CN108129414B - Preparation method of mosapride citrate intermediate - Google Patents
Preparation method of mosapride citrate intermediate Download PDFInfo
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- CN108129414B CN108129414B CN201810133973.0A CN201810133973A CN108129414B CN 108129414 B CN108129414 B CN 108129414B CN 201810133973 A CN201810133973 A CN 201810133973A CN 108129414 B CN108129414 B CN 108129414B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- YPELFRMCRYSPKZ-UHFFFAOYSA-N 4-amino-5-chloro-2-ethoxy-N-({4-[(4-fluorophenyl)methyl]morpholin-2-yl}methyl)benzamide Chemical compound CCOC1=CC(N)=C(Cl)C=C1C(=O)NCC1OCCN(CC=2C=CC(F)=CC=2)C1 YPELFRMCRYSPKZ-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 229960004085 mosapride Drugs 0.000 title claims abstract description 16
- VDUIPQNXOQMTBF-UHFFFAOYSA-N n-ethylhydroxylamine Chemical compound CCNO VDUIPQNXOQMTBF-UHFFFAOYSA-N 0.000 claims abstract description 18
- NAYYNDKKHOIIOD-UHFFFAOYSA-N phthalamide Chemical compound NC(=O)C1=CC=CC=C1C(N)=O NAYYNDKKHOIIOD-UHFFFAOYSA-N 0.000 claims abstract description 18
- KBRVYEPWGIQEOF-UHFFFAOYSA-N 2-(3-chloro-2-hydroxypropyl)isoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(CC(CCl)O)C(=O)C2=C1 KBRVYEPWGIQEOF-UHFFFAOYSA-N 0.000 claims abstract description 12
- QEZDCTNHTRSNMD-UHFFFAOYSA-N 1,2-dichloropropan-2-ol Chemical compound CC(O)(Cl)CCl QEZDCTNHTRSNMD-UHFFFAOYSA-N 0.000 claims abstract description 11
- BYXYCUABYHCYLY-UHFFFAOYSA-N isoindole-1,3-dione;potassium Chemical compound [K].C1=CC=C2C(=O)NC(=O)C2=C1 BYXYCUABYHCYLY-UHFFFAOYSA-N 0.000 claims abstract description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 43
- 238000006243 chemical reaction Methods 0.000 claims description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- 238000010438 heat treatment Methods 0.000 claims description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 235000019441 ethanol Nutrition 0.000 claims description 12
- 238000000967 suction filtration Methods 0.000 claims description 12
- 238000005406 washing Methods 0.000 claims description 12
- 238000001704 evaporation Methods 0.000 claims description 11
- 238000010992 reflux Methods 0.000 claims description 11
- 238000001035 drying Methods 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 239000000463 material Substances 0.000 claims description 9
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 9
- 238000001816 cooling Methods 0.000 claims description 8
- 239000007788 liquid Substances 0.000 claims description 8
- 239000000706 filtrate Substances 0.000 claims description 7
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 6
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 238000004321 preservation Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 9
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 description 66
- KWEPMOQQKUYWIN-UHFFFAOYSA-N 2-[(4-fluorophenyl)methylamino]ethanol Chemical compound OCCNCC1=CC=C(F)C=C1 KWEPMOQQKUYWIN-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- JHSPPBBJOLKJDH-UHFFFAOYSA-N [4-[(4-fluorophenyl)methyl]morpholin-2-yl]methanamine Chemical compound C1COC(CN)CN1CC1=CC=C(F)C=C1 JHSPPBBJOLKJDH-UHFFFAOYSA-N 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- DUILGEYLVHGSEE-UHFFFAOYSA-N 2-(oxiran-2-ylmethyl)isoindole-1,3-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1CC1CO1 DUILGEYLVHGSEE-UHFFFAOYSA-N 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 3
- NXSHODVXBOPCHO-UHFFFAOYSA-N benzene-1,2-dicarboxamide;potassium Chemical compound [K].NC(=O)C1=CC=CC=C1C(N)=O NXSHODVXBOPCHO-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 230000003472 neutralizing effect Effects 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- UOQXIWFBQSVDPP-UHFFFAOYSA-N 4-fluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1 UOQXIWFBQSVDPP-UHFFFAOYSA-N 0.000 description 2
- 238000003763 carbonization Methods 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 150000002466 imines Chemical class 0.000 description 2
- 210000001153 interneuron Anatomy 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 238000003746 solid phase reaction Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 108091005482 5-HT4 receptors Proteins 0.000 description 1
- 102000015554 Dopamine receptor Human genes 0.000 description 1
- 108050004812 Dopamine receptor Proteins 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 230000030135 gastric motility Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of mosapride citrate intermediate IV4- (4-fluorobenzyl) -2-aminomethyl morpholine, which comprises the following steps: the potassium phthalimide salt reacts with dichloroisopropanol to generate an intermediate II N- (2-hydroxy-3-chloropropyl) phthalimide, then the intermediate II N- (2-hydroxy-3-chloropropyl) phthalimide is condensed with an intermediate I2- (4-fluorobenzylamino) ethanol to prepare an intermediate III N-3- [ 4-fluorobenzyl-2- (hydroxy-ethylamine) -2-hydroxyisopropyl ] phthalic diamide, and the intermediate III is cyclized and hydrolyzed to obtain an intermediate IV4- (4-fluorobenzyl) -2-aminomethyl morpholine. The invention has short route and reduced production cost, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly provides a preparation method of an intermediate 4- (4-fluorobenzyl) -2-aminomethyl morpholine of mosapride citrate.
Background
With the acceleration of the pace of social life, the improvement of the living standard of people, the change of dietary structure and other factors, the number of people suffering from the hypogastric motility is increasing, and the living quality of people is greatly influenced. And the mosapride citrate is a selective 5-hydroxytryptamine 4(5-HT4) receptor agonist, and promotes the release of acetylcholine by exciting 5-HT4 receptors of choline interneurons and interneurons of gastrointestinal tracts, thereby enhancing gastrointestinal tract movement, improving gastrointestinal tract symptoms of patients with functional dyspepsia, and not affecting the secretion of gastric acid. Mosapride citrate as a gastric motility drug without dopamine receptor antagonism has the advantages of strong receptor selectivity, good pharmacokinetics, small dosage, safety, high efficiency and the like. Because the Chinese medicinal composition has good clinical curative effect and low side effect, the Chinese medicinal composition is widely applied at home and abroad, and provides selection and help for relieving pains and recovering health of patients.
The existing production and preparation process of mosapride citrate is complex, intermediates in each step influence the quality of a final product, and particularly, the Intermediate (IV)4- (4-fluorobenzyl) -2-aminomethyl morpholine has the following structure:
the intermediate IV has low purity, poor stability and poor color, is a dark brown oily liquid and has decisive influence on the quality of the final mosapride citrate product. Meanwhile, the intermediate IV is used as a key intermediate for preparing the mosapride citrate, the preparation is complex, the yield is very low, the cost of the intermediate IV accounts for a large part of the whole production cost of the mosapride citrate, and the market competitiveness of the mosapride citrate is determined by the high cost of the intermediate IV. Secondly, the preparation of the intermediate IV has higher requirements on production equipment, the solid-phase reaction is basically reported in documents, and the incomplete yield reduction of material reaction and excessive impurities in local carbonization are easily caused by nonuniform conduction heating, so that the product quality and yield are sharply reduced by amplifying production after the production reaches a certain scale.
Disclosure of Invention
In order to solve the problems of low purity, high cost and great production difficulty of the mosapride citrate, the invention provides a novel preparation method of an important intermediate 4- (4-fluorobenzyl) -2-aminomethyl morpholine of the mosapride citrate.
The technical scheme of the invention comprises the following contents:
a method for preparing mosapride citrate intermediate IV4- (4-fluorobenzyl) -2-aminomethyl morpholine comprises the following steps:
taking an intermediate I2- (4-fluorobenzylamino) ethanol and an intermediate II N- (2-hydroxy-3-chloropropyl) phthalimide as raw materials, preparing an intermediate III N-3- [ 4-fluorobenzyl-2- (hydroxy-ethylamine) -2-hydroxyisopropyl ] phthalic diamide through a condensation reaction, and cyclizing and hydrolyzing the intermediate III to obtain an intermediate IV4- (4-fluorobenzyl) -2-aminomethyl morpholine; the synthetic route is as follows:
specifically, the preparation method of the mosapride citrate intermediate IV comprises the following steps:
(1) preparation of intermediate III N-3- [ 4-fluorobenzyl-2- (hydroxy-ethylamine) -2-hydroxyisopropyl ] phthalamide:
adding potassium phthalimide salt and absolute ethyl alcohol into a reaction kettle, heating to 60-70 ℃, stirring for dissolving, adding dichloroisopropanol and triethylamine after the materials are dissolved, heating, carrying out reflux reaction for 6 hours to generate an intermediate II N- (2-hydroxy-3-chloropropyl) phthalimide; cooling to 50-60 ℃, dropwise adding an ethanol solution of the intermediate I2- (4-fluorobenzylamino) ethanol, reacting for 3 hours under heat preservation, evaporating the ethanol under reduced pressure, adding ethyl acetate for dissolving, performing suction filtration, washing the filtrate with water, performing salt washing, separating liquid, drying with anhydrous magnesium sulfate, performing suction filtration, and evaporating under reduced pressure to obtain a light yellow oily intermediate III;
(2) preparation of intermediate IV4- (4-fluorobenzyl) -2-aminomethyl morpholine:
heating the intermediate III to 90-100 ℃, dropwise adding concentrated sulfuric acid, reacting at the temperature of 110-.
Preferably, the molar ratio of the phthalimide potassium salt to the dichloroisopropanol in the step (1) is: 1:1.2-1.5.
Preferably, the molar ratio of the potassium phthalimide salt to the intermediate I in the step (1) is as follows: 1:1-1.2.
Preferably, the molar ratio of the potassium phthalimide salt to the triethylamine in the step (1) is as follows: 1:1.2-1.5.
Preferably, the molar ratio of the intermediate III to the concentrated sulfuric acid in the step (2) is 1: 5-6.
The preparation method of the intermediate I comprises the following steps:
methanol is taken as a solvent, p-fluorobenzaldehyde is taken as a raw material, nucleophilic addition is carried out on 2-aminoethanol, the addition product loses water to obtain imine, and the imine is NaBH4Reducing and post-treating to obtain an intermediate I.
The synthetic route is as follows:
the beneficial effects of the invention are as follows:
(1) the invention prepares a new compound intermediate (II) N- (2-hydroxy-3-chloropropyl) phthalimide by the reaction of potassium phthalamide and dichloroisopropanol, and the new compound intermediate reacts with the intermediate I to prepare an intermediate IV; the method reported in the literature takes phthalimide as a starting material, the phthalimide reacts with epichlorohydrin to obtain N- (2, 3-epoxypropyl) phthalimide after potassium salt is prepared, the N- (2, 3-epoxypropyl) phthalimide reacts with an intermediate I to prepare an intermediate IV, compared with the method in the literature, the starting material is changed into phthalic diamide potassium salt and dichloroisopropanol, the method is shortened, the phthalic diamide potassium salt is directly taken as the starting material, and the production cost is greatly reduced.
(2) The invention obtains a compound intermediate (III) N-3- [ 4-fluorobenzyl-2- (hydroxy-ethylamine) -2-hydroxyisopropyl ] phthalic diamide by the condensation reaction of an intermediate (I) 2- (4-fluorobenzylamino) ethanol and an intermediate (II) N- (2-hydroxy-3-chloropropyl) phthalimide, directly reacts with the intermediate (I) 2- (4-fluorobenzylamino) ethanol without separation in the preparation process of the intermediate (II) N- (2-hydroxy-3-chloropropyl) phthalimide, and then the intermediate (III) N-3- [ 4-fluorobenzyl-2- (hydroxy-ethylamine) -2-hydroxyisopropyl ] phthalic diamide is obtained after separation and purification, the reaction with concentrated sulfuric acid to obtain a light yellow oily Intermediate (IV)4- (4-fluorobenzyl) -2-aminomethyl morpholine, compared with literature reports, the operation is simplified, and the new compound intermediate (III) N-3- [ 4-fluorobenzyl-2- (hydroxy-ethylamine) -2-hydroxyisopropyl ] phthalic diamide with high purity is obtained by separation and purification, so that the purity of the Intermediate (IV)4- (4-fluorobenzyl) -2-aminomethyl morpholine is greatly improved and reaches over 99.6%.
(3) The Intermediate (IV)4- (4-fluorobenzyl) -2-aminomethyl morpholine is obtained by reacting the intermediate (III) N-3- [ 4-fluorobenzyl-2- (hydroxy-ethylamine) -2-hydroxyisopropyl ] phthalic acid diamide with concentrated sulfuric acid, and the reaction is a homogeneous reaction, and has the advantages of mild conditions, uniform material mixing, sufficient reaction, less product impurities and high yield. The Intermediate (IV)4- (4-fluorobenzyl) -2-aminomethyl morpholine prepared by the literature is a solid-phase reaction, the materials are not uniformly mixed, impurities appear in local carbonization, and the yield and purity can be greatly reduced along with the expansion of the production scale, so that the method is not suitable for industrial production.
Detailed Description
The advantageous effects of the present invention will now be further described by the following examples, which are for illustrative purposes only and do not limit the scope of the present invention, and variations and modifications apparent to those of ordinary skill in the art according to the present invention are also included in the scope of the present invention.
Example 1
Preparation of intermediate N-3- [ 4-fluorobenzyl-2- (hydroxy-ethylamine) -2-hydroxyisopropyl ] phthalamide:
adding phthalimide potassium salt (33.4g, 0.18mol) and 166ml of absolute ethyl alcohol into a 500ml four-necked bottle, heating to 60-70 ℃, stirring for dissolving, adding 0.216mol of dichloroisopropanol and 0.216mol of triethylamine after dissolving the materials, heating for reflux reaction for 6 hours to generate an intermediate N- (2-hydroxy-3-chloropropyl) phthalimide, cooling to 50-60 ℃, dropwise adding an ethanol solution of the intermediate (30.5g, 0.18mol)2- (4-fluorobenzylamino) ethanol, keeping the temperature for reaction for 3 hours, evaporating the ethanol under reduced pressure, adding ethyl acetate for dissolving, carrying out suction filtration, washing the filtrate with water, carrying out salt washing, carrying out liquid separation, drying the anhydrous magnesium sulfate, carrying out suction filtration, and obtaining a light yellow oily substance which is the intermediate N-3- [ 4-fluorobenzyl-2- (hydroxy-ethylamine) -2-hydroxyisopropyl ] phthalic diamide (yield is 84.9%, purity 99.9%).
Example 2
Preparation of intermediate N-3- [ 4-fluorobenzyl-2- (hydroxy-ethylamine) -2-hydroxyisopropyl ] phthalamide:
adding phthalimide potassium salt (33.4g, 0.18mol) and 166ml of absolute ethyl alcohol into a 500ml four-necked bottle, heating to 60-70 ℃, stirring for dissolving, adding 0.27mol of dichloroisopropanol and 0.27mol of triethylamine after dissolving the materials, heating for reflux reaction for 6 hours to generate an intermediate N- (2-hydroxy-3-chloropropyl) phthalimide, cooling to 50-60 ℃, dropwise adding an ethanol solution of 0.216mol of 2- (4-fluorobenzylamino) ethanol of the intermediate, keeping the temperature for reaction for 3 hours, evaporating the ethanol under reduced pressure, adding ethyl acetate for dissolving, performing suction filtration, washing the filtrate with water, performing salt washing, separating, drying the anhydrous magnesium sulfate, performing suction filtration, and evaporating under reduced pressure to obtain a light yellow oily intermediate N-3- [ 4-fluorobenzyl-2- (hydroxy-ethylamine) -2-hydroxyisopropyl ] phthalic diamide (yield is 83.6 percent), purity 99.7%).
Example 3
Preparation of intermediate N-3- [ 4-fluorobenzyl-2- (hydroxy-ethylamine) -2-hydroxyisopropyl ] phthalamide:
adding phthalimide potassium salt (33.4g, 0.18mol) and 166ml of absolute ethyl alcohol into a 500ml four-necked bottle, heating to 60-70 ℃, stirring for dissolving, adding 0.3mol of dichloroisopropanol and 0.216mol of triethylamine after dissolving the materials, heating for reflux reaction for 6 hours to generate an intermediate N- (2-hydroxy-3-chloropropyl) phthalimide, cooling to 50-60 ℃, dropwise adding an ethanol solution of the intermediate (30.5g, 0.18mol)2- (4-fluorobenzylamino) ethanol, keeping the temperature for reaction for 3 hours, evaporating the ethanol under reduced pressure, adding ethyl acetate for dissolving, carrying out suction filtration, washing the filtrate with water, carrying out salt washing, carrying out liquid separation, drying the anhydrous magnesium sulfate, carrying out suction filtration, and evaporating under reduced pressure to obtain a light yellow oily intermediate N-3- [ 4-fluorobenzyl-2- (hydroxy-ethylamine) -2-hydroxyisopropyl ] phthalic diamide (yield is 78.7%, purity 98.6%).
Example 4
Preparation of intermediate N-3- [ 4-fluorobenzyl-2- (hydroxy-ethylamine) -2-hydroxyisopropyl ] phthalamide:
adding phthalimide potassium salt (33.4g, 0.18mol) and 166ml of absolute ethyl alcohol into a 500ml four-necked bottle, heating to 60-70 ℃, stirring for dissolving, adding 0.216mol of dichloroisopropanol and 0.3mol of triethylamine after dissolving the materials, heating for reflux reaction for 6 hours to generate an intermediate N- (2-hydroxy-3-chloropropyl) phthalimide, cooling to 50-60 ℃, dropwise adding an ethanol solution of the intermediate (30.5g, 0.18mol)2- (4-fluorobenzylamino) ethanol, keeping the temperature for reaction for 3 hours, evaporating the ethanol under reduced pressure, adding ethyl acetate for dissolving, carrying out suction filtration, washing the filtrate with water, carrying out salt washing, carrying out liquid separation, drying the anhydrous magnesium sulfate, carrying out suction filtration, and evaporating under reduced pressure to obtain a light yellow oily intermediate N-3- [ 4-fluorobenzyl-2- (hydroxy-ethylamine) -2-hydroxyisopropyl ] phthalic diamide (yield is 79.1%, purity 98.3%).
Example 5
Preparation of 4- (4-fluorobenzyl) -2-aminomethyl morpholine:
adding an intermediate N-3- [ 4-fluorobenzyl-2- (hydroxy-ethylamine) -2-hydroxyisopropyl ] phthalic diamide (55.8g, 0.15mol) into a 250ml four-mouth bottle, heating to 90-100 ℃, slowly dropwise adding 0.75mol of concentrated sulfuric acid, controlling the temperature not to exceed 110 ℃, after the temperature is controlled to be 110 ℃ and 120 ℃ and the reaction is carried out for 2h, then heating to 140 ℃ and 150 ℃ and carrying out the reaction for 3h, stirring in cold water for 2h, then neutralizing with a sodium hydroxide solution, extracting with chloroform, drying the organic phase, and concentrating to dryness to obtain a light yellow oily Intermediate (IV), namely 4- (4-fluorobenzyl) -2-aminomethyl morpholine (30.0g, the yield is 89.3%, and the purity is 99.0%).
Example 6
Preparation of 4- (4-fluorobenzyl) -2-aminomethyl morpholine:
adding an intermediate N-3- [ 4-fluorobenzyl-2- (hydroxy-ethylamine) -2-hydroxyisopropyl ] phthalic diamide (55.8g, 0.15mol) into a 250ml four-mouth bottle, heating to 90-100 ℃, slowly dropwise adding 0.9mol of concentrated sulfuric acid, controlling the temperature not to exceed 110 ℃, after the temperature is controlled to be 110 ℃ and 120 ℃ and the reaction is carried out for 2h, then heating to 140 ℃ and 150 ℃ and carrying out the reaction for 3h, stirring in cold water for 2h, then neutralizing with a sodium hydroxide solution, extracting with chloroform, drying the organic phase, and concentrating to dryness to obtain a light yellow oily Intermediate (IV), namely 4- (4-fluorobenzyl) -2-aminomethyl morpholine (29.5g, the yield is 87.8%, and the purity is 98.7%).
Example 7
Preparation of 2- (4-fluorobenzylamino) ethanol:
adding p-fluorobenzaldehyde (24.8g, 0.2mol) and 2-aminoethanol (15.3g, 0.25mol) into a reaction bottle containing methanol (250ml), heating and refluxing, keeping the temperature at 65 ℃ for reaction for 4h, cooling, adding sodium borohydride (9.2g, 0.24mol), stirring for reaction, filtering after the reaction is finished, concentrating, and collecting fractions to obtain colorless oily liquid 2- (4-fluorobenzylamino) ethanol (30.5g, yield 90.2%, purity 98.7%).
Example 8
Preparation of N- (2, 3-epoxypropyl) phthalimide:
adding 0.18mol of phthalimide potassium salt and 68ml of epichlorohydrin into a reaction bottle, heating the mixture to 110-120 ℃ for feed liquid reflux, refluxing for 5h, distilling the epichlorohydrin under reduced pressure after the reflux is finished, adding 136ml of absolute ethyl alcohol after the distillation is finished, refluxing and dissolving for 30min, filtering, crystallizing, and drying to obtain the N- (2, 3-epoxypropyl) phthalimide (26.92g, the yield is 72.11 percent, and the purity is 85.3 percent).
Preparation of 4- (4-fluorobenzyl) -2-aminomethyl morpholine:
adding 2- (4-fluorobenzylamino) ethanol (28.7g and 0.17mol) and N- (2, 3-epoxypropyl) phthalimide (35.0g and 0.13mol) into a reaction kettle, heating to 70-80 ℃, preserving heat for reaction for 3 hours, then dropwise adding concentrated sulfuric acid at the temperature of 70-90 ℃, preserving heat for reaction for 2.5 hours at the temperature of 145 ℃, transferring the mixture into cold water, cooling to about 0 ℃, crystallizing, filtering to obtain phthalic acid, neutralizing the filtrate with sodium hydroxide, extracting with chloroform, drying an organic phase, concentrating the chloroform, and concentrating to dryness to obtain a light yellow oily substance 4- (4-fluorobenzyl) -2-aminomethyl morpholine (25.35g, yield 75.1%, purity 80.2%).
Claims (1)
1. A preparation method of mosapride citrate intermediate IV4- (4-fluorobenzyl) -2-aminomethyl morpholine is characterized by comprising the following steps:
(1) preparation of intermediate III N-3- [ 4-fluorobenzyl-2- (hydroxy-ethylamine) -2-hydroxyisopropyl ] phthalamide:
adding potassium phthalimide salt and absolute ethyl alcohol into a reaction kettle, heating to 60-70 ℃, stirring for dissolving, adding dichloroisopropanol and triethylamine after the materials are dissolved, heating, carrying out reflux reaction for 6 hours to generate an intermediate II N- (2-hydroxy-3-chloropropyl) phthalimide; cooling to 50-60 ℃, dropwise adding an ethanol solution of the intermediate I2- (4-fluorobenzylamino) ethanol, reacting for 3 hours under heat preservation, evaporating the ethanol under reduced pressure, adding ethyl acetate for dissolving, performing suction filtration, washing the filtrate with water, performing salt washing, separating liquid, drying with anhydrous magnesium sulfate, performing suction filtration, and evaporating under reduced pressure to obtain a light yellow oily intermediate III;
(2) preparation of intermediate IV4- (4-fluorobenzyl) -2-aminomethyl morpholine:
heating the intermediate III to 90-100 ℃, dropwise adding concentrated sulfuric acid, reacting at the temperature of 110-;
the molar ratio of the phthalimide potassium salt to the dichloroisopropanol in the step (1) is as follows: 1:1.2 or 1: 1.5; the molar ratio of the phthalimide potassium salt to the intermediate I is as follows: 1:1 or 1.2; the molar ratio of the phthalimide potassium salt to the triethylamine is as follows: 1:1.2 or 1: 1.5;
the molar ratio of the intermediate III to the concentrated sulfuric acid in the step (2) is 1:5 or 1: 6.
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| 枸橼酸莫沙必利的合成;郑琦宏等;《宁波大学学报（理工版）》;20020630;第15卷(第2期);第20-22页 * |
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