between Deca in above-mentioned reactant mixture
Afterwards, the mixture is heated slowly to into 70～90 DEG C, insulation reaction 6 hours；Detected by thin layer chromatography in course of reaction
(mobile phase is normal hexane and 10% ethyl acetate, under 254nm uviol lamps), if thin layer chromatography reaction is not substantially, then adds
Enter a fluorine bromobenzyl (4.5g, 0.023mol), until reaction proceeds to thin layer chromatography colour developing well；
After completion of the reaction, reactant is cooled to into room temperature, is filtered to remove inorganic salt, residual solid phase is washed with 25mL toluene,
Filtrate is concentrated under 50～55 DEG C of reduced pressure, the bromo- 4- of 3- (3- fluorine benzyloxies) benzaldehyde crude product is obtained；
Purification：The bromo- 4- of 3- (3- fluorine benzyloxies) benzaldehyde crude product adds toluene (25mL) stirring and dissolving at 25～30 DEG C,
Under agitation, to Deca normal hexane (50mL) in solution, the suspension for obtaining is cooled to 0～5 DEG C and places 1 hour；Filter solid
Body, filter cake normal hexane washs (25mL), wet filter cake is placed in 45～50 DEG C of decompression baking oven and is dried 4 hours, obtains 3-
Bromo- 4- (3- fluorine benzyloxies) benzaldehyde.
As shown in figs. 1 to 6, the quality of the bromo- 4- of gained 3- (3- fluorine benzyloxies) benzaldehyde is 31g, and yield is 80.6%, GC
Chromatograph measures purity and measures purity for 99.34% for 99.66%, HPLC.
Step 2：P-methyl benzenesulfonic acid (5g, 0.029mol) is added in reactor, under nitrogen protection, four is continuously added
Hydrogen furan (40mL), room temperature reaction；Reaction solution is cooled to into 0～5 DEG C, then, in solution Deca pyridine (2.75g,
0.035mol), and ensure to be dripped in 20～30 minutes, then stir 30 minutes；
Filter under nitrogen protection, gained filter cake is washed with 5mL tetrahydrofurans, place it in 45～50 DEG C of decompression baking oven
Middle drying 4 hours, obtains 4- toluene sulfonic acide pyridines.
As shown in Fig. 7～11, gained 4- toluene sulfonic acide pyridines quality is 6g, and yield 82.19%, HPLC detects purity
100%.
Step 3：Bromo- 4- (the 3- fluorine benzyloxies) benzaldehydes (25g, 0.081mol) of 3- are added in reactor, in stirring
Under, add toluene (500mL), ethylene glycol (10g, 0.161mol), 4- toluene sulfonic acide pyridines (1g, 0.04mol)；Will reaction
Mixture is slowly heated to backflow, steams solvent, and reaction solution at a reflux temperature distill 5 hours by azeotrope with water, gas chromatogram
Detection reaction, if reaction is not carried out according to plan, adds ethylene glycol (5g, 0.081mol) and ensures that reaction continues；Reaction terminates
Afterwards, cooling, 50mL NaHCO3Solution is washed；Product after washing is dried in 5.0g sodium sulfate, at a temperature of 25～30 DEG C,
It is concentrated under reduced pressure to give 2- (the bromo- 4- of 3- (3- fluorine benzyloxies) phenyl) -1,3- dioxolanes.
As shown in Figure 12～16, the mass of gained compound 7 is 27.5g, yield 96.3%, and gas chromatographic detection purity is
98.89%.
3- is prepared using noval chemical compound 2- (the bromo- 4- of 3- (3- fluorine benzyloxies) the phenyl) -1,3- dioxolanes of the present embodiment
The step of (3- luorobenzyls) -4- (3- fluorine benzyloxies) benzaldehyde, is as follows：
A () adds compound 7 (25g, 0.071mol) in reactor, be subsequently added tetrahydrofuran (375mL) and boric acid
Three isopropyl esters (24g, 0.127mol), under nitrogen protection normal-temperature reaction；Mixture is cooled to -78 DEG C, at such a temperature slowly
Deca n-BuLi-hexane mixture (11.3g, 0.176mol), reacts 1 hour under nitrogen protection, stirs after completion of dropping
Mix reaction 4 hours；Thin layer chromatography chromatograph (TLC) detects extent of reaction, if detect reacting undesirable, adds normal-butyl
Lithium-hexane mixture (1g, 0.015mol), maintains reaction to continue；
After reaction terminates, with dilute hydrochloric acid (1:1) pH to 1～2 is adjusted, reactant mixture is heated to 25～30 DEG C, adds
25ml water, stirs 30 minutes；Ethyl acetate extracts (3 × 75mL), and sodium sulfate is dried organic faciess (10g), subtracts at 50～55 DEG C
Pressure concentration, obtains crude product 2- (3- fluorine benzyloxies) -5- formylphenylboronic acids.
Purification：At room temperature, dichloromethane (50mL) is added in 2- (3- fluorine benzyloxies) -5- formylphenylboronic acid crude products,
Lower Deca normal hexane (250mL) of stirring, the suspension for obtaining is cooled to 0～5 DEG C and places 1 hour；Filter, normal hexane washing filter
Cake (25mL), wet filter cake is placed in decompression baking oven and is dried 4 hours, obtains 2- (3- fluorine benzyloxies) -5- formoxyl benzene boron
Acid.
As shown in Figure 17～21, gained 2- (3- fluorine benzyloxies) -5- formylphenylboronic acids quality be 13.8g, yield
71.13%, HPLC detect purity 96.19%.
B () adds 2- (3- fluorine benzyloxies) -5- formylphenylboronic acids (25g, 0.91mol) in reactor, in room temperature, nitrogen
Under the conditions of gas, Isosorbide-5-Nitrae-dioxanes (250mL), water (25mL), a fluorine bromobenzyl (25.8g, 0.136mol) are added, then, lead to 30 points
Clock nitrogen；Add Pd2(dba)3(1.75g, 0.002mol), is to slowly warm up to 70 DEG C, stirring reaction two hours, by thin layer
Chromatograph detection reaction；
After reaction terminates, mixture is cooled to room temperature, is filtered with kieselguhr, Isosorbide-5-Nitrae-dioxanes (25mL) washing filter cake；So
Afterwards vacuum distillation obtains oil phase at 60～65 DEG C of Rotary Evaporators；Remaining oil phase adds water (100ml), then uses ethyl acetate
Extraction (3 × 100mL), sodium sulfate (10g) is dried organic faciess, in 50～55 DEG C of drying under reduced pressure crude products, obtain 3- (3- luorobenzyls)-
4- (3- fluorine benzyloxies) benzaldehyde；
Purification：3- (3- luorobenzyls) -4- (3- fluorine benzyloxies) benzaldehyde crude product Jing silica gel column chromatographies (mesh-20) (is washed
De- liquid：Normal hexane：Ethyl acetate (9.8:0.2)) purification.
As shown in Figure 22～26, gained 3- (3- luorobenzyls) -4- (3- fluorine benzyloxies) benzaldehyde quality is 20g, and yield is
64.85%, HPLC detection purity is 97.82%.
It can be seen that, compared with the method for 3- (3- luorobenzyls) -4- (3- fluorine benzyloxies) benzaldehyde is prepared in prior art, this reality
Apply example and prepare 3- (3- luorobenzyls) -4- using noval chemical compound 2- (the bromo- 4- of 3- (3- fluorine benzyloxies) phenyl) -1,3- dioxolanes
The yield of (3- fluorine benzyloxies) benzaldehyde is significantly improved.
Claims (6)
1. a kind of noval chemical compound 2- (the bromo- 4- of 3- (3- fluorine benzyloxies) phenyl)-DOX, it is characterised in that structural formula is such as
Under：
2. the preparation of noval chemical compound 2- described in a kind of claim 1 (the bromo- 4- of 3- (3- fluorine benzyloxies) phenyl) -1,3- dioxolanes
Method, it is characterised in that comprise the following steps：
(1) bromo- 4- (the 3- fluorine benzyloxies) benzaldehydes of 3- are prepared
In the presence of potassium carbonate, tetrabutyl ammonium bromide, the bromo- 4- hydroxy benzaldehydes (chemical combination of following formula 1 of 3- is added in organic solvent
Thing) and a fluorine bromobenzyl (compound of following formula 2), after reaction, obtain the bromo- 4- of 3- (3- fluorine benzyloxies) benzaldehyde (compound of following formula 3)；
(2) 4- toluene sulfonic acide pyridines are prepared
With pyridine (compound of following formula 5) under nitrogen protection, reaction generates 4- methylbenzene sulphurs to p-methyl benzenesulfonic acid (compound of following formula 4)
Sour pyridine (compound of following formula 6)；
(3) 2- (the bromo- 4- of 3- (3- fluorine benzyloxies) phenyl) -1,3- dioxolanes are synthesized
Bromo- 4- (the 3- fluorine benzyloxies) benzaldehydes (compound of formula 3) of step (1) gained 3- and step (2) gained 4- toluene sulfonic acides
Pyridine (compound of formula 6) reacts, and obtains 2- (the bromo- 4- of 3- (the 3- fluorine benzyloxies) phenyl)-DOX (chemical combination of following formula 7
Thing).
3. the preparation of noval chemical compound 2- (the bromo- 4- of 3- (3- fluorine benzyloxies) phenyl) -1,3- dioxolanes according to claim 2
Method, it is characterised in that：Step (1) is carried 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 benzyloxies) phenyl) -1,3- dioxolanes according to claim 3
Method, it is characterised in that：After completion of the reaction, reactant is cooled to into room temperature, is filtered, remove inorganic salt, residual solid phase is with organic
Solvent is washed, then concentrating under reduced pressure filtrate, obtains the bromo- 4- of 3- (3- fluorine benzyloxies) benzaldehyde, is purified standby.
5. the preparation of noval chemical compound 2- (the bromo- 4- of 3- (3- fluorine benzyloxies) phenyl) -1,3- dioxolanes according to claim 2
Method, it is characterised in that：Step (2) is carried out under nitrogen protection, and reaction temperature is 0～5 DEG C, after completion of the reaction, drying under reduced pressure,
Obtain 4- toluene sulfonic acide pyridines.
6. the preparation of noval chemical compound 2- (the bromo- 4- of 3- (3- fluorine benzyloxies) phenyl) -1,3- dioxolanes according to claim 2
Method, it is characterised in that：In the presence of ethylene glycol solvent, reaction temperature is more than 90 DEG C to step (3)；Cool down after completion of the reaction,
Washing, drying under reduced pressure obtain 2- (the bromo- 4- of 3- (3- fluorine benzyloxies) phenyl) -1,3- dioxolanes.
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| CN101952234A (en) * | 2008-02-06 | 2011-01-19 | 诺西拉有限公司 | Phenyl-prenyl derivatives, of marine and synthetic origin, for the treatment of cognitive, neurodegenerative or neuronal diseases or disorders |
| CN102249918A (en) * | 2011-05-20 | 2011-11-23 | 华南农业大学 | Preparation method of magnesium lithospermate |
| WO2016029214A1 (en) * | 2014-08-22 | 2016-02-25 | Biocryst Pharmaceuticals, Inc. | Compositions and uses of amidine derivatives |
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