CN108341788A - A kind of mosapride citrate intermediate and purposes - Google Patents
A kind of mosapride citrate intermediate and purposes Download PDFInfo
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- CN108341788A CN108341788A CN201810133972.6A CN201810133972A CN108341788A CN 108341788 A CN108341788 A CN 108341788A CN 201810133972 A CN201810133972 A CN 201810133972A CN 108341788 A CN108341788 A CN 108341788A
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- luorobenzyls
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- ethyl alcohol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
Abstract
The invention belongs to medical chemistries to synthesize field, provide a kind of IV 4 (4 luorobenzyl) 2 aminomethyl alkylbenzyldimethylasaltsum saltsum of mosapride citrate intermediate and the preparation method of mosapride citrate.With 2 (4 fluorobenzene methylamino) ethyl alcohol and N (2,3 glycidyl) phthalimide for raw material, logical peracid treatment obtains 2 aminomethyl alkylbenzyldimethylasaltsum saltsum of intermediate IV 4 (4 luorobenzyl).Then using intermediate IV and V 2 ethyoxyl of intermediate, 4 acetylamino, 5 chlorobenzoic acid ethyl ester compound as raw material, using dichloromethane as solvent, using EDCl and DMAP as catalyst, Mosapride salt is generated, then it is reacted with aqueous solution of citric acid, generates mosapride citrate.Product yield high of the present invention, raw material are easy to get, and production cost is low, are suitble to industrialized production.
Description
Technical field
The invention belongs to medical chemistries to synthesize field, and in particular to a kind of important centre of synthesis mosapride citrate
The preparation method of body 4- (4- luorobenzyls) -2- aminomethyls alkylbenzyldimethylasaltsum saltsums and mosapride citrate.
Background technology
Mosapride citrate is selective serotonin 4 (5-HT4) receptor stimulating agent, by excited gastrointestinal tract choline
Between 5-HT4 receptors neural between neuron and flesh, promote the release of acetylcholine, to enhance gastrointestinal movement, improve function
The gastrointestinal symptom of property indigestion patient, does not influence the secretion of hydrochloric acid in gastric juice.Mosapride citrate is as no dopamine receptor
The medicine for stomach dynamic of antagonism has many advantages, such as that receptor-selective is strong, pharmacokinetics is good, dosage is small, safe efficient.Due to it
Clinical efficacy is good, and side effect is low to be at home and abroad widely used, for patient's releasing is ailing, getting well provides selection
And help.
Existing mosapride citrate purity is less than 99.9%, and the height of purity is pure by synthesis technology and its intermediate
Degree determines.And mosapride citrate Material synthesis technique deficiency shows 4- (4- luorobenzyls) -2- aminomethyls first at present
The synthesis yield of quinoline (formula (I)) is relatively low, and purity is low, and stability is poor, shade deviation, is dark-brown oily liquids.
It being found through experiment, the purity of final finished mosapride citrate is mainly influenced by intermediate formula (I) purity, from
And affect the popularization and use of mosapride citrate.Except this, during synthesizing mosapride citrate, 2- ethyoxyls-
- NH in 4- acetylaminohydroxyphenylarsonic acid 5- chlorobenzoic acids (formula (II))2It is easy to citric acid and amidation process occurs, generates impurity (III), lead
The purity of final products is caused to decline.Therefore, it improves the purity of intermediate (I) and protects the-NH in intermediate (II)2It is to carry
The key point of high mosapride citrate quality.
By improving Mosapride salifying process in patent WO2011107903A1, make final products mosapride citrate
Purity >=99.9%.We operate in strict accordance with technique described in WO2011107903A1, and final products citric acid is not husky
Purity that must be sharp only has 97.32%.
Invention content
The present invention is to solve the problems, such as that mosapride citrate purity is low, provides a kind of the important of mosapride citrate
The new preparation method of intermediate 4- (4- luorobenzyls) -2- aminomethyls alkylbenzyldimethylasaltsum saltsums and mosapride citrate.
One aspect of the present invention provides a kind of mosapride citrate intermediate IV, and chemical name is：4- (4- luorobenzyls)-
2- aminomethyl alkylbenzyldimethylasaltsum saltsums, structure are as follows：
The invention also discloses the preparation methods of intermediate IV, include the following steps：
2- (4- fluorobenzene methylamino) ethyl alcohol and N- (2,3- glycidyl) phthalimide are added in reaction kettle,
It is heated to 70-80 DEG C, insulation reaction 3h, then 70-90 DEG C of addition concentrated sulfuric acid of temperature control, insulation reaction 2.5h at 125-145 DEG C turns
Into cold water, sodium hydroxide neutralizes, chloroform extraction, and dry organic phase concentrates chloroform, and raffinate is dissolved by heating with ethyl alcohol, and acid is added dropwise
It is stirred to react, cool down crystallization, and filtering obtains IV 4- of white solid intermediate (4- luorobenzyls) -2- aminomethyl alkylbenzyldimethylasaltsum saltsums.
Preferably, the molar ratio of 2- (4- fluorobenzene methylamino) ethyl alcohol and N- (2,3- glycidyl) phthalimide
For：1:0.5-0.8.
Preferably, the one kind of acid in hydrochloric acid, sulfuric acid, phosphoric acid, citric acid described in acid adding step is dripped, it is furthermore preferred that institute
It is hydrochloric acid to state acid.
Preferably, the molar ratio of 2- (4- fluorobenzene methylamino) ethyl alcohol and the concentrated sulfuric acid is 1:5-6.
Wherein, the preparation of 2- (4- fluorobenzene methylamino) ethyl alcohol includes the following steps：
Using methanol as solvent, using 4-Fluorobenzaldehyde as raw material, through 2- ethylaminoethanol nucleophilic additions, addition compound product dehydration obtains
Imines, imines is by NaBH4Reduction, it is then post-treated, obtain colorless oil 2- (4- fluorobenzene methylamino) ethyl alcohol；
Synthetic route is as follows：
The preparation of N- (2,3- glycidyl) phthalimide includes the following steps：
Phthalimide, absolute ethyl alcohol are added to fill potassium hydroxide and in the reaction kettle of alcohol mixeding liquid,
It is heated to reflux, cools down, filter, obtain white flaky solid, then itself and epoxychloropropane are added in reaction kettle, are heated to reflux,
Epoxychloropropane is evaporated off, adds ethyl alcohol, it is cooling, it filters, obtains white solid N- (2,3- glycidyl) phthalimide；
Synthetic route is as follows：
The present invention also provides the purposes that mosapride citrate is prepared using intermediate IV.And disclose it is a kind of utilize institute
The preparation method that intermediate IV prepares mosapride citrate is stated, i.e., by V 2- ethyoxyl -4- acetylaminohydroxyphenylarsonic acid 5- chlorobenzenes of intermediate
Ethyl formate, catalyst input fill in the reaction bulb of dichloromethane, and insulation reaction 1h is cooled to -10~-5 DEG C, and three second are added
Amine, drop finish, and intermediate IV 4- (4- luorobenzyls) -2- aminomethyl morpholine hydrochlorides are added, is stirred to react, handles to obtain white solid 4-
Acetamido -5- chloro-2-ethoxies-n- [[4- (4- luorobenzyls) -2- morpholinyls] methyl] benzamide, then with citron sour water
Solution reaction generates mosapride citrate.
Synthetic route is as follows：
Preferably, the molar ratio of intermediate IV and intermediate V is 1:0.5-0.7.
Preferably, catalyst is the combination of EDCl and DMAF；The molar ratio of wherein EDCl and DMAF is 1:1.
Preferably, it is 1 that the dosage of the catalyst, which is the molar ratio of intermediate IV and catalyst,:1.2-1.6.
V 2- ethyoxyl -4- acetylaminohydroxyphenylarsonic acid 5- chlorobenzoic acid ethyl ester structures of intermediate are as follows：
V preparation method of intermediate includes the following steps：
It uses sodium para-aminosalicylate for starting material, product is obtained through acetylation, double ethylizations, three step of chloro,
Synthetic route is：
Beneficial effects of the present invention are shown：
(1) present invention is prepared for IV 4- of intermediate (4- luorobenzyls) -2- aminomethyl alkylbenzyldimethylasaltsum saltsums, compared with intermediate I, property
Shape becomes white solid from original dark brown oil liquid, not only facilitates the synthesis of lower step intermediate but also IV 4- of intermediate
The purity of (4- luorobenzyls) -2- aminomethyl alkylbenzyldimethylasaltsum saltsums greatly improves, and improves the quality and yield of finished product mosapride citrate,
Finished product purity >=99.9%.
(2) citric acid Mo Shabi is prepared using V 2- ethyoxyl -4- acetylaminohydroxyphenylarsonic acid 5- chlorobenzoic acids ethyl esters of intermediate as raw material
Profit the, due to-NH of V compound of intermediate2It is protected, avoids III chemical combination of impurity in mosapride citrate preparation process
The generation of object, and its raw material is easy to get, and reduces production cost, improves the quality and yield of finished product.
Specific implementation mode
Beneficial effects of the present invention are now further described by following embodiment, embodiment is only used for the purpose of illustration,
It does not limit the scope of the invention, while the obvious change and modification that those of ordinary skill in the art are made according to the present invention
It is also contained within the scope of the invention.
The preparation of 1 2- of embodiment (4- fluorobenzene methylamino) ethyl alcohol:
4-Fluorobenzaldehyde (24.8g, 0.2mol), 2- ethylaminoethanols (15.25g, 0.25mol) addition are filled into methanol
It in the reaction bulb of (250ml), is heated to reflux, insulation reaction 4h at 65 DEG C, cools down, sodium borohydride (9.18g, 0.24mol) is added,
It is stirred to react, reaction finishes, and filters, and concentration collects fraction, obtains colourless oil liquid 2- (4- fluorobenzene methylamino) ethyl alcohol
(30.35g, yield 89.81%).
The preparation of embodiment 2N- (2,3- glycidyl) phthalimide：
Potassium hydroxide (11.76g, 0.21mol) is dissolved in the mixed solution of water and ethyl alcohol for use, phthalimide
(29.4g, 0.2mol), absolute ethyl alcohol (300ml) put into reaction bulb, and flow back dissolving at 75 DEG C, and dissolving finishes, clear liquid is poured into
It states in stock solution, is heated to reflux 20-30min, reflux temperature is not higher than 85 DEG C, and cooling generates chip solid, filters, washing,
Dry white flaky solid Mosapride sylvite (34.26g, 92.6%) reacts it with epoxychloropropane (68ml) input
It in bottle, is heated to reflux, temperature is not higher than 120 DEG C, and reflux terminates, and epoxychloropropane is evaporated off, and absolute ethyl alcohol (140ml) is added residual
In excess, reflux dissolving 20-30min is filtered, crystallization obtains white granular solid N- (2,3- glycidyl) phthalyl
Imines (36.03g, yield 68.54%).
The preparation of 3 intermediate IV of embodiment
The preparation of 4- (4- luorobenzyls) -2- aminomethyl morpholine sulfate：
By 2- (4- fluorobenzene methylamino) ethyl alcohol (28.7g, 0.17mol) and N- (2,3- glycidyl) phthalimide
(22.9g, 0.085mol) is added in reaction kettle, is heated to 70-80 DEG C, insulation reaction 3h, then 70-90 DEG C of dropwise addition of temperature control
The 0.85mol concentrated sulfuric acids, insulation reaction 2.5h at 125-145 DEG C, go in cold water, are cooled to 0 DEG C or so, crystallization, filtering obtains adjacent
Phthalic acid, filtrate are neutralized with sodium hydroxide, chloroform extraction, and dry organic phase concentrates chloroform, and raffinate is dissolved by heating with ethyl alcohol,
20% sulfuric acid solution is added dropwise, is stirred to react 2h, cool down crystallization, and filtering obtains white solid 4- (4- luorobenzyls) -2- aminomethyl morpholines
Sulfate (yield 89.88%, purity 98.83%).
The preparation of 4 intermediate IV of embodiment
The preparation of 4- (4- luorobenzyls) -2- aminomethyl morpholine hydrochlorides：
By 2- (4- fluorobenzene methylamino) ethyl alcohol (28.7g, 0.17mol) and N- (2,3- glycidyl) phthalimide
(36.6g, 0.136mol) is added in reaction kettle, is heated to 70-80 DEG C, insulation reaction 3h, then 70-90 DEG C of dropwise addition of temperature control
1.02mol the concentrated sulfuric acid, insulation reaction 2.5h at 125-145 DEG C, go in cold water, sodium hydroxide neutralizes, and chloroform extraction, drying has
Machine phase concentrates chloroform, and raffinate is dissolved by heating with ethyl alcohol, and 30% hydrochloric acid solution is added dropwise, and is stirred to react 1.5h, and cool down crystallization, filtering,
Obtain white solid 4- (4- luorobenzyls) -2- aminomethyls morpholine hydrochlorides (yield 92.70%, purity 99.14%).In embodiment 5
The preparation of mesosome IV
The phosphatic preparation of 4- (4- luorobenzyls) -2- aminomethyl morpholines：
By 2- (4- fluorobenzene methylamino) ethyl alcohol (28.7g, 0.17mol) and N- (2,3- glycidyl) phthalimide
(27.45g, 0.102mol) is added in reaction kettle, is heated to 70-80 DEG C, insulation reaction 3h, then 70-90 DEG C of dropwise addition of temperature control
The 1.02mol concentrated sulfuric acids, insulation reaction 2.5h at 125-145 DEG C, go in cold water, and sodium hydroxide neutralizes, and chloroform extraction, drying has
Machine phase concentrates chloroform, and raffinate is dissolved by heating with ethyl alcohol, and 40% phosphoric acid solution is added dropwise, and is stirred to react 1.5h, and cool down crystallization, filtering,
Obtain white solid 4- (4- luorobenzyls) -2- aminomethyl morpholines phosphate (yield 88.27%, purity 98.36%).In embodiment 6
The preparation of mesosome IV
The preparation of 4- (4- luorobenzyls) -2- aminomethyl morpholine Chinese holly edge hydrochlorates：
By 2- (4- fluorobenzene methylamino) ethyl alcohol (28.7g, 0.17mol) and N- (2,3- glycidyl) phthalimide
(32.30g, 0.12mol) is added in reaction kettle, is heated to 70-80 DEG C, insulation reaction 3h, then 70-90 DEG C of dropwise addition of temperature control
The 0.94mol concentrated sulfuric acids, insulation reaction 2.5h at 125-145 DEG C, go in cold water, and sodium hydroxide neutralizes, and chloroform extraction, drying has
Machine phase concentrates chloroform, and raffinate is dissolved by heating with ethyl alcohol, and 30% Chinese holly edge acid solution is added dropwise, and is stirred to react 1.5h, and cool down crystallization, mistake
Filter, obtains white solid 4- (4- luorobenzyls) -2- aminomethyl morpholine Chinese holly edge hydrochlorates (yield 88.53%, purity 98.66%).
The preparation of 7 intermediate of embodiment, V 2- ethyoxyl -4- acetylaminohydroxyphenylarsonic acid 5- chlorobenzoic acid ethyl esters
Step 1：The salicylic preparation of acetparaminosalol：
Sodium para-aminosalicylate (17.5g, 0.1mol) is soluble in water, addition acetic anhydride (10.24g, 0.1mol), 45 DEG C
Lower reaction 4 hours adjusts pH to acidity, off-white powder is precipitated, filtering obtains intermediate acetparaminosalol salicylic acid after having reacted
(16.39g, yield 84.12%).
Step 2：The preparation of 2- ethyoxyl -4- acetaminobenzoic acid ethyl esters：
By acetparaminosalol salicylic acid (16.0g, 0.082mol), DMF (50ml), potassium carbonate (22.67g, 0.164mol)
It is added in reaction bulb with bromoethane (21.73g, 0.205mol), reaction 4 hours is stirred at room temperature, has reacted and reaction solution is poured into ice
Stirring and crystallizing in water filters, and washs, dry, and obtaining white solid 2- ethyoxyl -4- acetaminobenzoic acids ethyl ester, (18.61g is received
Rate 90.41%).
Step 3：The preparation of 2- ethyoxyl -4- acetylaminohydroxyphenylarsonic acid 5- chlorobenzoic acid ethyl esters：
By 2- ethyoxyl -4- acetaminobenzoic acids ethyl esters (18.0g, 0.072mol), DMF (60ml), NCS (12.24g,
Reaction bulb 0.092mol) is put into, heating stirring is reacted, and insulation reaction 3h at 80 DEG C has reacted and poured into reaction solution
Stirring and crystallizing in ice water filters, and washs, dry, obtains white solid 2- ethyoxyl -4- acetylaminohydroxyphenylarsonic acid 5- chlorobenzoic acid ethyl esters
(19.00g, yield 91.23%).
8 4- acetamido -5- chloro-2-ethoxies-n- of embodiment [[4- (4- luorobenzyls) -2- morpholinyls] methyl] benzene first
The preparation of amide：
By intermediate (V) 2- ethyoxyl -4- acetylaminohydroxyphenylarsonic acid 5- chlorobenzoic acids ethyl esters (12.9g, 0.045mol), EDCl
(10.35g, 0.054mol), DMAF (6.60g, 0.054mol) are put into the reaction bulb for filling dichloromethane 250ml, and heat preservation is anti-
1h is answered, is cooled to -10~-5 DEG C, triethylamine (0.09mol) is added, drop finishes, and intermediate (IV) 4- (4- luorobenzyls) -2- ammonia is added
Methyl morpholine sulfate (28.85g, 0.09mol), is stirred to react, and mixture is gone in purified water, cooling, and crystallization filters, and does
It is dry, obtain white solid 4- acetamido -5- chloro-2-ethoxies-n- [[4- (4- luorobenzyls) -2- morpholinyls] methyl] benzamide
(yield 84.63%, purity 99.57%).
9 4- acetamido -5- chloro-2-ethoxies-n- of embodiment [[4- (4- luorobenzyls) -2- morpholinyls] methyl] benzene first
The preparation of amide：
By intermediate (V) 2- ethyoxyl -4- acetylaminohydroxyphenylarsonic acid 5- chlorobenzoic acids ethyl esters (18.0g, 0.063mol), EDCl
(13.80g, 0.072mol), DMAF (8.80g, 0.072mol) are put into the reaction bulb for filling dichloromethane 250ml, and heat preservation is anti-
1h is answered, is cooled to -10~-5 DEG C, triethylamine (0.09mol) is added, drop finishes, and intermediate (IV) 4- (4- luorobenzyls) -2- ammonia is added
Methyl morpholine hydrochloride (23.41g 0.09mol), is stirred to react, and mixture is gone in purified water, cooling, and crystallization filters, and does
It is dry, obtain white solid 4- acetamido -5- chloro-2-ethoxies-n- [[4- (4- luorobenzyls) -2- morpholinyls] methyl] benzamide
(yield 85.49%, purity 99.66%).
10 4- acetamido -5- chloro-2-ethoxies-n- of embodiment [[4- (4- luorobenzyls) -2- morpholinyls] methyl] benzene first
The preparation of amide：
By intermediate (V) 2- ethyoxyl -4- acetylaminohydroxyphenylarsonic acid 5- chlorobenzoic acids ethyl esters (15.4g, 0.054mol), EDCl
(13.80g, 0.072mol), DMAF (8.80g, 0.072mol) are put into the reaction bulb for filling dichloromethane 250ml, and heat preservation is anti-
1h is answered, is cooled to -10~-5 DEG C, triethylamine (0.09mol) is added, drop finishes, and intermediate (IV) 4- (4- luorobenzyls) -2- ammonia is added
Methyl morpholine phosphate (28.76g, 0.09mol), is stirred to react, and mixture is gone in purified water, cooling, and crystallization filters, and does
It is dry, obtain white solid 4- acetamido -5- chloro-2-ethoxies-n- [[4- (4- luorobenzyls) -2- morpholinyls] methyl] benzamide
(yield 83.11%, purity 99.43%).
11 4- acetamido -5- chloro-2-ethoxies-n- of embodiment [[4- (4- luorobenzyls) -2- morpholinyls] methyl] benzene first
The preparation of amide：
By intermediate (V) 2- ethyoxyl -4- acetylaminohydroxyphenylarsonic acid 5- chlorobenzoic acids ethyl esters (18.0g, 0.063mol), EDCl
(13.80g, 0.072mol), DMAF (8.80g, 0.072mol) are put into the reaction bulb for filling dichloromethane 250ml, and heat preservation is anti-
1h is answered, is cooled to -10~-5 DEG C, triethylamine (0.09mol) is added, drop finishes, and intermediate (IV) 4- (4- luorobenzyls) -2- ammonia is added
Methyl morpholine Chinese holly edge hydrochlorate (37.24g, 0.09mol), is stirred to react, and mixture is gone in purified water, cooling, and crystallization filters,
It is dry, obtain white solid 4- acetamido -5- chloro-2-ethoxies-n- [[4- (4- luorobenzyls) -2- morpholinyls] methyl] benzoyl
Amine (yield 83.78%, purity 99.14%).
The preparation of 12 mosapride citrate of embodiment：
By 4- acetamido -5- chloro-2-ethoxies-n- [[4- (4- luorobenzyls) -2- morpholinyls] methyl] benzamide
(20.00g, 0.046mol) is put into the reaction bulb for filling methanol 200ml solvents, and dissolving is heated to reflux at 65 DEG C, and dissolving is complete,
50 DEG C are cooled to, aqueous solution of citric acid is added, insulation reaction 30-45min, after having reacted, cooling, crystallization filters, obtains citric acid
Mosapride (yield 88.7%, purity 99.93%).
The preparation of 1 intermediate IV of comparative example
The preparation of 4- (4- luorobenzyls) -2- aminomethyl morpholine tartrates：
By 2- (4- fluorobenzene methylamino) ethyl alcohol (28.7g, 0.17mol) and N- (2,3- glycidyl) phthalimide
(36.6g, 0.136mol) is added in reaction kettle, is heated to 70-80 DEG C, insulation reaction 3h, then 70-90 DEG C of dropwise addition of temperature control
The 1.02mol concentrated sulfuric acids, insulation reaction 2.5h at 125-145 DEG C, go in cold water, and sodium hydroxide neutralizes, and chloroform extraction, drying has
Machine phase concentrates chloroform, and raffinate is dissolved by heating with ethyl alcohol, and 30% tartaric acid solution is added dropwise, and is stirred to react 1.5h, and cool down crystallization, mistake
Filter, obtains white solid) 4- (4- luorobenzyls) -2- aminomethyl morpholines tartrate (yield 85.43%, purity 97.57%).
The preparation of 2 Chinese holly edge acid Mosapride of comparative example
Step (1)：The preparation of 4- (4- luorobenzyls) -2- aminomethyls morpholines (intermediate compound I)：
By 2- (4- fluorobenzene methylamino) ethyl alcohol (28.7g, 0.17mol) and N- (2,3- glycidyl) phthalimide
(35.0g, 0.13mol) is added in reaction kettle, is heated to 70-80 DEG C, insulation reaction 3h, and then 70-90 DEG C of dropwise addition of temperature control is dense
Sulfuric acid, insulation reaction 2.5h at 125-145 DEG C, goes in cold water, is cooled to 0 DEG C or so, and crystallization, filtering obtains phthalic acid,
Filtrate is neutralized with sodium hydroxide, chloroform extraction, and dry organic phase concentrates chloroform, is concentrated to dryness to obtain pale yellow oil 4- (4- fluorine
Benzyl) -2- aminomethyls morpholine (yield 75.1%, purity 80.2%).
Step (2)：4- acetamido -5- chloro-2-ethoxies-n- [[4- (4- luorobenzyls) -2- morpholinyls] methyl] benzene first
Amide
By 2- ethyoxyl -4- acetylaminohydroxyphenylarsonic acid 5- chlorobenzoic acids ethyl esters (18.0g, 0.063mol), EDCl (13.80g,
0.072mol), DMAF (8.80g, 0.072mol) is put into the reaction bulb for filling dichloromethane (250ml), insulation reaction 1h, drop
Warm to -10~-5 DEG C, triethylamine (0.09mol) is added, drop finishes, addition 4- (4- luorobenzyls) -2- aminomethyls morpholine (14.74g,
0.09mol), it is stirred to react, mixture is gone in purified water, cooling, and crystallization filters, dry, obtains white solid 4- acetamides
Base -5- chloro-2-ethoxies-n- [[4- (4- luorobenzyls) -2- morpholinyls] methyl] benzamide (yield 80.32%, purity
98.48%).
Step (3)：The preparation of mosapride citrate：
By 4- acetamido -5- chloro-2-ethoxies-n- [[4- (4- luorobenzyls) -2- morpholinyls] methyl] benzamide
(20.00g, 0.046mol) is put into the reaction bulb for filling methanol (200ml) solvent, and dissolving is heated to reflux at 65 DEG C, has been dissolved
Entirely, 50 DEG C are cooled to, aqueous solution of citric acid is added, insulation reaction 30-45min, after having reacted, cooling, crystallization filters, obtains Chinese holly
Rafter acid Mosapride (yield 80.31%, purity 99.59%).
The preparation of 3 Chinese holly edge acid Mosapride of comparative example
The preparation of step (1) solution A：
At room temperature, 100ml methanol, 10g Mosapride alkali are added in reaction bulb, are warming up to 65-67 DEG C, stirred to complete
Molten, complete molten rear addition 0.5g activated carbons stir 20min, filtering, with 20ml methanol detergent active charcoals, filtrate is cooled to 40 DEG C, obtains
Solution A.
The preparation of step (2) solution B：
At room temperature, 100ml purified waters, 6.0g citric acids are added in reaction bulb, stirring and dissolving, Quan Ronghou is filtered, obtained molten
Liquid B.
The preparation of step (3) mosapride citrate：
Solution A is added into reaction bulb, is warming up to 45 DEG C, solution B is added dropwise, drop finishes, and insulation reaction 30min is cooled to 5
DEG C, stirring and crystallizing, filtering, filter cake purifying water washing is dry, obtain white solid mosapride citrate (yield 83.56%,
Purity 97.32%).
Claims (10)
1. a kind of mosapride citrate intermediate IV, chemical name are：4- (4- luorobenzyls) -2- aminomethyl alkylbenzyldimethylasaltsum saltsums, structure
It is as follows：
2. the preparation method of intermediate IV described in a kind of claim 1, which is characterized in that include the following steps：
2- (4- fluorobenzene methylamino) ethyl alcohol and N- (2,3- glycidyl) phthalimide are added in reaction kettle, heated
To 70-80 DEG C, insulation reaction 3h, then 70-90 DEG C of the temperature control addition concentrated sulfuric acid, insulation reaction 2.5h at 125-145 DEG C is gone to cold
In water, sodium hydroxide neutralizes, chloroform extraction, and dry organic phase concentrates chloroform, and raffinate is dissolved by heating with ethyl alcohol, and acid stirring is added dropwise
Reaction, cool down crystallization, and filtering, it is IV 4- of intermediate (4- luorobenzyls) -2- aminomethyl alkylbenzyldimethylasaltsum saltsums to obtain white solid.
3. the preparation method of intermediate IV according to claim 2, which is characterized in that 2- (4- fluorobenzene methylamino) ethyl alcohol and
The molar ratio of N- (2,3- glycidyl) phthalimide is 1:0.5-0.8.
4. the preparation method of intermediate IV according to claim 2, which is characterized in that acid is selected from salt described in drop acid adding step
One kind in acid, sulfuric acid, phosphoric acid, citric acid, it is preferred that acid described in drop acid adding step is hydrochloric acid.
5. the preparation method of intermediate IV according to claim 2, which is characterized in that 2- (4- fluorobenzene methylamino) ethyl alcohol with
The molar ratio of the concentrated sulfuric acid is 1:5-6.
6. intermediate formula IV as described in claim 1 is used to prepare the purposes of mosapride citrate.
7. a kind of method preparing mosapride citrate, which is characterized in that by V 2- ethyoxyl -4- acetylaminohydroxyphenylarsonic acids of intermediate
5- chlorobenzoic acids ethyl ester, catalyst input fill in the reaction bulb of dichloromethane, and insulation reaction 1h is cooled to -10~-5 DEG C, adds
Enter triethylamine, drop finishes, and intermediate IV 4- (4- luorobenzyls) -2- aminomethyl morpholine hydrochlorides are added, is stirred to react, handles white
Solid 4- acetamido -5- chloro-2-ethoxies-n- [[4- (4- luorobenzyls) -2- morpholinyls] methyl] benzamide, then with Chinese holly
Rafter aqueous acid reacts, and generates mosapride citrate.
8. preparation method according to claim 7, which is characterized in that the molar ratio of intermediate IV and intermediate V is 1:
0.5-0.7。
9. preparation method according to claim 7, which is characterized in that the catalyst is the combination of EDCl and DMAF,
Wherein, the molar ratio of EDCl and DMAF is 1:1.
10. preparation method according to claim 9, which is characterized in that the dosage of the catalyst is intermediate IV and urges
The molar ratio of agent is 1:1.2-1.6.
Priority Applications (1)
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| CN111285820A (en) * | 2018-12-07 | 2020-06-16 | 成都康弘药业集团股份有限公司 | Mosapride citrate related substance and preparation method thereof |
| CN112209895A (en) * | 2020-10-16 | 2021-01-12 | 深圳市祥根生物科技有限公司 | Preparation method of mosapride citrate impurity |
| CN113801034A (en) * | 2020-06-15 | 2021-12-17 | 鲁南制药集团股份有限公司 | Mosapride impurity compound |
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