CN104961646B - Mosapride active metabolites, preparation method and uses thereof - Google Patents
Mosapride active metabolites, preparation method and uses thereof Download PDFInfo
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Abstract
The present invention belongs to the technical field of medicine, and provides mosapride active metabolites (R)-N-[2-hydroxy-3-(4-fluorobenzyl)amino]propyl-5-chloro-4-amino-2-ethoxy benzamide (levo isomer) and (S)-N-[2-hydroxy-3-(4-fluorobenzyl)amino]propyl-5-chloro-4-amino-2-ethoxy benzamide (dextro isomer), salts of the (R)-N-[2-hydroxy-3-(4-fluorobenzyl)amino]propyl-5-chloro-4-amino-2-ethoxy benzamide (levo isomer) and the (S)-N-[2-hydroxy-3-(4-fluorobenzyl)amino]propyl-5-chloro-4-amino-2-ethoxy benzamide (dextro isomer), a synthesis method of (R,S)-N-[2-hydroxy-3-(4-fluorobenzyl)amino]propyl-5-chloro-4-amino-2-ethoxy benzamide (racemate), and uses in gastrointestinal tract motility drug preparation. According to the present invention, the mouse small intestine charcoal powder propelling model is used to respectively investigate the gastrointestinal motility promoting effects of the levo isomer, the dextro isomer and the racemate, and the results show that under the same dose, the activity of the levo isomer is weak, the racemate and the dextro isomer have the significant gastrointestinal motility promoting effects, and the activity of the dextro isomer is significantly surprior to the activity of the racemate.
Description
Technical field
The invention belongs to pharmaceutical technology field, it is related to active metabolite of mosapride and its production and use, tool
Body be related to the active metabolite of mosapride and its pharmaceutically acceptable salt and the pharmaceutically useful compositionss containing them and
Preparation method, and their applications in preparing gastric motility medicine.
Background technology
Mosapride is new third generation medicine for stomach dynamic, is mainly used in treating esophageal reflux disease.This medicine can strengthen stomach
Bowel movement, but do not affect gastric acid secretion, the no side effect such as the extrapyramidal symptoms and diarrhoea simultaneously, and toleration is good.
Research shows, mosapride topmost metabolic response in human body be N- go to luorobenzyl, beautiful jade ring open loop and
N- oxidation reaction.The metabolite of medicine is studied, is an important channel finding new drug.The seminar of inventor is not to
The metabolism of husky Billy conducts in-depth research.Research finds, its metabolite (R, S)-N- [2- hydroxyl -3- (4- luorobenzyl) ammonia
Base] propyl group -5- chloro- 4- amino -2- ethoxy benzamide have significantly in vitro promote digestive tract power effect (Sun Xiaohong. Mo Sha
Must sharp metabolite and pharmacokinetic study [D]. Shenyang Pharmaceutical University, 2009；Xiao H S, et a1.J.Mol.Catal.B-
Enzym.2009,59:82-89；).This compound is furtherd investigate, there is to discovery the drug candidate of clinical value
Have great importance.
Content of the invention
It is an object of the invention to provide mosapride active metabolite (R)-N- [2- hydroxyl -3- (4- luorobenzyl) amino] third
Base -5- chloro- 4- amino -2- ethoxy benzamide (levo form) and (S)-N- [2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -
5- chloro- 4- amino -2- ethoxy benzamide (d-isomer) and its synthetic method, (R, S)-N- [2- hydroxyl -3- (4- luorobenzyl)
Amino] propyl group -5- chloro- 4- amino -2- ethoxy benzamide (racemic modification) preparation method.
1) (R)-N- [2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxy benzamide (I-
1)
2) (S)-N- [2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxy benzamide (I-
2)
Present invention also offers synthesis (R)-N- [2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2-
Ethoxy benzamide (I-1), (S)-N- [2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethyoxyl
Benzoylamide (I-2) and (R, S)-N- [2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxy benzonitrile
The intermediate of amide (I), they are selected from：
1) (R) -2- [2- hydroxyl -3- (4- luorobenzyl) amino] tetrapropylisoindoline -1,3- diketone
2) (S) -2- [2- hydroxyl -3- (4- luorobenzyl) amino] tetrapropylisoindoline -1,3- diketone
3) (R, S) -2- [2- hydroxyl -3- (4- luorobenzyl) amino] tetrapropylisoindoline -1,3- diketone
4) (R) -1- amino -3- (4- luorobenzyl) amino -2- propanol
5) (S) -1- amino -3- (4- luorobenzyl) amino -2- propanol.
The present invention adopts two kinds of different synthetic method preparation N- [2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro-
4- amino -2- ethoxy benzamide：
Carry out alkylation reaction with corresponding N- (2,3- glycidyl) phthalimide for raw material and 4-Fluorobenzylamine to obtain
2- [2- hydroxyl -3- (4- luorobenzyl) amino] tetrapropylisoindoline -1,3- diketone, then hydrazinolysis obtain corresponding 1- amino -3-
(4- luorobenzyl) amino -2- propanol, last 4- amino -2- ethoxybenzoic acid chloro- with 5- is condensed to yield；
Or alkylation reaction is carried out for raw material and 4-Fluorobenzylamine with corresponding N- (2,3- glycidyl) phthalimide
Obtain 2- [2- hydroxyl -3- (4- luorobenzyl) amino] tetrapropylisoindoline -1,3- diketone, then obtain corresponding N- through protection, hydrazinolysis
1- amino -3- (4- luorobenzyl) amino -2- propanol of protection (i.e. benzyl amido protecting), then 4- amino -2- ethyoxyl chloro- with 5-
Benzoic acid is condensed to yield corresponding acylate, and last deprotection obtains target compound.
Described N- (2,3- glycidyl) phthalic amide can be (R)-N- (2,3- glycidyl) O-phthalic
Amide, (S)-N- (2,3- glycidyl) phthalic amide or (R, S)-N- (2,3- glycidyl) phthalic amide.
The preferred tertbutyloxycarbonyl of described blocking group, p-toluenesulfonyl.
Comprise the following steps that：
(1) alkylation reaction is carried out for raw material and 4-Fluorobenzylamine with N- (2,3- glycidyl) phthalimide, preparation
(I-3) 2- [2- hydroxyl -3- (4- luorobenzyl) amino] tetrapropylisoindoline -1,3- diketone shown in：
Step includes：By described N- (2,3- glycidyl) phthalic amide with 4-Fluorobenzylamine according to mol ratio 1:
0.8～1:5 are preferably in a proportion of 1:1～1:2 are added in solvent, 20～100 DEG C, 60～100 DEG C of reaction 5～7h of preferable temperature,
After reaction terminating, stand overnight, sucking filtration, solid solvent is washed, obtain 2- [2- hydroxyl -3- (4- luorobenzyl) amino] the different Yin of propyl group
Diindyl quinoline -1,3- diketone.
In above-mentioned preparation method, optional solvent includes but is not limited to methanol, ethanol, propanol, isopropanol, acetonitrile and each
The mixed solvent of solvent and water, preferred solvent is methanol, isopropanol, N- (2,3- glycidyl) phthalic amide and solvent
Ratio is 1:3～10 (m/v).
Described 2- [2- hydroxyl -3- (4- luorobenzyl) amino] tetrapropylisoindoline -1,3- diketone is (R) -2- [2- hydroxyl
Base -3- (4- luorobenzyl) amino] tetrapropylisoindoline -1,3- diketone, (S) -2- [2- hydroxyl -3- (4- luorobenzyl) amino] propyl group
Isoindoline -1,3- diketone or (R, S) -2- [2- hydroxyl -3- (4- luorobenzyl) amino] tetrapropylisoindoline -1,3- diketone.
(2) with 2- [2- hydroxyl -3- (4- luorobenzyl) amino] tetrapropylisoindoline -1,3- diketone (I-3) or N-protected -2-
[2- hydroxyl -3- (4- luorobenzyl) amino] tetrapropylisoindoline -1,3- diketone (I-6) hydrazinolysis prepare the 1- amino shown in (I-4) -
3- (4- luorobenzyl) amino -2- propanol or N-protected -1- amino -3- (4- luorobenzyl) amino -2- propanol：
Step includes：By described 2- [2- hydroxyl -3- (4- luorobenzyl) amino] tetrapropylisoindoline -1,3- diketone or N-
Protection -2- [2- hydroxyl -3- (4- luorobenzyl) amino] tetrapropylisoindoline -1,3- diketone is with hydrazine hydrate according to mol ratio 1:1～
1:8, it is preferably in a proportion of 1:5～1:7 are added in solvent, 20～80 DEG C, and preferable temperature is 40～60 DEG C of reaction 5～6h, reaction
After termination, it is spin-dried for solvent, extractant room temperature is pulled an oar, sucking filtration obtains filtrate, sloughs solvent, obtain 1- amino -3- (4- luorobenzyl) ammonia
Base -2- propanol or N-protected -1- amino -3- (4- luorobenzyl) amino -2- propanol.
In above-mentioned preparation method, can be selected for solvent and include but is not limited to methanol, ethanol, propanol, isopropanol, acetonitrile, excellent
Select solvent to be methanol, isopropanol, 2- [2- hydroxyl -3- (4- luorobenzyl) amino] tetrapropylisoindoline -1,3- diketone or N-protected -
The ratio of 2- [2- hydroxyl -3- (4- luorobenzyl) amino] tetrapropylisoindoline -1,3- diketone and solvent is 1:3～10 (m/v)；Can
Include but is not limited to methanol, ethanol, propanol, isopropanol, ethyl acetate, dichloromethane from extractant, preferred solvent is dichloro
Methane.
Described 1- amino -3- (4- luorobenzyl) amino -2- propanol is (R) -1- amino -3- (4- luorobenzyl) amino -2-
Propanol, (S) -1- amino -3- (4- luorobenzyl) amino -2- propanol or (R, S) -1- amino -3- (4- luorobenzyl) amino -2- third
Alcohol.
Described N-protected -1- amino -3- (4- luorobenzyl) amino -2- propanol is (R)-N-protected -1- amino -3- (4-
Luorobenzyl) amino -2- propanol, (S)-N-protected -1- amino -3- (4- luorobenzyl) amino -2- propanol or (R, S)-N-protected -1-
Amino -3- (4- luorobenzyl) amino -2- propanol.
The preferred tertbutyloxycarbonyl of described blocking group, p-toluenesulfonyl.
Wherein, described N-protected -2- [2- hydroxyl -3- (4- luorobenzyl) amino] tetrapropylisoindoline -1,3- diketone (I-
6) it is prepared via a method which：
With 2- [2- hydroxyl -3- (4- luorobenzyl) amino] tetrapropylisoindoline -1,3- diketone and protection reagent reacting preparation
N-protected -2- [2- hydroxyl -3- (4- luorobenzyl) amino] tetrapropylisoindoline -1,3- diketone as shown in (I-6)：
Step includes：By described 2- [2- hydroxyl -3- (4- luorobenzyl) amino] tetrapropylisoindoline -1,3- diketone and guarantor
Shield reagent is according to mol ratio 1:1～1:5, it is preferably in a proportion of 1:1～1:3 and catalyst be added in solvent, -20～50 DEG C, excellent
Select temperature to be -15～0 DEG C of reaction 30min～1h, obtain N-protected -2- [2- hydroxyl -3- (4- luorobenzyl) amino] the different Yin of propyl group
Diindyl quinoline -1,3- diketone.
Described solvent is methanol, ethanol, propanol, isopropanol, acetonitrile or DMF, and preferred solvent is DMF, 2- [2- hydroxyl-
3- (4- luorobenzyl) amino] ratio of tetrapropylisoindoline -1,3- diketone and solvent is 1:3～14 (m/v)；Catalyst is anhydrous
One or more of sodium carbonate, sodium bicarbonate, Anhydrous potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide or triethylamine,
Preferred catalyst is Anhydrous potassium carbonate, triethylamine, 2- [2- hydroxyl -3- (4- luorobenzyl) amino] tetrapropylisoindoline -1,3- bis-
The mol ratio of ketone and catalyst is 1:1～5.
The preferred tertbutyloxycarbonyl of blocking group, p-toluenesulfonyl.
(3) with 1- amino -3- (4- luorobenzyl) amino -2- propanol or N-protected -1- amino -3- (4- luorobenzyl) amino -
N- [2- hydroxyl -3- (4- luorobenzyl) ammonia shown in (I) is prepared in 2- propanol and 5- chloro- 4- amino -2- ethoxybenzoic acid condensation
Base] propyl group -5- chloro- 4- amino -2- ethoxy benzamide or the N-protected shown in (I-5) N- [2- hydroxyl -3- (4- fluorine benzyl
Base) amino] propyl group -5- chloro- 4- amino -2- ethoxy benzamide：
Step includes：By described 1- amino -3- (4- luorobenzyl) amino -2- propanol or N-protected -1- amino -3- (4-
Luorobenzyl) amino -2- propanol and 5- chloro- 4- amino -2- ethoxybenzoic acid, EDCI, HOBt be according to mol ratio 1:(0.8-2):
(1-3):(1-3), it is preferably in a proportion of 1:(0.8-1):(1-1.5):(1-1.5), and catalyst is added in solvent, -25～80
DEG C, preferable temperature is -25～-10 DEG C of reaction 30min～1h, obtains N- [2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5-
Chloro- 4- amino -2- ethoxy benzamide or N-protected-[2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -
2- ethoxy benzamide.
In above-mentioned preparation method, can be selected for solvent and include but is not limited to DMF, methanol, ethanol, isopropanol, preferably molten
Agent is DMF, 1- amino -3- (4- luorobenzyl) amino -2- propanol or N-protected -1- amino -3- (4- luorobenzyl) amino -2- propanol
Ratio with solvent is 1:3～15 (m/v)；Available catalyst includes but is not limited to natrium carbonicum calcinatum, sodium bicarbonate, anhydrous
One or more of potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, triethylamine, preferred catalyst is Carbon Dioxide
Potassium, triethylamine, 1- amino -3- (4- luorobenzyl) amino -2- propanol or N-protected -1- amino -3- (4- luorobenzyl) amino -2- third
The mol ratio of alcohol and catalyst is 1:2.5～5.
Described N- [2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxy benzamide is
(R)-N- [2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxy benzamide, (S)-N- [2- hydroxyl
Base -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxy benzamide or (R, S)-N- [2- hydroxyl -3- (4-
Luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxy benzamide.
Described N-protected-[2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxybenzene formyl
Amine for (R)-N-protected-[2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxy benzamide is,
(S)-N-protected-[2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxy benzamide be or (R,
S)-N-protected-[2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxy benzamide.
Wherein, N-protected-[2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxybenzene formyl
N- [2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino as shown in (I) of amine (I-5) and sour deprotection preparation -
2- ethoxy benzamide：
Step includes：By described N-protected-[2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- second
Oxybenzamide and acid are according to mol ratio 1:1～1:6, it is preferably in a proportion of 1:3～1:5 are added in solvent, -25～40 DEG C,
Preferable temperature is -25～0 DEG C of reaction 1～4h, pours in aqueous alkali, extractant extracts, sloughs solvent, obtains N- [2- hydroxyl -3-
(4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxy benzamide.
In above-mentioned preparation method, can be selected for solvent and include but is not limited to dichloromethane, chloroform, preferred solvent is dichloro
Methane, N-protected-[2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxy benzamide and solvent
Ratio be 1:3～10 (m/v)；Described extractant is dichloromethane, ethyl acetate, ethyl acetate；Described acid is
Hydrogen chloride, acetic acid, trifluoroacetic acid, preferably trifluoroacetic acid.
Described N- [2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxy benzamide is
(R)-N- [2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxy benzamide, (S)-N- [2- hydroxyl
Base -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxy benzamide or (R, S)-N- [2- hydroxyl -3- (4-
Luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxy benzamide.
The pharmaceutically acceptable salt of compound of the present invention is prepared via a method which：
With N- [2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxy benzamide and processed with acid
Standby corresponding salt：
Step includes：By described N- [2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxybenzene
Methanamide and acid are according to mol ratio 1:1-1:5, it is preferably in a proportion of 1:1～1:3 are added in solvent, 0～45 DEG C, and preferable temperature is
20～30 DEG C of reaction 1～3h, separate out solid, sucking filtration, obtain N- [2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- ammonia
Base -2- ethoxy benzamide hydrochlorate.
Described solvent is ethyl acetate, dichloromethane, acetone, methyl tertiary butyl ether(MTBE), methanol, ethanol, isopropanol and wherein
Mixed solvent, preferably acetone, ethyl acetate, ethanol, methyl tertiary butyl ether(MTBE) and its mixed solvent, N- [2- hydroxyl -3- (4- fluorine
Benzyl) amino] ratio of propyl group -5- chloro- 4- amino -2- ethoxy benzamide and solvent is 1:2～1:8(m/v).
Described acid be hydrochloric acid, acetic acid, tartaric acid, succinic acid, fumaric acid, maleic acid, phosphoric acid, preferably hydrochloric acid, succinic acid,
Tartaric acid, fumaric acid, maleic acid.
Described N- [2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxy benzamide is
(R)-N- [2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxy benzamide, (S)-N- [2- hydroxyl
Base -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxy benzamide or (R, S)-N- [2- hydroxyl -3- (4-
Luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxy benzamide.
So that tertbutyloxycarbonyl is as protection group as a example, the synthetic route of the present invention is expressed as follows：
Compound of the present invention, and its pharmaceutically acceptable salt is as active ingredient, and pharmaceutically acceptable
Carrier or excipient are prepared by mixing into Pharmaceutical composition, and are prepared into clinically acceptable dosage form, above-mentioned pharmaceutically acceptable
Excipient refer to any diluent that can be used for pharmaceutical field, adjuvant and/or carrier.
The Pharmaceutical composition of the present invention with can become pharmaceutical preparation by some conventional excipient in drug world.Described
Preparation can be injection, tablet, capsule, aerosol, suppository, membrane, drop pill, externally-applied liniment, ointment etc..
Excipient for pharmaceutical composition of the present invention or pharmaceutical preparation includes：Binding agent, lubricant, disintegrating agent, hydrotropy
Agent, diluent, stabilizer, suspending agent, non-pigment, correctivess, preservative, solubilizer and substrate etc..Pharmaceutical preparation can be oral
Clothes or parenteral (such as intravenouss, subcutaneous, intraperitoneal or local) administration, if some drugses are unstable under the conditions of stomach
Fixed, enteric coated tablets can be configured to.
The present invention investigates racemic modification, the d-isomer and levo form work to gastrointestinal peristalsiss by mouse small intestine propulsion model
With.Raceme and d-isomer cause mice gastrointestinal dysfunction to have therapeutical effect lumbar injection atropine.
The compound or pharmaceutically acceptable salt thereof of the present invention can be used alone as gastric motility medicine, or can with listed
Gastric motility medicine (as metoclopramide, Domperidone, tegaserod, itopride etc.) be used in combination.Therapeutic alliance is passed through
By each therapeutic component simultaneously, order or separate administration and to realize.
Examples provided hereinafter and preparation example are further elucidated with and illustrate the compounds of this invention and its preparation side
Method and the preparation method with Pharmaceutical composition.It should be appreciated that the scope of following examples and preparation example limiting never in any form
The scope of the present invention.
Specific embodiment：
Present invention N- to be synthesized [2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethyoxyl
Benzoylamide and corresponding salt can be carried out as follows：
Embodiment 1
1) (R) -2- [2- hydroxyl -3- (4- luorobenzyl) amino] tetrapropylisoindoline -1,3- diketone
In 1L three-necked bottle, add (S)-N- (2,3- glycidyl) phthalic amide 100g, 4-Fluorobenzylamine 74g and different
Propanol 600mL, back flow reaction 2.5h, after reaction terminating, stand overnight, sucking filtration, solid isopropanol is washed, dichloromethane is pulled an oar, do
Dry white solid powder 127.2g, yield 78.7%, mp:170.6～171.5 DEG C, ESI-MS m/z:329.1[M+H]+；
351.1[M+Na]+,1H NMR(600MHz,CDCl3) δ 7.85 7.81 (m, 2H), 7.73 7.69 (m, 2H), 7.25 (d, J=
5.7Hz, 1H), 7.23 (s, 1H), 6.97 (t, J=8.7Hz, 2H), 3.98 3.93 (m, J=9.1,7.0,4.9Hz, 1H),
3.82 3.77 (m, 1H), 3.75 (s, 1H), 3.74 (d, J=2.3Hz, 1H), 3.72 (d, J=5.2Hz, 1H), 2.74 (dd, J
=12.3,4.0Hz, 1H), 2.61 (dd, J=12.3,7.2Hz, 1H).
2) (S) -1- amino -3- (4- luorobenzyl) amino -2- propanol
In 2L three-necked bottle, add (R) -2- [2- hydroxyl -3- (4- luorobenzyl) amino] tetrapropylisoindoline -1,3- diketone
127.2g, 80% hydrazine hydrate 760mL and methanol 250mL, 45 DEG C of reaction 5h, after reaction terminating, remove solvent under reduced pressure, residue is used
Ethanol room temperature is pulled an oar, sucking filtration, removes solvent in filtrate, obtains transparent oily liquid 63.0g, yield 82%, ESI-MS m/z:
199.1[M+H]+；221.1[M+Na]+,1H NMR(600MHz,CDCl3) δ 7.42 (s, 2H), 7.21 (t, J=8.6Hz, 2H),
4.10-3.85(s,2H),3.78(m,3H),2.76(m,2H),2.59(m,2H)..
3) (R)-N- [2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxy benzamide
In 1L three-necked bottle, addition (S) -1- amino -3- (4- luorobenzyl) amino -2- propanol 63.0g, EDCI 88.2g,
HOBt 78.5g, 5- chloro- 4- amino -2- ethoxybenzoic acid 76.0g, triethylamine 45.5g and DMF 500mL, -25 DEG C of reactions
1h, after reaction terminating, pours in aqueous alkali, separates out solid, sucking filtration, washing, is dried, Gossypol recrystallized from chloroform, obtains white solid 106.2g,
Yield 84.5%, HPLC (area normalization method)：97.2%, mp:115.5～116.5 DEG C, ESI-MS m/z:396.3[M+H
]+,1H NMR(400MHz,CDCl3) δ 8.19 (s, 1H), 8.07 (s, 1H), 7.26 (d, J=5.5Hz, 1H), 7.23 (s, 1H),
7.02 6.92 (m, 2H), 6.24 (s, 1H), 4.34 (d, J=9.0Hz, 2H), 4.05 (q, J=7.0Hz, 2H), 3.83 3.67
(m, 3H), 3.60 (dd, J=13.9,5.8, Hz, 1H), 3.41 (dd, J=13.9,5.9Hz, 1H), 2.74 (dd, J=12.1,
3.9Hz, 1H), 2.60 (dd, J=12.1,8.3Hz, 1H), 1.45 (t, J=7.0Hz, 3H).
4) (R)-N- [2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxy benzamide salt
Hydrochlorate
In 1L three-necked bottle, add (R)-N- [2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- second
Oxybenzamide 106.2g, acetone 530mL, are stirred at room temperature, and after solid dissolving, are slowly added dropwise hydrogen chloride ether in solution
Solution 380mL (1.78mol/L), is stirred at room temperature reaction 1h, separates out solid, sucking filtration, filter cake acetone is washed, and is vacuum dried white solid
Body 102.0g, yield 87.9%, HPLC (area normalization method)：97.9%, mp:140.0～141.7 DEG C, ESI-MS m/z:
396.3[M+H]+.
Embodiment 2
1) (R) -2- [2- hydroxyl -3- (4- luorobenzyl) amino] tetrapropylisoindoline -1,3- diketone
In 500mL three-necked bottle, add (S)-N- (2,3- glycidyl) phthalic amide 78g, 4-Fluorobenzylamine 55.5g
With isopropanol 430mL, back flow reaction 2.5h, after reaction terminating, stand overnight, sucking filtration, solid isopropanol is washed, and dichloromethane is beaten
Slurry, dry white solid powder 90.7g, yield 72.0%, mp:170.6～171.5 DEG C, ESI-MS m/z:329.1[M+H
]+；351.1[M+Na]+,1H NMR(600MHz,CDCl3)δ7.84–7.82(m,2H),7.73–7.68(m,2H),7.25(d,J
=5.7Hz, 1H), 7.23 (s, 1H), 6.96 (t, J=8.7Hz, 2H), 3.97 3.93 (m, J=9.1,7.0,4.9Hz, 1H),
3.842 3.78 (m, 1H), 3.77 (s, 1H), 3.74 (d, J=2.3Hz, 1H), 3.73 (d, J=5.2Hz, 1H), 2.75 (dd, J
=12.3,4.0Hz, 1H), 2.61 (dd, J=12.3,7.2Hz, 1H).
2) (S)-N- tertbutyloxycarbonyl -2- [2- hydroxyl -3- (4- luorobenzyl) amino] tetrapropylisoindoline -1,3- diketone
In 1L three-necked bottle, add (R) -2- [2- hydroxyl -3- (4- luorobenzyl) amino] tetrapropylisoindoline -1,3- diketone
90.7g, triethylamine 56g and DMF 700mL, Deca (Boc) at -10～0 DEG C2O 66.7g, reacts 1h at a temperature of this, reaction is eventually
After only, it is poured into water, sucking filtration, solid is washed, dry product 97.6g, yield 82.5%, mp:120.7～121.3 DEG C, ESI-
MS m/z:428.7[M+H]+；450.7[M+Na]+,1H NMR(400MHz,CDCl3) δ 7.82 (s, 2H), 7.72 (d, J=
2.8Hz, 2H), 7.15 (d, J=33.7Hz, 2H), 6.88 (s, 2H), 4.48 (d, J=15.2Hz, 1H), 4.39 (d, J=
14.7Hz, 1H), 4.01 (s, 1H), 3.69 (s, 2H), 3.46 (dd, J=14.0,7.0Hz, 1H), 3.28 (s, 1H), 1.42 (s,
9H).
3) (S)-N- tertbutyloxycarbonyl -1- amino -3- (4- luorobenzyl) amino -2- propanol
In 1L three-necked bottle, add (S)-N- tertbutyloxycarbonyl -2- [2- hydroxyl -3- (4- luorobenzyl) amino] the different Yin of propyl group
Diindyl quinoline -1,3- diketone 97.6g, 80% hydrazine hydrate 580mL and methanol 200mL, 45 DEG C of reaction 5h, after reaction terminating, decompression is divided exactly
Solvent, residue is pulled an oar with dichloromethane room temperature, and sucking filtration obtains filtrate, sloughs solvent and obtain pale yellow oily liquid 54.0g, yield
79.5%, ESI-MS m/z:299.2[M+H]+；321.2[M+Na]+,1H NMR(400MHz,CDCl3)δ7.21–7.13(m,
2H), 6.96 (t, J=8.6Hz, 2H), 4.58 4.31 (m, 2H), 3.68 (s, 1H), 3.60 (s, 2H), 3.25 (s, 1H), 3.16
(s, 1H), 2.74 (d, J=11.3Hz, 1H), 2.54 (s, 1H), 1.42 (s, 9H).
4) (S)-N- tertbutyloxycarbonyl-[2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethyoxyl
Benzoylamide
In 500mL three-necked bottle, add (S)-N- tertbutyloxycarbonyl -1- amino -3- (4- luorobenzyl) amino -2- propanol
54.0g, 5- chloro- 4- amino -2- ethoxybenzoic acid 43.3g, EDCI 49.8g, HOBt 44.5g triethylamine 26.3g and DMF
300mL, -25～10 DEG C of reaction 1h, after reaction terminating, pour in aqueous alkali, separate out solid, sucking filtration, solid is washed, the product being dried
71.8g, yield 80.0%, mp:101.5～102.7 DEG C, ESI-MS m/z:496.4[M+H]+；518.3[M+Na]+,1H NMR
(400MHz,CDCl3) δ 8.37 (s, 1H), 8.08 (s, 1H), 7.23 7.11 (m, 2H), 6.96 (t, J=8.6Hz, 2H), 6.27
(s, 1H), 4.60 (s, 1H), 4.49 (d, J=15.2Hz, 1H), 4.37 (s, 2H), 4.08 (q, J=6.7Hz, 2H), 3.88 (s,
1H), 3.67 (s, 1H), 3.30 (d, J=9.7Hz, 3H), 1.46 (d, J=4.5Hz, 3H), 1.43 (s, 9H).
5) (R)-N- [2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxy benzamide
In 1L three-necked bottle, propyl group -5- is chloro- to add (S)-N- tertbutyloxycarbonyl-[2- hydroxyl -3- (4- luorobenzyl) amino]
4- amino -2- ethoxy benzamide 71.8g and dichloromethane 280mL, Deca trifluoroacetic acid 280mL at -15～-10 DEG C, this
At a temperature of react 3h, pour in aqueous alkali, ethyl acetate extract, anhydrous sodium sulfate drying, slough solvent afforded crude material, Gossypol recrystallized from chloroform
Obtain sterling 39.8g, yield 69.5%, mp:115.5～116.5 DEG C, HPLC (area normalization method)：99.6%, ESI-MS m/
z:396.3[M+H]+,1H NMR(400MHz,CDCl3) δ 8.20 (s, 1H), 8.07 (s, 1H), 7.25 (d, J=5.5Hz, 1H),
7.20 (s, 1H), 7.02 6.91 (m, 2H), 6.24 (s, 1H), 4.35 (d, J=9.0Hz, 2H), 4.05 (q, J=7.0Hz,
2H), 3.83 3.67 (m, 3H), 3.63 (dd, J=13.9,5.8, Hz, 1H), 3.421 (dd, J=13.9,5.9Hz, 1H),
2.74 (dd, J=12.1,3.9Hz, 1H), 2.60 (dd, J=12.1,8.3Hz, 1H), 1.45 (t, J=7.0Hz, 3H).
6) (R)-N- [2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxy benzamide amber
Amber hydrochlorate
In 100mL three-necked bottle, addition (R)-N- [2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -
2- ethoxy benzamide 10g, ethyl acetate 50mL, 30 DEG C of stirring 30min, after solid dissolving, it is slowly added to succinic acid
3.2g, stirring reaction 1h, separate out solid, sucking filtration, filter cake ethyl acetate is washed, and is vacuum dried to obtain white solid 10.9g, yield
83.6%, mp:130.1～132.5 DEG C, ESI-MS m/z:396.3[M+H]+.
7) (R)-N- [2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxy benzamide wine
Stone acid hydrochlorate
In 100mL three-necked bottle, addition (R)-N- [2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -
2- ethoxy benzamide 10g, acetone 55mL, 30 DEG C of stirring 30min, after solid dissolving, it is slowly added to tartaric acid 4g, stirring
Reaction 1h, separates out solid, sucking filtration, filter cake acetone is washed, and is vacuum dried to obtain white solid 11.8g, yield 85.5%, mp:201.5
～203.4 DEG C, ESI-MS m/z:396.3[M+H]+.
8) (R)-N- [2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxy benzamide horse
Carry out hydrochlorate
In 100mL three-necked bottle, addition (R)-N- [2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -
2- ethoxy benzamide 10g, ethyl acetate 60mL, 30 DEG C of stirring 40min, after solid dissolving, it is slowly added to maleic acid
3.1g, stirring reaction 1.5h, separate out solid, sucking filtration, filter cake ethyl acetate is washed, and is vacuum dried to obtain white solid 10.6g, yield
82.0%, mp:157.5～159.0 DEG C, ESI-MS m/z:396.3[M+H]+.
9) (R)-N- [2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxy benzamide is rich
Horse hydrochlorate
In 100mL three-necked bottle, addition (R)-N- [2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -
2- ethoxy benzamide 9.8g, ethyl acetate 50mL, 30 DEG C of stirring 55min, after solid dissolving, it is slowly added to fumaric acid
3.0g, stirring reaction 2h, separate out solid, sucking filtration, filter cake ethyl acetate is washed, and is vacuum dried to obtain white solid 10.8g, yield
84.8%, mp:174.5～176.7 DEG C, ESI-MS m/z:396.3[M+H]+.
Embodiment 3
1) (S) -2- [2- hydroxyl -3- (4- luorobenzyl) amino] tetrapropylisoindoline -1,3- diketone
In 1L three-necked bottle, add (R)-N- (2,3- glycidyl) phthalic amide 100g, 4-Fluorobenzylamine 74g and different
Propanol 600mL, back flow reaction 2h, after reaction terminating, stand overnight, next day sucking filtration, solid isopropanol is washed, and dichloromethane is beaten
Slurry, dry white solid powder 121g, yield 75%, mp:170.4～171.2 DEG C, ESI-MS m/z:329.1[M+H]+；
351.1[M+Na]+,1H NMR(600MHz,CDCl3) δ 7.84 7.81 (m, 2H), 7.75 7.69 (m, 2H), 7.24 (d, J=
5.7Hz, 1H), 7.29 (s, 1H), 6.97 (t, J=8.7Hz, 2H), 3.96 3.93 (m, J=9.1,7.0,4.9Hz, 1H),
3.82 3.79 (m, 1H), 3.75 (s, 1H), 3.75 (d, J=2.3Hz, 1H), 3.72 (d, J=5.2Hz, 1H), 2.74 (dd, J
=12.3,4.0Hz, 1H), 2.61 (dd, J=12.3,7.2Hz, 1H).
2) (R)-N- tertbutyloxycarbonyl -2- [2- hydroxyl -3- (4- luorobenzyl) amino] tetrapropylisoindoline -1,3- diketone
In 1L three-necked bottle, add (S) -2- [2- hydroxyl -3- (4- luorobenzyl) amino] tetrapropylisoindoline -1,3- diketone
121g, triethylamine 74.7g and DMF 600mL, Deca (Boc) at -15 DEG C2O 88.7g, reacts 30min at a temperature of this, reaction is eventually
After only, it is poured into water, sucking filtration, solid is washed, dry product 137.8g, yield 87%, mp:119.5～121.0 DEG C, ESI-
MS m/z:428.7[M+H]+；450.7[M+Na]+,1H NMR(400MHz,CDCl3) δ 7.83 (s, 2H), 7.71 (d, J=
2.8Hz, 2H), 7.15 (d, J=33.7Hz, 2H), 6.91 (s, 2H), 4.49 (d, J=15.2Hz, 1H), 4.38 (d, J=
14.7Hz, 1H), 4.00 (s, 1H), 3.69 (s, 2H), 3.46 (dd, J=14.0,7.0Hz, 1H), 3.25 (s, 1H), 1.42 (s,
9H).
3) (R)-N- tertbutyloxycarbonyl -1- amino -3- (4- luorobenzyl) amino -2- propanol
In 2L three-necked bottle, add (R)-N- tertbutyloxycarbonyl -2- [2- hydroxyl -3- (4- luorobenzyl) amino] the different Yin of propyl group
Diindyl quinoline -1,3- diketone 138.7g, 80% hydrazine hydrate 900mL and methanol 280mL, 45 DEG C of reaction 5h, after reaction terminating, remove under reduced pressure
Solvent, residue is pulled an oar with dichloromethane room temperature, and sucking filtration obtains filtrate, sloughs solvent and obtain pale yellow oily liquid 78.9g, yield
81.7%, ESI-MS m/z:299.2[M+H]+；321.2[M+Na]+,1H NMR(400MHz,CDCl3)δ7.21–7.12(m,
2H), 6.97 (t, J=8.6Hz, 2H), 4.58 4.31 (m, 2H), 3.75 (s, 3H), 3.25 (s, 2H), 3.17 (s, 1H), 2.74
(d, J=11.3Hz, 1H), 2.54 (s, 1H), 1.42 (s, 9H).
4) (R)-N- tertbutyloxycarbonyl-[2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethyoxyl
Benzoylamide
In 500mL three-necked bottle, add (R)-N- tertbutyloxycarbonyl -1- amino -3- (4- luorobenzyl) amino -2- propanol
78.9g, 5- chloro- 4- amino -2- ethoxybenzoic acid 63.2g, EDCI 73.3g, HOBt 65.4g, triethylamine 38.6g and DMF
400mL, -25 DEG C of reaction 30min, after reaction terminating, pour in aqueous alkali, separate out solid, sucking filtration, solid is washed, the product being dried
92g, yield 88%, mp:107.0～108.5 DEG C, ESI-MS m/z:496.4[M+H]+；518.3[M+Na]+,1H NMR
(400MHz,CDCl3) δ 8.36 (s, 1H), 8.06 (s, 1H), 7.21 7.10 (m, 2H), 6.96 (t, J=8.6Hz, 2H), 6.25
(s, 1H), 4.60 (s, 1H), 4.48 (d, J=15.2Hz, 1H), 4.36 (s, 3H), 4.08 (q, J=6.7Hz, 2H), 3.87 (s,
1H), 3.67 (s, 1H), 3.30 (d, J=9.7Hz, 3H), 1.47 (d, J=4.5Hz, 3H), 1.43 (s, 9H).
5) (S)-N- [2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxy benzamide
In 1L three-necked bottle, propyl group -5- is chloro- to add (R)-N- tertbutyloxycarbonyl-[2- hydroxyl -3- (4- luorobenzyl) amino]
4- amino -2- ethoxy benzamide 92g and dichloromethane 370mL, Deca trifluoroacetic acid 370mL at -15 DEG C are anti-at a temperature of this
Answer 2h, pour in aqueous alkali, ethyl acetate extracts, anhydrous sodium sulfate drying sloughs solvent afforded crude material, Gossypol recrystallized from chloroform obtains sterling,
56.2g, yield 76.5%, mp:118.7～119.0 DEG C, HPLC (area normalization method)：99.6%, ESI-MS m/z:396.3
[M+H]+,1H NMR(400MHz,CDCl3) δ 8.18 (s, 1H), 8.07 (s, 1H), 7.25 (d, J=5.5Hz, 1H), 7.23 (s,
1H), 7.02 6.92 (m, 2H), 6.23 (s, 1H), 4.34 (d, J=9.0Hz, 2H), 4.08 (q, J=7.0Hz, 2H), 3.85
3.69 (m, 3H), 3.60 (dd, J=13.9,5.8, Hz, 1H), 3.43 (dd, J=13.9,5.9Hz, 1H), 2.74 (dd, J=
12.1,3.9Hz, 1H), 2.60 (dd, J=12.1,8.3Hz, 1H), 1.45 (t, J=7.0Hz, 3H).
6) (S)-N- [2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxy benzamide salt
Hydrochlorate
In 1L three-necked bottle, add (S)-N- [2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- second
Oxybenzamide 56.2g, acetone 300mL, are stirred at room temperature, and after solid dissolving, are slowly added dropwise hydrogen chloride ether in solution
Solution 254mL (1.4mol/L), is stirred at room temperature reaction 1h, separates out solid, add methyl tertiary butyl ether(MTBE) 254mL, stir 0.5h, take out
Filter, filter cake acetone is washed, and is vacuum dried to obtain white solid 52.2g, yield 85.0%, HPLC (area normalization method)：99.6%,
mp:142.1～143.9 DEG C, ESI-MS m/z:396.3[M+H]+.
Embodiment 4
1) (R, S) -2- [2- hydroxyl -3- (4- luorobenzyl) amino] tetrapropylisoindoline -1,3- diketone
In 500mL three-necked bottle, add (R, S)-N- (2,3- glycidyl) phthalic amide 55g, 4-Fluorobenzylamine
40.7g and methanol 220mL, back flow reaction 3h, after reaction terminating, stand overnight, sucking filtration, solid methanol is washed, dichloromethane is pulled an oar,
The white solid powder 65.3g being dried, yield 73.5%, mp:184.1～185.3 DEG C, ESI-MS m/z:329.1(M+H)+；
351.1(M+Na)+,1H NMR(600MHz,CDCl3) δ 7.85 7.82 (m, 2H), 7.74 7.69 (m, 2H), 7.27 (d, J=
5.7Hz, 1H), 7.26 (s, 1H), 6.97 (t, J=8.7Hz, 2H), 3.98 3.92 (m, J=9.1,7.0,4.9Hz, 1H),
3.82 3.77 (m, 1H), 3.75 (s, 1H), 3.74 (d, J=2.3Hz, 1H), 3.73 (d, J=5.2Hz, 1H), 2.74 (dd, J
=12.3,4.0Hz, 1H), 2.61 (dd, J=12.3,7.2Hz, 1H).
2) (R, S)-N- tertbutyloxycarbonyl -2- [2- hydroxyl -3- (4- luorobenzyl) amino] tetrapropylisoindoline -1,3- diketone
In 1L three-necked bottle, add (R, S) -2- [2- hydroxyl -3- (4- luorobenzyl) amino] tetrapropylisoindoline -1,3- bis-
Ketone 65.3g, Anhydrous potassium carbonate 44.9g and DMF 410mL, Deca (Boc) at -10～0 DEG C2O 47.9g, room temperature reaction 1h, instead
After should terminating, it is poured into water, sucking filtration, solid is washed, dry product 85.5g, yield 82.5%, mp:150.1～151.8 DEG C,
ESI-MS m/z:428.7[M+H]+；450.7[M+Na]+,1H NMR(600MHz,CDCl3) δ 7.85 (s, 2H), 7.71 (d, J=
2.8Hz, 2H), 7.15 (d, J=33.7Hz, 2H), 6.92 (s, 2H), 4.49 (d, J=15.2Hz, 1H), 4.39 (d, J=
14.7Hz, 1H), 4.01 (s, 1H), 3.69 (s, 2H), 3.46 (dd, J=14.0,7.0Hz, 1H), 3.25 (s, 1H), 1.42 (s,
9H).
3) (R, S)-N- tertbutyloxycarbonyl -1- amino -3- (4- luorobenzyl) amino -2- propanol
In 1L three-necked bottle, add (R, S)-N- tertbutyloxycarbonyl -2- [2- hydroxyl -3- (4- luorobenzyl) amino] propyl group different
Indoline -1,3- diketone 85.5g, 80% hydrazine hydrate 512mL and methanol 170mL, 45 DEG C of reaction 5h, after reaction terminating, decompression is whole
Except solvent, dichloromethane room temperature is pulled an oar, and sucking filtration obtains filtrate, sloughs solvent and obtains pale yellow oily liquid 47.3g, yield 79.5%,
ESI-MS m/z:299.2[M+H]+；321.2[M+Na]+,1H NMR(400MHz,CDCl3)δ7.20–7.12(m,2H),6.98
(t, J=8.6Hz, 2H), 4.56 4.31 (m, 2H), 3.68 (s, 1H), 3.25 (s, 2H), 2.74 (d, J=11.3Hz, 1H),
2.54(s,4H),1.42(s,9H).
4) (R, S)-N- tertbutyloxycarbonyl-[2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxy
Yl-benzamide
In 500mL three-necked bottle, add (R, S)-N- tertbutyloxycarbonyl -1- amino -3- (4- luorobenzyl) amino -2- propanol
47.3g, 5- chloro- 4- amino -2- ethoxybenzoic acid 37.9g, EDCI 43.9g, HOBt 39.1g, triethylamine 23.1g and DMF
300mL, -25～0 DEG C of reaction 1h, after reaction terminating, pour in aqueous alkali, separate out solid, sucking filtration, solid is washed, dry product
62.9g, yield 80.0%, mp:130.8～131.6 DEG C, ESI-MS m/z:496.4[M+H]+；518.3[M+Na]+,1H NMR
(400MHz,CDCl3) δ 8.35 (s, 1H), 8.06 (s, 1H), 7.22 7.10 (m, 2H), 6.96 (t, J=8.6Hz, 2H), 6.25
(s, 1H), 4.60 (s, 1H), 4.48 (d, J=15.2Hz, 1H), 4.36 (s, 2H), 4.08 (q, J=6.7Hz, 2H), 3.87 (s,
1H), 3.67 (s, 1H), 3.30 (d, J=9.7Hz, 3H), 1.47 (d, J=4.5Hz, 3H), 1.43 (s, 9H).
5) (R, S)-N- [2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxy benzamide
In 1L three-necked bottle, add (R, S)-N- tertbutyloxycarbonyl-[2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5-
Chloro- 4- amino -2- ethoxy benzamide 62.9g and dichloromethane 250mL, Deca trifluoroacetic acid 250mL at -10～-5 DEG C,
React 3h at a temperature of this, pour in aqueous alkali, ethyl acetate extracts, anhydrous sodium sulfate drying sloughs solvent afforded crude material 27.3g, chlorine
Imitative recrystallization obtains sterling 33.9g, yield 67.5%, mp:126.5～127.3 DEG C, HPLC (area normalization method)：99.5%,
ESI-MS m/z:396.3[M+H]+,1H NMR(400MHz,CDCl3) δ 8.18 (s, 1H), 8.05 (s, 1H), 7.26 (d, J=
5.5Hz, 1H), 7.23 (s, 1H), 7.03 6.92 (m, 2H), 6.23 (s, 1H), 4.35 (d, J=9.0Hz, 2H), 4.08 (q, J
=7.0Hz, 2H), 3.85 3.68 (m, 3H), 3.60 (dd, J=13.9,5.8, Hz, 1H), 3.44 (dd, J=13.9,5.9Hz,
1H), 2.74 (dd, J=12.1,3.9Hz, 1H), 2.60 (dd, J=12.1,8.3Hz, 1H), 1.45 (t, J=7.0Hz, 3H).
6) (R, S)-N- [2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxy benzamide
Hydrochlorate
In 1L three-necked bottle, add (R, S)-N- [2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2-
Ethoxy benzamide 33.9g, acetone 240mL, are stirred at room temperature, and after solid dissolving, are slowly added dropwise hydrogen chloride second in solution
Ethereal solution 153mL (1.4mol/L), is stirred at room temperature reaction 1.5h, separates out solid, adds methyl tertiary butyl ether(MTBE) 240mL, stirring
0.5h, sucking filtration, filter cake acetone is washed, and is vacuum dried to obtain white solid 32.2g, yield 86.9%, HPLC (area normalization method)：
99.6%, mp:157.6～159.3 DEG C, ESI-MS m/z:396.3[M+H]+.
Embodiment 5：The pharmacology test of the compounds of this invention：
1) experiment material
Test medicine and reagent
Test medicine title：
Mosapride
(R, S)-N- [2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxy benzamide (disappears
Rotation body)
(R)-N- [2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxy benzamide is (left-handed
Body)
(S)-N- [2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxy benzamide (dextrorotation
Body)
Unit is provided：There is provided by medicine analyticses teaching and research room of Shenyang Pharmaceutical University
Reagent and offer unit：
Atropine sulfate, He'nan Runhong Pharmaceutical Co., Ltd.'s lot number：1206071
Carboxymethyl cellulose sodium, Tianjin Bo Di Chemical Co., Ltd. lot number：XK-13-011-00003
Normal saline, Dou Bang Pharmaceutical limited company of Jilin Province lot number：1303260307
Activated carbon powder, Tianjin Standard Science company limited lot number：20050615
Mosapride, Shanxi Yabao Pharmaceutical Group Corp.'s lot number：140310
The preparation of reagent：
0.01% atropine sulfate injection：
Commercial sulfuric acid atropine (1mg/2mL) adds normal saline dilution to 0.1mg/mL.This liquid matching while using.1% hydroxyl
Sodium carboxymethylcellulose pyce：
Weigh Carboxymethyl cellulose sodium 1g, measure 100mL distilled water and be placed in beaker, Carboxymethyl cellulose sodium is uniformly spread
In distillation water surface, stand 24h.
5% charcoal end suspension：
Analytical balance weighs activated carbon powder 1g and is added in 20mL 1% Carboxymethyl cellulose sodium, mix homogeneously.Using front
Can gavage after should stirring uniformly.
Prepared by mosapride solution：
Take commercially available medicine mosapride 1 (every 3.52mg containing mosapride), be placed in reagent bottle, inject tolerance with 20mL
Take in distilled water 22.7mL reagent bottle, can gavage after fully dissolving.
Prepared by test medicine solution：
Analytical balance weighs test medicine and adds in distilled water, and ultrasonic dissolution 5min can gavage after fully dissolving.
Laboratory animal
KM mice, SPF level, male, body weight 18～22g, Shenyang Pharmaceutical University's animal center provides, the quality certification：
No.211002300005190, credit number：SCXK (distant) 20100001.
Rearing conditions：Temperature, 18～26 DEG C；Humidity, 40～70%.Feedstuff is by Shenyang City Yuhong District Qian Min animal feed factory
There is provided.
2) method and result
Take KM mice 110, after raising and train three days, be randomly divided into 11 groups, every group 10, respectively blank group, model group, not
Sha Bili group, the high, medium and low dosage group of racemic modification, the high, medium and low dosage group of levo form (I-1), d-isomer (I-2) is high, medium and low
Dosage group.Each administration group is given the test medicine of corresponding dosage respectively by table 1 gavage, and blank group and model group gavage give to distill
Water, administered volume be 0.2mL/10g, after 30min in addition to blank group remaining each group all according to 1mg/kg lumbar injection 0.01% Ah
Tropine, continues timing 30min, and the equal gavage of all animals gives 5% charcoal end suspension (0.3mL/ is only), and after 30min, mice takes off neck
Vertebra is put to death, abdominal cut, ligation stomach cardia and pylorus end, takes out small intestinal rapidly, is not added with drawing and is laid in glass plate with a scale
Upper (glass plate scribbles normal saline in advance), the distance measuring pyloric part to ileocecus respectively is total small intestinal length, and pylorus is to charcoal
Last suspension forward position is charcoal end advance distance, calculates Intestinal propulsive rate, Intestinal propulsive rate=charcoal end suspension advance distance/small intestinal
Total length × 100%.
Table 1 each group dosage
Table 2：The facilitation to the gastrointestinal propulsive movement of gastrointestinal dysfunction mice caused by atropine for the test medicine
*P<0.05 administration group Vs blank control group * * P<0.01 administration group Vs blank control group
#P<0.05 reagent group Vs negative control ##P<0.01 reagent group Vs negative control
From Table 2, it can be seen that model group compares propulsion rate with blank being remarkably decreased, illustrate that atropine causes Mouse Stomach
Intestinal dysfunction model modeling success；Raceme high dose group, d-isomer is high, middle dose group propulsion rate compared with model group is notable
Increase, illustrate that raceme high dose, d-isomer high dose and d-isomer middle dosage cause mice gastrointestinal work(to lumbar injection atropine
Can have promotion gastrointestinal motility effect by Disorder Model, levo form is invalid.
Conclusion：Under same dose, the activity of d-isomer is more than raceme, and d-isomer and raceme are to lumbar injection atropic
Product cause mice gastrointestinal dysfunction to have therapeutical effect, and levo form does not have the effect promoting gastrointestinal motility.
Embodiment 6：Tablet
With containing compound (d-isomer compound) 10g in claim 1, adding adjuvant according to the general pressed disc method of pharmaceuticss
After 20g mixes, it is pressed into 100, every weight 300mg.
Embodiment 7：Capsule
With containing compound (d-isomer compound) 10g in claim 1, the requirement according to pharmaceuticss capsule will be auxiliary
After material 20g mixes, load Capsuleses, each capsule weight 300mg.
Embodiment 8：Injection
With containing compound (d-isomer compound) 10g in claim 1, according to pharmaceuticss conventional method, being lived
Property charcoal absorption, after 0.65 μM of filtering with microporous membrane, insert nitrogen pot and make hydro-acupuncture preparation, every dress 2mL, 100 bottles of fill altogether.
Claims (26)
1. (R)-N- [2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxy benzamide (I-1),
(S)-N- [2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxy benzamide (I-2) or N- [2-
Hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxy benzamide intermediate, they are selected from：
1) (R) -2- [2- hydroxyl -3- (4- luorobenzyl) amino] tetrapropylisoindoline -1,3- diketone
2) (S) -2- [2- hydroxyl -3- (4- luorobenzyl) amino] tetrapropylisoindoline -1,3- diketone
3) 2- [2- hydroxyl -3- (4- luorobenzyl) amino] tetrapropylisoindoline -1,3- diketone
2. one kind prepares (R)-N- [2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxybenzene formyl
Amine, (S)-N- [2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxy benzamide or N- [2- hydroxyl
Base -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxy benzamide method；It is characterized in that,
(1) alkylation reaction is carried out for raw material and 4-Fluorobenzylamine with corresponding N- (2,3- glycidyl) phthalimide and obtain 2-
[2- hydroxyl -3- (4- luorobenzyl) amino] tetrapropylisoindoline -1,3- diketone；
(2) 2- [2- hydroxyl -3- (4- luorobenzyl) amino] tetrapropylisoindoline -1,3- diketone hydrazinolysis obtain corresponding 1- amino -
3- (4- luorobenzyl) amino -2- propanol；
(3) 1- amino -3- (4- luorobenzyl) amino -2- propanol 4- chloro- with 5- amino -2- ethoxybenzoic acid condensation obtains final product；Or
(1 ＇) carries out alkylation reaction with corresponding N- (2,3- glycidyl) phthalimide for raw material and 4-Fluorobenzylamine and obtains
2- [2- hydroxyl -3- (4- luorobenzyl) amino] tetrapropylisoindoline -1,3- diketone；
(2 ＇) is again through protecting to obtain N-protected -2- [2- hydroxyl -3- (4- luorobenzyl) amino] tetrapropylisoindoline -1,3- diketone, hydrazine
Solution obtains 1- amino -3- (4- luorobenzyl) amino -2- propanol of corresponding N-protected；
(3 ＇) and then 4- amino -2- ethoxybenzoic acid chloro- with 5- is condensed to yield corresponding acylate N-protected-[2- hydroxyl -3-
(4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxy benzamide, last deprotection obtains final product；
Described N- (2,3- glycidyl) phthalimide be (R)-N- (2,3- glycidyl) phthalimide,
(S)-N- (2,3- glycidyl) phthalimide or N- (2,3- glycidyl) phthalimide.
3. preparation method as claimed in claim 2 is it is characterised in that in step (1) or (1 ＇), by N- (2,3- glycidyl)
Phthalic amide and 4-Fluorobenzylamine are according to mol ratio 1:0.8～1:5, it is added in solvent, 20～100 DEG C of reaction 5～7h, obtain
Obtain 2- [2- hydroxyl -3- (4- luorobenzyl) amino] tetrapropylisoindoline -1,3- diketone；Described solvent be methanol, ethanol, third
Alcohol, the mixed solvent of isopropanol, acetonitrile or each solvent and water.
4. preparation method as claimed in claim 2 or claim 3 is it is characterised in that in step (1) or (1 ＇), N- (2,3- epoxies third
Base) phthalic amide and 4-Fluorobenzylamine mol ratio be 1:1～1:2.
5. preparation method as claimed in claim 2 or claim 3 is it is characterised in that in step (1) or (1 ＇), temperature is 60～100
℃.
6. preparation method as claimed in claim 2 or claim 3 is it is characterised in that in step (1) or (1 ＇), solvent is methanol or different
Propanol.
7. preparation method as claimed in claim 2 is it is characterised in that in step (2) or (2 ＇), by 2- [2- hydroxyl -3- (4-
Luorobenzyl) amino] tetrapropylisoindoline -1,3- diketone or N-protected -2- [2- hydroxyl -3- (4- luorobenzyl) amino] the different Yin of propyl group
Diindyl quinoline -1,3- diketone and hydrazine hydrate are according to mol ratio 1:1～1:8, it is added in solvent, 20～80 DEG C of reaction 5～6h, obtain 1-
Amino -3- (4- luorobenzyl) amino -2- propanol or N-protected -1- amino -3- (4- luorobenzyl) amino -2- propanol；Described is molten
Agent is methanol, ethanol, propanol, isopropanol or acetonitrile.
8. the preparation method as described in claim 2 or 7 is it is characterised in that in step (2) or (2 ＇), 2- [2- hydroxyl -3- (4-
Luorobenzyl) amino] tetrapropylisoindoline -1,3- diketone or N-protected -2- [2- hydroxyl -3- (4- luorobenzyl) amino] the different Yin of propyl group
Diindyl quinoline -1,3- diketone and hydrazine hydrate mol ratio are 1:5～1:7.
9. the preparation method as described in claim 2 or 7 is it is characterised in that in step (2) or (2 ＇), and hydrazinolysis temperature is 40～
60℃.
10. the preparation method as described in claim 2 or 7 is it is characterised in that in step (2) or (2 ＇), hydrazinolysis solvent is methanol
Or isopropanol.
11. preparation methoies as claimed in claim 2 it is characterised in that in step (3) or (3 ＇), 1- ammonia that (2) are obtained
N-protected -1- amino -3- (4- luorobenzyl) amino -2- propanol that base -3- (4- luorobenzyl) amino -2- propanol or (2 ') obtain with
5- chloro- 4- amino -2- ethoxybenzoic acid, EDCI, HOBt are according to mol ratio 1:(0.8-2):(1-3):, and catalyst (1-3)
It is added in solvent, -25～80 DEG C, react 30min～1h, obtain N- [2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5-
Chloro- 4- amino -2- ethoxy benzamide or N-protected-[2- hydroxyl -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -
2- ethoxy benzamide；Described solvent is DMF, methanol, ethanol or isopropanol；Catalyst is natrium carbonicum calcinatum, bicarbonate
One or more of sodium, Anhydrous potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide or triethylamine.
12. preparation methoies as described in claim 2 or 11 it is characterised in that in step (3) or (3 ＇), the 1- ammonia that (2) obtain
N-protected -1- amino -3- (4- luorobenzyl) amino -2- propanol that base -3- (4- luorobenzyl) amino -2- propanol or (2 ') obtain with
5- chloro- 4- amino -2- ethoxybenzoic acid, EDCI, HOBt mol ratio are 1:(0.8-1):(1-1.5):(1-1.5).
13. preparation methoies as described in claim 2 or 11 are it is characterised in that in step (3) or (3 ＇), condensation temp is -25
～-10 DEG C.
14. preparation methoies as described in claim 2 or 11 are it is characterised in that in step (3) or (3 ＇), condensation solvent is
DMF.
15. preparation methoies as described in claim 2 or 11 are it is characterised in that in step (3) or (3 ＇), condensation catalyst is
Anhydrous potassium carbonate or triethylamine.
16. preparation methoies as claimed in claim 2 it is characterised in that in step (2 ＇), 2- that (1 ＇) is obtained [2- hydroxyl-
3- (4- luorobenzyl) amino] tetrapropylisoindoline -1,3- diketone with protection reagent according to mol ratio 1:1～1:5, and catalyst adds
Enter in solvent, -20～50 DEG C, react 30min～1h, obtain N-protected -2- [2- hydroxyl -3- (4- luorobenzyl) amino] propyl group
Isoindoline -1,3- diketone；
Described solvent is methanol, ethanol, propanol, isopropanol, acetonitrile or DMF；Catalyst be natrium carbonicum calcinatum, sodium bicarbonate,
One or more of Anhydrous potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide or triethylamine；Blocking group is tertiary fourth oxygen
Carbonyl, p-toluenesulfonyl.
17. preparation methoies as claimed in claim 16 it is characterised in that in step (2 ＇), 2- that (1 ＇) obtains [2- hydroxyl-
3- (4- luorobenzyl) amino] tetrapropylisoindoline -1,3- diketone with protection reagent mol ratio be 1:1～1:3.
18. preparation methoies as claimed in claim 16 are it is characterised in that in step (2 ＇), temperature is -15～0 DEG C.
19. preparation methoies as claimed in claim 16 are it is characterised in that in step (2 ＇), described solvent is DMF.
20. preparation methoies as claimed in claim 16 are it is characterised in that in step (2 ＇), described catalyst is anhydrous carbon
Sour potassium, triethylamine.
21. preparation methoies as claimed in claim 2 it is characterised in that in step (3 ＇), by described N-protected-[2- hydroxyl
Base -3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxy benzamide with acid according to mol ratio 1:1～1:6,
Be added in solvent, -25～40 DEG C of reaction 1～4h, pour in aqueous alkali, extractant extracts, and sloughs solvent, obtain N- [2- hydroxyl -
3- (4- luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxy benzamide；Described solvent is dichloromethane, chloroform；
Described extractant is dichloromethane, ethyl acetate；Described acid is hydrogen chloride, acetic acid, trifluoroacetic acid.
22. preparation methoies as claimed in claim 21 it is characterised in that in step (3 ＇), N-protected-[2- hydroxyl -3- (4-
Luorobenzyl) amino] propyl group -5- chloro- 4- amino -2- ethoxy benzamide with acid mol ratio be 1:3～1:5.
23. preparation methoies as claimed in claim 21 are it is characterised in that in step (3 ＇), temperature is -25～0 DEG C.
24. preparation methoies as claimed in claim 21 are it is characterised in that in step (3 ＇), described solvent is dichloromethane.
25. preparation methoies as claimed in claim 21 are it is characterised in that in step (3 ＇), described extractant is acetic acid second
Ester.
26. preparation methoies as claimed in claim 21 are it is characterised in that in step (3 ＇), described acid is trifluoroacetic acid.
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