CN106565521B - (S) preparation method of -2- [3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzyl amino] propionamide and its salt - Google Patents
(S) preparation method of -2- [3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzyl amino] propionamide and its salt Download PDFInfo
- Publication number
- CN106565521B CN106565521B CN201610717934.6A CN201610717934A CN106565521B CN 106565521 B CN106565521 B CN 106565521B CN 201610717934 A CN201610717934 A CN 201610717934A CN 106565521 B CN106565521 B CN 106565521B
- Authority
- CN
- China
- Prior art keywords
- luorobenzyl
- fluorine benzyloxy
- compound
- reaction
- oxygroup
- 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.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/64—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of functional groups containing oxygen only in singly bound form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/127—Preparation from compounds containing pyridine rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
- C07D213/20—Quaternary compounds thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- 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
- C07D317/14—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 with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/18—Radicals substituted by singly bound oxygen or sulfur atoms
- C07D317/22—Radicals substituted by singly bound oxygen or sulfur atoms etherified
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to the preparation methods of one kind (S) -2- [3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzyl amino] propionamide and its salt, wherein, (S) salt of -2- [3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzyl amino] propionamide refers to (S) -2- [3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzyl amino] propionamide mesylate, the preparation method is by synthesizing new compound 2- (the bromo- 4- of 3- ((3- luorobenzyl) oxygroup) phenyl) -1, 3- dioxolanes and compound 2- ((3- luorobenzyl) oxygroup) -5- formylphenylboronic acid carry out the preparation of target product, belong to completely new preparation method, and [3- (3- luorobenzyl) -4- (3- fluorine benzyloxy of (S) -2- prepared by the preparation method Base) benzyl amino] propionamide yield be 49.57%, HPLC purity reaches 78.92%, the salt yield of prepared (S) -2- [3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzyl amino] propionamide is 50.40%, HPLC purity reaches 96.35%, is greatly improved compared with the prior art.
Description
Technical field
The present invention relates to one kind (S) -2- [3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzyl amino] propionamide and its salt
Preparation method.
Background technique
Safinamide (Safinamide) is a kind of sodium channel inhibitor, calcium channel modulators, monoamine oxidase B (MAO-
B) inhibitor, Glutamate Release Inhibitor and Dopamine Metabolism In The Rat regulator.The prior art is in the technique of preparation safinamide
It is related to two kinds of important impurity, as (S) -2- [3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzyl amino] propionamide (chemical combination
Object 10) and its salt (compound 11).
Presently, there are many drugs just because of the presence of special impurities, unpredictable poison is generated to the metabolism of human body
Property and abandon continuing to research and develop.According in the prior art to safinamide studies have shown that above-mentioned impurity is shown to cytochromes
The enzyme of P450 system has high toxicity.Therefore, particularly significant to the research of impurity 10,11, and at present about above-mentioned impurity
The document report of synthetic method is relatively fewer, and yield and purity are also difficult to be guaranteed.
Summary of the invention
The technical problem to be solved by the invention for the present situation of prior art is to provide one kind (S) -2- [3- (3- fluorine benzyls
Base) -4- (3- fluorine benzyloxy) benzyl amino] propionamide and its salt preparation method, this method is remarkably improved purity and yield.
The technical scheme of the invention to solve the technical problem is: one kind (S) -2- [3- (3- luorobenzyl) -4-
(3- fluorine benzyloxy) benzyl amino] propionamide and its salt preparation method, it is characterised in that the following steps are included:
(1) the bromo- 4- of 3- [(3- luorobenzyl) oxygroup] benzaldehyde is synthesized
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), end of reaction obtain the synthesis bromo- 4- of 3- [(3- luorobenzyl) oxygroup] benzaldehyde (under
3 compound of formula)；
(2) 4- toluenesulfonic acid pyridine is synthesized
P-methyl benzenesulfonic acid (4 compound of following formula) reacts under nitrogen protection with pyridine (5 compound of following formula) generates 4- methyl
Benzene sulfonic acid pyridine (6 compound of following formula)；
(3) 2- (the bromo- 4- of 3- ((3- luorobenzyl) oxygroup) phenyl) -1,3- dioxolanes is synthesized
4- first obtained by 3- bromo- 4- [(3- luorobenzyl) oxygroup] benzaldehyde (3 compound of formula) and step (2) obtained by step (1)
Base benzene sulfonic acid pyridine (6 compound of formula) reaction generates 2- (the bromo- 4- of 3- ((3- luorobenzyl) oxygroup) phenyl) -1,3- dioxolanes
(7 compound of following formula)；
(4) 2- ((3- luorobenzyl) oxygroup) -5- formylphenylboronic acid is synthesized
2- (the bromo- 4- of 3- ((3- luorobenzyl) oxygroup) phenyl) -1,3- dioxolanes (7 compound of formula) obtained by step (3) according to
It is secondary to react to obtain 2- ((3- luorobenzyl) oxygroup) -5- formylphenylboronic acid (8 chemical combination of following formula with triisopropyl borate ester, n-BuLi
Object)；
(5) 3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzaldehyde is synthesized
2- ((3- luorobenzyl) oxygroup) -5- formylphenylboronic acid (8 compound of formula) obtained by step (4) is first disliked with 1,4- bis-
Alkane, fluorine bromobenzyl reaction, are then added tris(dibenzylideneacetone) dipalladium, end of reaction obtains target product into the reactant
Crude product 3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzaldehyde (9 compound of following formula)；
(6) (S) -2- [3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzyl amino] propionamide is synthesized
In the presence of anhydrous magnesium sulfate, triethylamine and sodium cyanoborohydride, 3- (3- luorobenzyl) -4- (3- obtained by step (5)
Fluorine benzyloxy) benzaldehyde (9 compound of formula) and L- alanimamides hydrochloric acid reactant salt, obtain (S) -2- [3- (3- fluorine benzyl
Base) -4- (3- fluorine benzyloxy) benzyl amino] propionamide (10 compound of following formula).
In the above scheme, step (1) carries out under nitrogen protection, and reaction temperature is 80~~85 DEG C of (undetermined) 70~90
DEG C, the reaction time is 6~~7 hours (undetermined).After completion of the reaction, reactant is cooled to room temperature, is filtered, remove inorganic salts,
Filtrate is concentrated under reduced pressure in organic solvent washing 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, step (3) is in the presence of ethylene glycol solvent, and 90 DEG C of reaction temperature 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.
Preferably, the entire reaction process of step (4) carries out under nitrogen protection, 2- (the bromo- 4- of 3- ((3- luorobenzyl) oxygen
Base) phenyl) -1,3-dioxolane reacts at normal temperature with triisopropyl borate ester, then reacts at -78 DEG C with n-BuLi.
After reaction, the pH of reaction solution is adjusted to 1~2 with dilute hydrochloric acid, is heated to~25~30 DEG C, with organic extractant phase, 50
It is concentrated under reduced pressure to give 2- ((3- luorobenzyl) oxygroup) -5- formylphenylboronic acid crude product with Rotary Evaporators at~55 DEG C, after purification
It is spare.
Preferably, it is carried out under nitrogen protection in step (5), and is warming up to 70 after tris(dibenzylideneacetone) dipalladium is added
It DEG C is reacted.Diatomite filtering is added after end of reaction into reaction solution, gained filter cake is revolving after being washed with Isosorbide-5-Nitrae-dioxanes
Turn to be evaporated under reduced pressure at 60~65 DEG C in evaporimeter, drying, distillation obtain crude product 3- (3- after gained oil is mutually extracted with ethyl acetate
Luorobenzyl) -4- (3- fluorine benzyloxy) benzaldehyde.
The preparation method of the salt of one kind (S) -2- [3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzyl amino] propionamide, should
Entitled (S) -2- [3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzyl amino] propionamide mesylate of salt, it is characterised in that
The following steps are included:
(S) -2- [3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzyl amino] propionamide obtained by above-mentioned steps (6) (change by formula 10
Close object) it is reacted with methanesulfonic acid to get described (S) -2- [3- (3- luorobenzyl) -4- (the 3- fluorine benzyloxy) benzyl amino] propionamide is arrived
Mesylate (11 compound of following formula).
Compared with the prior art, the advantages of the present invention are as follows: the present invention provides one kind (S) -2- [3- (3- luorobenzyl) -
4- (3- fluorine benzyloxy) benzyl amino] propionamide and its salt preparation method, the preparation method is by synthesizing new compound 7 and changing
The preparation that object 8 carries out target product is closed, belongs to completely new preparation method, and [3- (the 3- fluorine benzyl of (S) -2- prepared by the preparation method
Base) -4- (3- fluorine benzyloxy) benzyl amino] propionamide yield be 49.57%, HPLC purity reach 78.92%, prepared (S) -2-
The salt yield of [3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzyl amino] propionamide is that 50.40%, HPLC purity reaches
96.35%, it is greatly improved compared with the prior art.
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-methyl benzenesulfonic 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 (4) product in the embodiment of the present invention；
Figure 18 is the TIC map of step (4) product in the embodiment of the present invention；
Figure 19 is the UV map of step (4) product in the embodiment of the present invention；
Figure 20 is the Mass map of step (4) product in the embodiment of the present invention；
Figure 21 is the IR map of step (4) product in inventive embodiments；
Figure 22 is the HPLC map of step (5) product in the embodiment of the present invention；
Figure 23 is the TIC map of step (5) product in the embodiment of the present invention；
Figure 24 is the UV map of step (5) product in the embodiment of the present invention；
Figure 25 is the Mass map of step (5) product in the embodiment of the present invention；
Figure 26 is the IR map of step (5) product in inventive embodiments；
Figure 27 is the HPLC map of step (6) product in inventive embodiments；
Figure 28 is the TIC map of step (6) product in the embodiment of the present invention；
Figure 29 is the UV map of step (6) product in the embodiment of the present invention；
Figure 30 is the Mass map of step (6) product in the embodiment of the present invention；
Figure 31 is the HPLC map of step (7) product in inventive embodiments；
Figure 32 is the TIC map of step (7) product in the embodiment of the present invention；
Figure 33 is the UV map of step (7) product in the embodiment of the present invention.
Specific embodiment
The present invention will be described in further detail below with reference to the embodiments of the drawings.
The preparation method packet of (S) -2- [3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzyl amino] propionamide of the present embodiment
Include following steps:
(1) the bromo- 4- hydroxy benzaldehyde (25g, 0.12mol) of 3-, toluene (250mL), carbonic acid are successively added into reactor
Potassium (22.2g, 0.161mol), tetrabutylammonium bromide (20g, 0.062mol), then pass to nitrogen, gained mixture is at room temperature
Stirring 10 minutes；
Under nitrogen protection, at room temperature, be added dropwise in introversive above-mentioned reaction mixture within 1 hour a fluorine bromobenzyl (23.5g,
0.124mol), after being added dropwise, which is heated slowly to 70~90 DEG C, insulation reaction 6 hours；In reaction process by
Thin layer chromatography (mobile phase is the ethyl acetate of n-hexane and 10%, under 254nm ultraviolet lamp) control extent of reaction, such as
The reaction of fruit thin-layer chromatography is unobvious, adds a fluorine bromobenzyl (4.5g, 0.023mol), until reaction continues until thin layer color
Spectrum colour developing is good；
After the reaction was completed, 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- luorobenzyl) oxygroup) benzaldehyde crude product；
Purification: toluene (25mL) stirring is added in the bromo- 4- of crude product 3- ((3- luorobenzyl) oxygroup) benzaldehyde at 25~30 DEG C
Dissolution, is added dropwise n-hexane (50mL) and is stirred continuously in the solution, and obtained suspension is cooled to 0~5 DEG C and places 1
Hour；Solid is filtered out, filter cake washs (25mL) with n-hexane, wet filter cake is placed in 45~50 DEG C of decompression baking oven dry
Obtain within 4 hours the bromo- 4- of 3- ((3- luorobenzyl) oxygroup) benzaldehyde.
As shown in figs. 1 to 6, the quality of the bromo- 4- of gained 3- ((3- luorobenzyl) oxygroup) benzaldehyde is 31g, and yield is
It is that measure purity be 99.34% to 99.66%, HPLC that 80.6%, GC chromatography, which measure purity,.
(2) p-methyl benzenesulfonic acid (5g, 0.029mol) is added into reactor, continuously adds dry tetrahydro under the conditions of nitrogen charging
Furans (40mL), is reacted at room temperature；Reaction solution is cooled to 0~5 DEG C, pyrrole is added dropwise into solution at such a temperature
Pyridine (2.75g, 0.035mol), adds in 20~30 minutes, stirs 30 minutes；
Reactant filters in nitrogen atmosphere, and gained filter cake is washed with the dry tetrahydrofuran of 5mL, and wet filter cake is placed on
Obtain 4- toluenesulfonic acid pyridine within dry 4 hours in 45~50 DEG C of decompression baking oven.
As shown in Fig. 7~11, the quality of gained 4- toluenesulfonic acid pyridine is 6g, and yield 82.19%, HPLC detects pure
Degree 100%.
(3) the bromo- 4- of 3- ((3- luorobenzyl) oxygroup) benzaldehyde (25g, 0.081mol) is added into reactor, makees in stirring
With lower addition toluene (500mL), ethylene glycol (10g, 0.161mol), 4- toluenesulfonic acid pyridine (1g, 0.04mol)；It will be anti-
It answers mixture to be heated slowly to flow back, steams 100 milliliters of toluene, reaction solution at a reflux temperature distill 5 hours by azeotrope with water,
It is reacted and is in progress by gas chromatographic detection, if reaction does not carry out according to plan, ethylene glycol (5g, 0.081mol) is added, reaction is allowed to continue
It carries out；After reaction, reactant is cooled to 25~30 DEG C, and with 50mL NaHCO3Aqueous solution washing；
Organic matter after washing is dry in 5.0g sodium sulphate, is concentrated under reduced pressure in Rotary Evaporators at a temperature of 25~30 DEG C
Obtain 2- (the bromo- 4- of 3- ((3- luorobenzyl) oxygroup) phenyl) -1,3- dioxolanes.
As shown in Figure 12~16, gained 2- (the bromo- 4- of 3- ((3- luorobenzyl) oxygroup) phenyl) -1,3-dioxolane quality is
27.5g, yield 96.3%, gas chromatographic detection purity are 98.89%.
(4) into reactor be added 2- (the bromo- 4- of 3- ((3- luorobenzyl) oxygroup) phenyl) -1,3- dioxolanes (25g,
0.071mol), dry tetrahydrofuran (375mL) and triisopropyl borate ester (24g, 0.127mol) is then added, is protected in nitrogen
It protects under lower room temperature and reacts；Mixture is cooled to -78 DEG C, and n-BuLi and hexanes mixtures are added dropwise at such a temperature
(11.3g, 0.176mol), the operation should carry out 1 hour in nitrogen atmosphere, be mixed 4 hours after being added dropwise；By thin layer
Thin layer chromatography (TLC) detects extent of reaction, if detecting the undesirable progress of reaction, adds n-BuLi and hexane
Mixture (1g, 0.015mol), until reaction can 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；It is extracted with ethyl acetate (3 × 75mL), organic phase is dry (10g) with sodium sulphate, at 50~55 DEG C
It is concentrated under reduced pressure to obtain crude product 2- ((3- luorobenzyl) oxygroup) -5- formylphenylboronic acid with Rotary Evaporators.
Purification: 2- ((3- luorobenzyl) oxygroup) -5- formylphenyl boronic acid crude product is added with stirring methylene chloride at 25~30 DEG C
N-hexane (250mL) is added dropwise into the solution in (50mL) under constant stirring, and the suspension of acquisition is cooled to 0~5 DEG C simultaneously
It places 1 hour；The solid was filtered, and filter cake washs (25mL) with n-hexane, and wet filter cake is placed on to 45~50 DEG C of decompression baking oven
2- ((3- luorobenzyl) oxygroup) -5- formylphenylboronic acid can be obtained for 4 hours in middle drying.
As shown in Figure 17~21, gained 2- ((3- luorobenzyl) oxygroup) -5- formylphenylboronic acid quality is 13.8g, yield
71.13%, HPLC detect purity 96.19%.
(5) 2- ((3- luorobenzyl) oxygroup) -5- formylphenylboronic acid (25g, 0.91mol) is added into reactor, in room
Isosorbide-5-Nitrae-dioxanes (250mL), water (25mL), fluorine bromobenzyl (25.8g, 0.136mol) are added one by one under temperature, condition of nitrogen gas, reacts
30 minutes nitrogen is passed through in mixture to exclude oxygen；Again into reactant be added tris(dibenzylideneacetone) dipalladium (1.75g,
0.002mol), reactant is slowly warming up to 70 DEG C to stir two hours, reaction process is detected by thin-layer chromatography；If reaction is not
It carries out according to plan, then tris(dibenzylideneacetone) dipalladium (0.2g) is added, the reaction was continued at 70 DEG C, until reaching objective result；
After reaction, mixture is cooled to room temperature, and is filtered with diatomite, and filter cake is washed by Isosorbide-5-Nitrae-dioxanes (25mL)；
Then vacuum distillation obtains oily phase at 60~65 DEG C of Rotary Evaporators；Remaining oil is added to water (100ml), then with acetic acid second
Ester extracts (3 × 100mL), and organic phase is dry using sodium sulphate (10g), then with Rotary Evaporators under 50~55 DEG C of reduced pressures
Dry crude product obtains 3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzaldehyde；
Purification: 3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzaldehyde crude product is mentioned through silica gel column chromatography (mesh-20)
Pure, use n-hexane: ethyl acetate (9.8:0.2) obtains 3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzene as eluent
Formaldehyde.
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,.
(6) under room temperature under nitrogen protection, methanol 150mL, 8.5g L- alanyl are sequentially added into the four-hole boiling flask of 250mL
Amine salt acid, finishes, and stirs 10min dissolved clarification, finishes, is cooled to 0~5 DEG C, and triethylamine 9g is added at a temperature of this, stirs 30min, keeps
Dissolved clarification；Finish, be cooled to 15~20 DEG C, and 10g compound 9 and 19.7g anhydrous magnesium sulfate are added at a temperature of this, at a temperature of this
Insulation reaction 15min protects and finishes, is cooled to 10~15 DEG C, insulation reaction 6h at a temperature of this；Heat preservation is finished, and is added in two batches under equality of temperature
Enter sodium cyanoborohydride 2.8g and insulation reaction 15h at a temperature of this；
Vacuum distillation removes methanol to most, process control vacuum degree P=after monitoring 9 fully reacting of compound by TLC
0.095Mpa, 40~50 DEG C of temperature；Steamed addition water 100mL, methylene chloride 200mL, finish, stir 15min at room temperature；
Finish, stratification, water layer is extracted twice with 30mL*2 methylene chloride；Merge methylene chloride organic layer to be washed with 25% ammonium hydroxide 25mL*2
It washs twice, it is dry to clarification with 10g anhydrous sodium sulphate to merge dichloromethane layer；Finish, removes to remove under reduced pressure methylene chloride to the greatest extent, this is excessively program-controlled
35~45 DEG C of temperature processed, vacuum degree P=0.095MPa obtains grease 10g；
Toluene 10mL is added into grease at room temperature, hexamethylene 100mL is added after dissolved clarification and stirs 30min；It is cooled to 0~
5 DEG C of crystallization 12h；Filtering is eluted with 30mL hexamethylene；It filters to dry taking-up solid and is dried under reduced pressure 12h in 40~45 DEG C, obtain
(S) -2- [3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzyl amino] propionamide.
As shown in Figure 27~30, gained (S) -2- [3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzyl amino] propionamide matter
Amount is 6g, and yield 49.57%, it is 78.92% that HPLC, which detects purity,.
The salt of (S) -2- [3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzyl amino] propionamide refers to (S)-in the present embodiment
2- [3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzyl amino] propionamide mesylate, preparation process is in above-mentioned steps (1)
Following step is increased on the basis of~(6):
(7) under room temperature under nitrogen protection, ethyl acetate 30mL, 2.0g above-mentioned steps are sequentially added into the four-hole boiling flask of 50mL
(6) gained compound (S) -2- [3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzyl amino] propionamide is finished, is warming up to 45~50
DEG C, insulated and stirred 15min；The mixed solution of 0.5g methanesulfonic acid and 10mL ethyl acetate composition, drop in about 15min are added dropwise after dissolved clarification
It adds；Finish, insulated and stirred 30min at a temperature of this；It protects and finishes, be cooled to 10~15 DEG C of crystallization 2h, finish, filtering, with 10mL acetic acid
Ethyl ester elutes filter cake, takes out filter cake in 45~50 DEG C and is dried under reduced pressure 2h, obtains target product (S) -2- [3- (3- luorobenzyl) -4-
(3- fluorine benzyloxy) benzyl amino] propionamide mesylate.
As shown in Figure 31~33, gained (S) -2- [3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzyl amino] propionamide first
Sulfonate is 1.5g, and yield 50.4%, it is 96.35% that HPLC, which detects purity,.
Claims (9)
1. the preparation method of one kind (S) -2- [3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzyl amino] propionamide, feature exist
In the following steps are included:
(1) the bromo- 4- of 3- [(3- luorobenzyl) oxygroup] benzaldehyde is synthesized
In the presence of potassium carbonate, tetrabutylammonium bromide, 1 compound of following formula and the fluorine bromobenzyl (change of following formula 2 are added into organic solvent
Close object), end of reaction obtains the synthesis bromo- 4- of 3- [(3- luorobenzyl) oxygroup] benzaldehyde (3 compound of following formula)；
(2) 4- toluenesulfonic acid pyridine is synthesized
P-methyl benzenesulfonic acid (4 compound of following formula) reacts under nitrogen protection with pyridine (5 compound of following formula) generates 4- methylbenzene sulphur
Sour pyridine (6 compound of following formula)；
(3) 2- (the bromo- 4- of 3- ((3- luorobenzyl) oxygroup) phenyl) -1,3- dioxolanes is synthesized
4- methylbenzene obtained by 3- bromo- 4- [(3- luorobenzyl) oxygroup] benzaldehyde (3 compound of formula) and step (2) obtained by step (1)
Sulfonic acid pyridine (6 compound of formula), glycol reaction generate 2- (the bromo- 4- of 3- ((3- luorobenzyl) oxygroup) phenyl) -1,3- dioxy
Penta ring (7 compound of following formula)；
(4) 2- ((3- luorobenzyl) oxygroup) -5- formylphenylboronic acid is synthesized
2- (the bromo- 4- of 3- ((3- luorobenzyl) oxygroup) phenyl) -1,3- dioxolanes (7 compound of formula) obtained by step (3) successively with
Triisopropyl borate ester, n-BuLi react to obtain 2- ((3- luorobenzyl) oxygroup) -5- formylphenylboronic acid (8 compound of following formula)；
(5) 3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzaldehyde is synthesized
2- ((3- luorobenzyl) oxygroup) -5- formylphenylboronic acid (8 compound of formula) elder generation and 1,4- dioxanes obtained by step (4),
The reaction of fluorine bromobenzyl, is then added tris(dibenzylideneacetone) dipalladium, end of reaction obtains the thick of target product into the reactant
Product 3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzaldehyde (9 compound of following formula)；
(6) (S) -2- [3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzyl amino] propionamide is synthesized
In the presence of anhydrous magnesium sulfate, triethylamine and sodium cyanoborohydride, 3- (3- luorobenzyl) -4- (3- fluorine benzyl obtained by step (5)
Oxygroup) benzaldehyde (9 compound of formula) and L- alanimamides hydrochloric acid reactant salt, obtain described (S) -2- [3- (3- the luorobenzyl) -4-
(3- fluorine benzyloxy) benzyl amino] propionamide (10 compound of following formula),
2. the system of (S) -2- [3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzyl amino] propionamide according to claim 1
Preparation Method, it is characterised in that: step (1) carries out under nitrogen protection, and reaction temperature is 70~90 DEG C；It after completion of the reaction, will be anti-
It answers object to be cooled to room temperature, filters, remove inorganic salts, then residual solid phase organic solvent washing is concentrated under reduced pressure filtrate, obtains 3-
Bromo- 4- (3- fluorine benzyloxy) benzaldehyde purifies spare.
3. the system of (S) -2- [3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzyl amino] propionamide according to claim 1
Preparation Method, it is characterised in that: step (2) carries out under nitrogen protection, and reaction temperature is 0~5 DEG C, and decompression is dry after completion of the reaction
It is dry, obtain 4- toluenesulfonic acid pyridine.
4. the system of (S) -2- [3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzyl amino] propionamide according to claim 1
Preparation Method, it is characterised in that: for step (3) in the presence of ethylene glycol solvent, reaction temperature is 90 DEG C or more.
5. the system of (S) -2- [3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzyl amino] propionamide according to claim 4
Preparation Method, it is characterised in that: cool down, wash after completion of the reaction, being dried under reduced pressure to obtain 2- (the bromo- 4- of 3- (3- fluorine benzyloxy) benzene
Base) -1,3- dioxolanes.
6. the system of (S) -2- [3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzyl amino] propionamide according to claim 1
Preparation Method, it is characterised in that: the entire reaction process of step (4) carries out under nitrogen protection, 2- (the bromo- 4- of 3- ((3- luorobenzyl)
Oxygroup) phenyl) -1,3-dioxolane first reacted at normal temperature with triisopropyl borate ester, then with n-BuLi at -78 DEG C instead
It answers.
7. the system of (S) -2- [3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzyl amino] propionamide according to claim 6
Preparation Method, it is characterised in that: after reaction, the pH of reaction solution is adjusted to 1~2 with dilute hydrochloric acid, is heated to 25~30 DEG C, used
Organic extractant phase is concentrated under reduced pressure to give 2- ((3- luorobenzyl) oxygroup) -5- formoxyl benzene with Rotary Evaporators at 50~55 DEG C
Crude boronic acid, it is spare after purification.
8. the system of (S) -2- [3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzyl amino] propionamide according to claim 1
Preparation Method, it is characterised in that: step carries out under nitrogen protection in (5), and heats up after tris(dibenzylideneacetone) dipalladium is added
It is reacted to 70 DEG C.
9. the system of (S) -2- [3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzyl amino] propionamide according to claim 8
Preparation Method, it is characterised in that: diatomite filtering is added after end of reaction into reaction solution, gained filter cake is washed with Isosorbide-5-Nitrae-dioxanes
It is evaporated under reduced pressure at 60~65 DEG C in Rotary Evaporators afterwards, drying, distillation obtain slightly after gained oil is mutually extracted with ethyl acetate
Product 3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzaldehyde.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610717934.6A CN106565521B (en) | 2016-08-24 | 2016-08-24 | (S) preparation method of -2- [3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzyl amino] propionamide and its salt |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610717934.6A CN106565521B (en) | 2016-08-24 | 2016-08-24 | (S) preparation method of -2- [3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzyl amino] propionamide and its salt |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106565521A CN106565521A (en) | 2017-04-19 |
| CN106565521B true CN106565521B (en) | 2019-03-08 |
Family
ID=58532337
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610717934.6A Active CN106565521B (en) | 2016-08-24 | 2016-08-24 | (S) preparation method of -2- [3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzyl amino] propionamide and its salt |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106565521B (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EA017123B1 (en) * | 2006-06-19 | 2012-10-30 | Ньюрон Фармасьютикалс С.П.А. | Process for the production of 2-[4-(3- and 2-fluorobenzyloxy)benzylamino]propanamides |
| CA2936209C (en) * | 2007-12-11 | 2020-02-11 | Newron Pharmaceuticals S.P.A. | Process for the production of 2-[4-(3- or 2-fluorobenzyloxy)benzylamino]propanamides with high purity degree |
| ES2954451T3 (en) * | 2014-08-22 | 2023-11-22 | Biocryst Pharm Inc | Compositions and uses of amidine derivatives |
-
2016
- 2016-08-24 CN CN201610717934.6A patent/CN106565521B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN106565521A (en) | 2017-04-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| SU537625A3 (en) | Method for producing 1,1-diamino ethylene derivatives | |
| NO172342B (en) | PROCEDURE FOR THE PREPARATION OF 2- (2- (4 - ((4-CHLORPHENYL) -PHENYLMETHYL) -1-PIPERAZINYL) -ETHOXY) -DETIC ACID AND ITS DIHYDROCHLORIDE, AND INTERMEDIATE PRODUCT FOR USE BY FRAME | |
| AU2003248280B2 (en) | New process for the industrial synthesis of tetraesters of 5-[bis(carboxymethyl)amino]-3-carboxymethyl-4-cyano-2-thiophenecarboxylic acid, and application to the synthesis of bivalent salts of ranelic acid and their hydrates | |
| CN114014787B (en) | Asymmetric synthesis method for preparing (2S,3R) -p-methylsulfonylphenylserine ethyl ester | |
| CN106977415B (en) | Intermediate of shakubiqu and preparation method thereof | |
| Tan et al. | Dilithiation of arenetricarbonylchromium (0) complexes with enantioselective quench: application to chiral biaryl synthesis | |
| CN110590627B (en) | Synthesis method of 3-aryl thiopropionamide derivative | |
| CN109456253B (en) | Method for synthesizing (S) -3- (4-bromophenyl) -piperidine or salt thereof through chiral induction | |
| CN110483549B (en) | Preparation method of nitroimidazole pyran antituberculosis drug | |
| CN106565521B (en) | (S) preparation method of -2- [3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzyl amino] propionamide and its salt | |
| Li et al. | Asymmetric and diastereoselective Mannich reactions using hydantoin as a chiral auxiliary | |
| CN106565442B (en) | The preparation method of 3- (3- luorobenzyl) -4- (3- fluorine benzyloxy) benzaldehyde | |
| CN106967057A (en) | A kind of efficient preparation technology of Aprepitant | |
| CN110156815A (en) | 12a hydrogen-benzo[f]pyridine[1,2-d][1,4]thiazepine and its preparation method | |
| CN113666865B (en) | Synthesis method of 2-isopropyl-3-amino-4-methylpyridine | |
| CN113121436B (en) | Preparation method of nertadalal dimethyl sulfonate | |
| CN101654426B (en) | Method for preparing ilomastat | |
| CN106187943B (en) | A kind of preparation method of 1,4- benzothiazines | |
| CN102010348A (en) | Salicylamide ester type derivative and preparation method and application thereof | |
| CN106632223B (en) | 2- (the bromo- 4- of 3- (3- fluorine benzyloxy) phenyl) -1,3- dioxolanes and preparation method thereof | |
| CN112961083B (en) | Synthesis method of clethodim impurities | |
| CN116375654B (en) | Method for preparing 2, 5-diketopiperazine from diglycolamine | |
| CN112430177B (en) | Synthesis method of montelukast sodium intermediate | |
| CN116162079B (en) | Synthesis method of aminocoumarin compound | |
| CN114315726B (en) | Preparation method of gem-difluoroallyl compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |