CN106220525A - A kind of preparation method of industrialization FCE-26743A mesylate - Google Patents
A kind of preparation method of industrialization FCE-26743A mesylate Download PDFInfo
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- CN106220525A CN106220525A CN201610624596.1A CN201610624596A CN106220525A CN 106220525 A CN106220525 A CN 106220525A CN 201610624596 A CN201610624596 A CN 201610624596A CN 106220525 A CN106220525 A CN 106220525A
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- Prior art keywords
- fluorine benzyloxy
- benzaldehyde
- fce
- compound
- propionic acid
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
-
- 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
Abstract
The present invention relates to the preparation method of a kind of industrialization FCE-26743A mesylate, belong to technical field of organic synthesis.The inventive method is by compound 3 fluorobenzyl chloride and compound hydroxy benzaldehyde reacting generating compound 4 (3 fluorine benzyloxy) benzaldehyde, then compound 4 (3 fluorine benzyloxy) benzaldehyde is prepared compound (S) 2 [4 (3 fluorine benzyloxy) benzamido group] propionic acid amide. with the condensation of (S) 2 aminopropanoate hydrochlorate, compound (S) 2 [4 (3 fluorine benzyloxy) benzamido group] propionic acid amide. becomes salt with methanesulfonic acid with Pd/C catalytic hydrogen reduction, product after re crystallization from toluene.The invention provides a kind of new industrialization synthesis selection mode, this synthesis mode has easy and simple to handle, and post processing is simple, the features such as cost is lower, environmentally friendly, it is possible to obtain high-quality target product, beneficially commercial production.
Description
Technical field
The present invention relates to technical field of organic synthesis, be specifically related to the preparation side of a kind of industrialization FCE-26743A mesylate
Method.
Background technology
FCE-26743A mesylate (Safinamide mesilate), chemistry entitled (S)-2-[4-(3-fluorine benzyloxy) benzyl
Amido] propionic acid amide. mesylate is the antiparkinsonism drug researched and developed by Newron drugmaker.This product has multiple effect machine
System, not only can high selectivity and reversible inhibition monoamine oxidase-B (MAO-B), it is also possible to suppression dopamine reuptake, blocks electricity
The sodium channel of pressure dependence, regulation calcium channel, thus suppress glutamic neuron.Central nervous system's bioavailability of FCE-26743A
Height, clinical display can improve motion and the cognitive function of Parkinsonian, prevent patient from the dyskinesia occur, and have good
Good toleration.But current industrialized process for preparing operation complexity, cost is high, big for environment pollution.
Summary of the invention
The technical problem to be solved in the present invention is the defect overcoming prior art, it is provided that a kind of industrialization FCE-26743A first sulphur
The preparation method of hydrochlorate.
In order to solve above-mentioned technical problem, the invention provides following technical scheme: a kind of industrialization FCE-26743A first
The preparation method of sulfonate, its scheme is as follows:
Prepared by 1.4-(3-fluorine benzyloxy) benzaldehyde:
Hydroxy benzaldehyde 15.2g, potassium carbonate 17.2g and potassium iodide 2.0g are added in dehydrated alcohol 170ml, stirring
15min, drips 3-fluorobenzyl chloride 17.3ml, heating reflux reaction 6h, filters, filter cake absolute ethanol washing, merging filtrate and washing
Liquid, concentrating under reduced pressure, residue pale yellow oil adds toluene and water, stirs 30min, stratification, separate toluene layer, decompression
Concentrate, residue toluene-normal hexane recrystallization, obtain 4-(3-fluorine benzyloxy) benzaldehyde；
2. prepared by (S)-2-[4-(3-fluorine benzyloxy) benzamido group] propionic acid amide.:
By (S)-2-aminopropanoate hydrochlorate 15.4g, 4-(3-fluorine benzyloxy) benzaldehyde 22.9g and triethylamine
11.2g joins in 200ml absolute methanol, addsMolecular sieve 20.0g, is stirred at room temperature 1.2h, filters, and adds in filtrate
10%Pd/C2.4g, is passed through hydrogen, in 35 DEG C of synthesis under normal pressure 5h, filters, and filter cake methanol washs, and merging filtrate and washing liquid subtract
Pressure is evaporated off solvent, residue re crystallization from toluene, obtains (S)-2-[4-(3-fluorine benzyloxy) benzamido group] propionic acid amide. and prepares；
3. prepared by FCE-26743A mesylate:
(S)-2-[4-(3-fluorine benzyloxy) benzamido group] propionic acid amide. 24.1g is joined in ethyl acetate 550ml, in 55 DEG C
Dropping methanesulfonic acid 8.8g, is stirred at room temperature 1h, filters, and filter cake ethyl acetate is washed, dried white solid FCE-26743A first
Sulfonate.
FCE-26743A of the present invention to prepare reaction condition gentle, yield is higher, and this synthesis mode has easy and simple to handle, locates afterwards
Reason is simple, the features such as cost is lower, environmentally friendly, it is possible to obtain high-quality target product, beneficially commercial production.
Detailed description of the invention
Embodiment 1
Prepared by 1.4-(3-fluorine benzyloxy) benzaldehyde (SFXA01):
By hydroxy benzaldehyde 15.2g (124.5mmol), potassium carbonate 17.2g (124.5mmol) and potassium iodide 2.0g
(12mmol) add in dehydrated alcohol 170ml, stir 15min, dropping 3-fluorobenzyl chloride 17.3ml (141.7mmol), be heated to reflux
Reaction 6h.Filtering, filter cake dehydrated alcohol (15ml × 3) washs, merging filtrate and washing liquid, and concentrating under reduced pressure remains faint yellow oil
Shape thing adds toluene 60ml and water 20ml, stirs 30min, stratification, separate toluene layer, concentrating under reduced pressure, residue first
Benzene-normal hexane (1 1) recrystallization, obtains white solid 4-(3-fluorine benzyloxy) benzaldehyde 26.1g (91%), mp 43.8～43.9
℃。
2. prepared by (S)-2-[4-(3-fluorine benzyloxy) benzamido group] propionic acid amide. (SFXA02):
By (S)-2-aminopropanoate hydrochlorate 15.4g (110mmol), 4-(3-fluorine benzyloxy) benzaldehyde (SFXA01)
22.9g (100mmol) and triethylamine 11.2g (111.5mmol) joins in 200ml absolute methanol, addsMolecular sieve
20.0g, is stirred at room temperature 1.2h, filters, and adds 10%Pd/C2.4g, be passed through hydrogen, in 35 DEG C of synthesis under normal pressure 5h, mistake in filtrate
Filter, filter cake methanol (20ml × 3) washs, and merging filtrate and washing liquid remove solvent, residue re crystallization from toluene under reduced pressure, obtain
White solid (S)-2-[4-(3-fluorine benzyloxy) benzamido group] propionic acid amide. (SFXA02) 26.5g, (87.7%), mp114.7～
115.5 DEG C, MS (m/z): 303 [M+H]+.
3. prepared by FCE-26743A mesylate (Safinamide Methanesulfonate):
(S)-2-[4-(3-fluorine benzyloxy) benzamido group] propionic acid amide. (SFXA02) 24.1g (79.7mmol) is joined acetic acid
In ethyl ester 550ml, in 55 DEG C of droppings methanesulfonic acid 8.8g (88.4mmol), 1h is stirred at room temperature, filters, filter cake ethyl acetate
(30ml × 3) wash, dried white solid FCE-26743A mesylate 30.1g (95%), mp217.3～218.1 DEG C pure
Degree 99.9%.The synthetic route of above-mentioned reaction is as follows:
Claims (1)
1. the preparation method of an industrialization FCE-26743A mesylate, it is characterised in that its scheme is as follows:
1. prepared by 4-(3-fluorine benzyloxy) benzaldehyde:
Hydroxy benzaldehyde 15.2g, potassium carbonate 17.2g and potassium iodide 2.0g are added in dehydrated alcohol 170ml, stir 15min,
Dropping 3-fluorobenzyl chloride 17.3ml, heating reflux reaction 6h, filter, filter cake absolute ethanol washing, merging filtrate and washing liquid, decompression
Concentrate, residue pale yellow oil adds toluene and water, stirs 30min, stratification, separate toluene layer, concentrating under reduced pressure, remain
Excess toluene-normal hexane recrystallization, obtains 4-(3-fluorine benzyloxy) benzaldehyde；
2. prepared by (S)-2-[4-(3-fluorine benzyloxy) benzamido group] propionic acid amide.:
(S)-2-aminopropanoate hydrochlorate 15.4g, 4-(3-fluorine benzyloxy) benzaldehyde 22.9g and triethylamine 11.2g is added
Enter in 200ml absolute methanol, addMolecular sieve 20.0g, is stirred at room temperature 1.2h, filters, and adds 10%Pd/ in filtrate
C2.4g, is passed through hydrogen, in 35 DEG C of synthesis under normal pressure 5h, filters, and filter cake methanol washs, and merging filtrate and washing liquid remove under reduced pressure molten
Agent, residue re crystallization from toluene, obtain (S)-2-[4-(3-fluorine benzyloxy) benzamido group] propionic acid amide. and prepare；
3. prepared by FCE-26743A mesylate:
(S)-2-[4-(3-fluorine benzyloxy) benzamido group] propionic acid amide. 24.1g is joined in ethyl acetate 550ml, in 55 DEG C of droppings
Methanesulfonic acid 8.8g, is stirred at room temperature 1h, filters, and filter cake ethyl acetate is washed, dried white solid FCE-26743A methanesulfonic acid
Salt.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610624596.1A CN106220525A (en) | 2016-07-31 | 2016-07-31 | A kind of preparation method of industrialization FCE-26743A mesylate |
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| CN201610624596.1A CN106220525A (en) | 2016-07-31 | 2016-07-31 | A kind of preparation method of industrialization FCE-26743A mesylate |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111689871A (en) * | 2019-03-14 | 2020-09-22 | 北京万全德众医药生物技术有限公司 | Synthetic preparation of safinamide mesylate |
| US11225457B2 (en) | 2019-08-06 | 2022-01-18 | Medichem, S.A. | Process for preparing safinamide |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101472880A (en) * | 2006-06-19 | 2009-07-01 | 纽朗制药有限公司 | Process for the production of 2-[4-(3- and 2-fluorobenzyloxy) benzylamino] propanamides |
| CN105061245A (en) * | 2015-08-25 | 2015-11-18 | 成都维恒医药科技有限公司 | High-purity Safinamide preparing method |
-
2016
- 2016-07-31 CN CN201610624596.1A patent/CN106220525A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101472880A (en) * | 2006-06-19 | 2009-07-01 | 纽朗制药有限公司 | Process for the production of 2-[4-(3- and 2-fluorobenzyloxy) benzylamino] propanamides |
| CN105061245A (en) * | 2015-08-25 | 2015-11-18 | 成都维恒医药科技有限公司 | High-purity Safinamide preparing method |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111689871A (en) * | 2019-03-14 | 2020-09-22 | 北京万全德众医药生物技术有限公司 | Synthetic preparation of safinamide mesylate |
| US11225457B2 (en) | 2019-08-06 | 2022-01-18 | Medichem, S.A. | Process for preparing safinamide |
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