CN104961646A - 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 medical art, active metabolite relating to mosapride and its production and use, be specifically related to the active metabolite of mosapride and pharmacy acceptable salt thereof and containing their pharmaceutically useful composition and preparation method, and they are preparing the application in gastric motility medicine.
Background technology
Mosapride is novel third generation medicine for stomach dynamic, is mainly used in treating esophageal reflux disease.This medicine can strengthen gastrointestinal motility, but does not affect gastric acid secretion, and simultaneously without the side effect such as the extrapyramidal symptoms and diarrhoea, and tolerance is good.
Research shows, mosapride topmost metabolic reaction in human body is that N-goes luorobenzyl, the open loop of beautiful jade ring and N-oxidizing reaction.Studying the metabolite of medicine, is the important channel finding new drug.The metabolism of seminar to not husky Billy of contriver conducts in-depth research.Research finds, its metabolite (R, S)-N-[2-hydroxyl-3-(4-luorobenzyl) amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide have significantly in vitro short digestive tract power effect (Sun Xiaohong. mosapride 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, to finding that the drug candidate with clinical value has great importance.
Summary of the invention
The object of this invention is to provide mosapride active metabolite (R)-N-[2-hydroxyl-3-(4-luorobenzyl) is amino] propyl group-5-chloro-4-amino-2-ethoxy benzamide (levo form) and (S)-N-[2-hydroxyl-3-(4-luorobenzyl) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide (dextrorotatory form) and synthetic method thereof, the preparation method of (R, S)-N-[2-hydroxyl-3-(4-luorobenzyl) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide (racemic modification).
1) (R)-N-[2-hydroxyl-3-(4-luorobenzyl) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide (I-1)
2) (S)-N-[2-hydroxyl-3-(4-luorobenzyl) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide (I-2)
Present invention also offers synthesis (R)-N-[2-hydroxyl-3-(4-luorobenzyl) is amino] propyl group-5-chloro-4-amino-2-ethoxy benzamide (I-1), (S)-N-[2-hydroxyl-3-(4-luorobenzyl) is amino] chloro-4-amino of propyl group-5--2-ethoxy benzamide (I-2) and (R, S) intermediate of-N-[2-hydroxyl-3-(4-luorobenzyl) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide (I), they are selected from:
1) (R)-2-[2-hydroxyl-3-(4-luorobenzyl) is amino] tetrapropylisoindoline-1,3-diketone
2) (S)-2-[2-hydroxyl-3-(4-luorobenzyl) is amino] tetrapropylisoindoline-1,3-diketone
3) (R, S)-2-[2-hydroxyl-3-(4-luorobenzyl) is amino] tetrapropylisoindoline-1,3-diketone
4) (R)-1-amino-3-(4-luorobenzyl) amino-2-propyl alcohol
5) (S)-1-amino-3-(4-luorobenzyl) amino-2-propyl alcohol.
The present invention adopts two kinds of different synthetic methods to prepare N-[2-hydroxyl-3-(4-luorobenzyl) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide:
With corresponding N-(2,3-epoxypropyl) phthalic imidine is that raw material and NSC 158269 are carried out alkylation reaction and obtained 2-[2-hydroxyl-3-(4-luorobenzyl) amino] tetrapropylisoindoline-1,3-diketone, then hydrazinolysis obtains corresponding 1-amino-3-(4-luorobenzyl) amino-2-propyl alcohol, and the last and chloro-4-amino of 5--2-ethoxybenzoic acid condensation obtains;
Or with corresponding N-(2; 3-epoxypropyl) phthalic imidine is that raw material and NSC 158269 are carried out alkylation reaction and obtained 2-[2-hydroxyl-3-(4-luorobenzyl) amino] tetrapropylisoindoline-1; 3-diketone; again through 1-amino-3-(4-luorobenzyl) amino-2-propyl alcohol protected, hydrazinolysis obtains corresponding N-protected (i.e. benzyl amido protecting); then 4-amino-2-ethoxybenzoic acid chloro-to 5-condensation obtains corresponding acylate, and last deprotection obtains target compound.
Described N-(2,3-epoxypropyl) phthalic diamide can be (R)-N-(2,3-epoxypropyl) phthalic diamide, (S)-N-(2,3-epoxypropyl) phthalic diamide or (R, S)-N-(2,3-epoxypropyl) phthalic diamide.
Described blocking group preferred tertiary butoxy carbonyl, p-toluenesulfonyl.
Concrete steps are as follows:
(1) with N-(2,3-epoxypropyl) phthalic imidine is that raw material and NSC 158269 carry out alkylation reaction, the 2-of preparation shown in (I-3) [2-hydroxyl-3-(4-luorobenzyl) is amino] tetrapropylisoindoline-1,3-diketone:
Step comprises: by described N-(2,3-epoxypropyl) phthalic diamide and NSC 158269 be that 1:1 ~ 1:2 joins in solvent according to mol ratio 1:0.8 ~ 1:5 preferred proportion, 20 ~ 100 DEG C, preferable temperature 60 ~ 100 DEG C reaction 5 ~ 7h, after reaction terminating, placement is spent the night, suction filtration, solid solvent is washed, and obtains 2-[2-hydroxyl-3-(4-luorobenzyl) is amino] tetrapropylisoindoline-1,3-diketone.
In above-mentioned preparation method, optional solvent includes but not limited to the mixed solvent of methyl alcohol, ethanol, propyl alcohol, Virahol, acetonitrile and each solvent and water, preferred solvent is methyl alcohol, Virahol, the ratio of N-(2,3-epoxypropyl) phthalic diamide and solvent is 1:3 ~ 10 (m/v).
Described 2-[2-hydroxyl-3-(4-luorobenzyl) is amino] tetrapropylisoindoline-1,3-diketone is (R)-2-[2-hydroxyl-3-(4-luorobenzyl) is amino] tetrapropylisoindoline-1,3-diketone, (S)-2-[2-hydroxyl-3-(4-luorobenzyl) is amino] tetrapropylisoindoline-1,3-diketone or (R, S)-2-[2-hydroxyl-3-(4-luorobenzyl) is amino] tetrapropylisoindoline-1,3-diketone.
(2) with 2-[2-hydroxyl-3-(4-luorobenzyl) is amino] tetrapropylisoindoline-1; 3-diketone (I-3) or N-protected-2-[2-hydroxyl-3-(4-luorobenzyl) is amino] tetrapropylisoindoline-1,3-diketone (I-6) hydrazinolysis prepare 1-amino-3-(4-luorobenzyl) amino-2-propyl alcohol shown in (I-4) or N-protected-1-amino-3-(4-luorobenzyl) amino-2-propyl alcohol:
Step comprises: by described 2-[2-hydroxyl-3-(4-luorobenzyl) is amino] tetrapropylisoindoline-1, 3-diketone or N-protected-2-[2-hydroxyl-3-(4-luorobenzyl) is amino] tetrapropylisoindoline-1, 3-diketone and hydrazine hydrate are according to mol ratio 1:1 ~ 1:8, preferred proportion is that 1:5 ~ 1:7 joins in solvent, 20 ~ 80 DEG C, preferable temperature is 40 ~ 60 DEG C of reaction 5 ~ 6h, after reaction terminating, be spin-dried for solvent, extraction agent room temperature is pulled an oar, suction filtration obtains filtrate, slough solvent, obtain 1-amino-3-(4-luorobenzyl) amino-2-propyl alcohol or N-protected-1-amino-3-(4-luorobenzyl) amino-2-propyl alcohol.
In above-mentioned preparation method, solvent can be selected to include but not limited to methyl alcohol, ethanol, propyl alcohol, Virahol, acetonitrile, preferred solvent is methyl alcohol, Virahol, 2-[2-hydroxyl-3-(4-luorobenzyl) is amino] tetrapropylisoindoline-1, the ratio of 3-diketone or N-protected-2-[2-hydroxyl-3-(4-luorobenzyl) is amino] tetrapropylisoindoline-1,3-diketone and solvent is 1:3 ~ 10 (m/v); Extraction agent can be selected to include but not limited to methyl alcohol, ethanol, propyl alcohol, Virahol, ethyl acetate, methylene dichloride, and preferred solvent is methylene dichloride.
Described 1-amino-3-(4-luorobenzyl) amino-2-propyl alcohol is (R)-1-amino-3-(4-luorobenzyl) amino-2-propyl alcohol, (S)-1-amino-3-(4-luorobenzyl) amino-2-propyl alcohol or (R, S)-1-amino-3-(4-luorobenzyl) amino-2-propyl alcohol.
Described N-protected-1-amino-3-(4-luorobenzyl) amino-2-propyl alcohol is (R)-N-protected-1-amino-3-(4-luorobenzyl) amino-2-propyl alcohol, (S)-N-protected-1-amino-3-(4-luorobenzyl) amino-2-propyl alcohol or (R, S)-N-protected-1-amino-3-(4-luorobenzyl) amino-2-propyl alcohol.
Described blocking group preferred tertiary butoxy carbonyl, p-toluenesulfonyl.
Wherein, described N-protected-2-[2-hydroxyl-3-(4-luorobenzyl) is amino] tetrapropylisoindoline-1,3-diketone (I-6) is prepared by the following method:
With 2-[2-hydroxyl-3-(4-luorobenzyl) is amino] tetrapropylisoindoline-1; 3-diketone and protection reagent react prepare N-protected-2-[2-hydroxyl-3-(4-luorobenzyl) is amino] tetrapropylisoindoline-1, the 3-diketone Ru shown in (I-6):
Step comprises: by described 2-[2-hydroxyl-3-(4-luorobenzyl) is amino] tetrapropylisoindoline-1; 3-diketone and protection reagent are according to mol ratio 1:1 ~ 1:5; preferred proportion is that 1:1 ~ 1:3 and catalyzer join in solvent;-20 ~ 50 DEG C; preferable temperature is-15 ~ 0 DEG C of reaction 30min ~ 1h; obtain N-protected-2-[2-hydroxyl-3-(4-luorobenzyl) is amino] tetrapropylisoindoline-1,3-diketone.
Described solvent is methyl alcohol, ethanol, propyl alcohol, Virahol, acetonitrile or DMF, preferred solvent is DMF, the ratio of 2-[2-hydroxyl-3-(4-luorobenzyl) is amino] tetrapropylisoindoline-1,3-diketone and solvent is 1:3 ~ 14 (m/v); Catalyzer is one or more in anhydrous sodium carbonate, sodium bicarbonate, Anhydrous potassium carbonate, saleratus, sodium hydroxide, potassium hydroxide or triethylamine, preferred catalyst is Anhydrous potassium carbonate, triethylamine, the mol ratio of 2-[2-hydroxyl-3-(4-luorobenzyl) is amino] tetrapropylisoindoline-1,3-diketone and catalyzer is 1:1 ~ 5.
Blocking group preferred tertiary butoxy carbonyl, p-toluenesulfonyl.
(3) N-[2-hydroxyl-3-(4-luorobenzyl) is amino] the chloro-4-amino of the propyl group-5--2-ethoxy benzamide of the N-protected shown in N-[2-hydroxyl-3-(4-luorobenzyl) the is amino] propyl group-5-chloro-4-amino-2-ethoxy benzamide shown in (I) or (I-5) is prepared with 1-amino-3-(4-luorobenzyl) amino-2-propyl alcohol or N-protected-1-amino-3-(4-luorobenzyl) amino-2-propyl alcohol and the condensation of 5-chloro-4-amino-2-ethoxybenzoic acid:
Step comprises: by described 1-amino-3-(4-luorobenzyl) amino-2-propyl alcohol or N-protected-1-amino-3-(4-luorobenzyl) amino-2-propyl alcohol and the chloro-4-amino of 5--2-ethoxybenzoic acid, EDCI, HOBt is according to mol ratio 1:(0.8-2): (1-3): (1-3), preferred proportion is 1:(0.8-1): (1-1.5): (1-1.5), and catalyzer joins in solvent,-25 ~ 80 DEG C, preferable temperature is-25 ~-10 DEG C of reaction 30min ~ 1h, obtain N-[2-hydroxyl-3-(4-luorobenzyl) is amino] propyl group-5-chloro-4-amino-2-ethoxy benzamide or N-protected-[2-hydroxyl-3-(4-luorobenzyl) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide.
In above-mentioned preparation method, solvent can be selected to include but not limited to DMF, methyl alcohol, ethanol, Virahol, preferred solvent is the ratio of DMF, 1-amino-3-(4-luorobenzyl) amino-2-propyl alcohol or N-protected-1-amino-3-(4-luorobenzyl) amino-2-propyl alcohol and solvent is 1:3 ~ 15 (m/v); Available catalyzer include but not limited in anhydrous sodium carbonate, sodium bicarbonate, Anhydrous potassium carbonate, saleratus, sodium hydroxide, potassium hydroxide, triethylamine one or more; preferred catalyst is Anhydrous potassium carbonate, triethylamine, and the mol ratio of 1-amino-3-(4-luorobenzyl) amino-2-propyl alcohol or N-protected-1-amino-3-(4-luorobenzyl) amino-2-propyl alcohol and catalyzer is 1:2.5 ~ 5.
Described N-[2-hydroxyl-3-(4-luorobenzyl) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide is (R)-N-[2-hydroxyl-3-(4-luorobenzyl) is amino] propyl group-5-chloro-4-amino-2-ethoxy benzamide, (S)-N-[2-hydroxyl-3-(4-luorobenzyl) is amino] propyl group-5-chloro-4-amino-2-ethoxy benzamide or (R, S)-N-[2-hydroxyl-3-(4-luorobenzyl) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide.
Described N-protected-[2-hydroxyl-3-(4-luorobenzyl) is amino] propyl group-5-chloro-4-amino-2-ethoxy benzamide is that (R)-N-protected-[2-hydroxyl-3-(4-luorobenzyl) is amino] propyl group-5-chloro-4-amino-2-ethoxy benzamide is, (S)-N-protected-[2-hydroxyl-3-(4-luorobenzyl) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide is or (R, S)-N-protected-[2-hydroxyl-3-(4-luorobenzyl) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide.
Wherein, N-protected-[2-hydroxyl-3-(4-luorobenzyl) is amino] propyl group-5-chloro-4-amino-2-ethoxy benzamide (I-5) and sour deprotection prepare N-[2-hydroxyl-3-(4-luorobenzyl) is amino] the chloro-4-amino of the propyl group-5--2-ethoxy benzamide Ru shown in (I):
Step comprises: by described N-protected-[2-hydroxyl-3-(4-luorobenzyl) amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide with acid according to mol ratio 1:1 ~ 1:6; preferred proportion is that 1:3 ~ 1:5 joins in solvent;-25 ~ 40 DEG C; preferable temperature is-25 ~ 0 DEG C of reaction 1 ~ 4h; pour in buck; extraction agent extracts, and sloughs solvent, obtains N-[2-hydroxyl-3-(4-luorobenzyl) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide.
In above-mentioned preparation method, solvent can be selected to include but not limited to methylene dichloride, chloroform, preferred solvent is methylene dichloride, and the ratio of N-protected-[2-hydroxyl-3-(4-luorobenzyl) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide and solvent is 1:3 ~ 10 (m/v); Described extraction agent is methylene dichloride, ethyl acetate, ethyl acetate; Described acid is hydrogenchloride, acetic acid, trifluoroacetic acid, preferred trifluoroacetic acid.
Described N-[2-hydroxyl-3-(4-luorobenzyl) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide is (R)-N-[2-hydroxyl-3-(4-luorobenzyl) is amino] propyl group-5-chloro-4-amino-2-ethoxy benzamide, (S)-N-[2-hydroxyl-3-(4-luorobenzyl) is amino] propyl group-5-chloro-4-amino-2-ethoxy benzamide or (R, S)-N-[2-hydroxyl-3-(4-luorobenzyl) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide.
The pharmacy acceptable salt of compound of the present invention is prepared by the following method:
Corresponding salt is prepared with acid with N-[2-hydroxyl-3-(4-luorobenzyl) is amino] propyl group-5-chloro-4-amino-2-ethoxy benzamide:
Step comprises: by described N-[2-hydroxyl-3-(4-luorobenzyl) amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide with acid according to mol ratio 1:1-1:5, preferred proportion is that 1:1 ~ 1:3 joins in solvent, 0 ~ 45 DEG C, preferable temperature is 20 ~ 30 DEG C of reaction 1 ~ 3h, separate out solid, suction filtration, obtains N-[2-hydroxyl-3-(4-luorobenzyl) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide hydrochlorate.
Described solvent is ethyl acetate, methylene dichloride, acetone, methyl tertiary butyl ether, methyl alcohol, ethanol, Virahol and mixed solvent wherein, preferred acetone, ethyl acetate, ethanol, methyl tertiary butyl ether and mixed solvent thereof, the ratio of N-[2-hydroxyl-3-(4-luorobenzyl) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide and solvent is 1:2 ~ 1:8 (m/v).
Described acid is hydrochloric acid, acetic acid, tartrate, succsinic acid, fumaric acid, toxilic acid, phosphoric acid, preferred hydrochloric acid, succsinic acid, tartrate, fumaric acid, toxilic acid.
Described N-[2-hydroxyl-3-(4-luorobenzyl) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide is (R)-N-[2-hydroxyl-3-(4-luorobenzyl) is amino] propyl group-5-chloro-4-amino-2-ethoxy benzamide, (S)-N-[2-hydroxyl-3-(4-luorobenzyl) is amino] propyl group-5-chloro-4-amino-2-ethoxy benzamide or (R, S)-N-[2-hydroxyl-3-(4-luorobenzyl) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide.
Take tertbutyloxycarbonyl as protecting group be example, synthetic route of the present invention is expressed as follows:
Compound of the present invention, and pharmacy acceptable salt is as active ingredient, medicinal compositions is prepared into pharmaceutically acceptable carrier or mixed with excipients, and being prepared into acceptable formulation clinically, above-mentioned pharmaceutically acceptable vehicle refers to any thinner, auxiliary and/or the carrier that can be used for pharmaceutical field.
Medicinal compositions of the present invention with can become pharmaceutical preparation by some conventional excipient in pharmaceutical field.Described preparation can be injection, tablet, capsule, aerosol, suppository, film, pill, externally-applied liniment, ointment etc.
Vehicle for pharmaceutical composition of the present invention or pharmaceutical preparation comprises: tackiness agent, lubricant, disintegrating agent, solubility promoter, thinner, stablizer, suspension agent, non-pigment, correctives, sanitas, solubilizing agent and matrix etc.Pharmaceutical preparation can oral administration or parenteral (such as intravenously, subcutaneous, intraperitoneal or local) administration, if some drugs is unstable under stomach condition, can be mixed with enteric coated tablets.
The present invention investigates racemic modification, dextrorotatory form and levo form to the effect of gastrointestinal peristalsis by mouse small intestine propulsion model.Raceme and dextrorotatory form cause Mouse Stomach intestinal dysfunction to abdominal injection coromegine and have therapeutic action.
Compound or pharmaceutically acceptable salt thereof of the present invention can be used as gastric motility medicine and is used alone, or can with the gastric motility medicine now gone on the market (as metoclopramide, domperidone, Tegaserod, itopride etc.) conbined usage.Combination therapy by by each treatment component simultaneously, order or separate administration to realize.
The compounds of this invention and preparation method thereof and the preparation method with medicinal compositions are illustrated and illustrated to the embodiment hereinafter provided and preparation example further.Should be appreciated that the scope of following example and preparation example and limit the scope of the invention never in any form.
Embodiment:
N-[2-hydroxyl-3-(4-luorobenzyl) is amino] the chloro-4-amino of the propyl group-5--2-ethoxy benzamide that the present invention will synthesize and corresponding salt can carry out as follows:
Embodiment 1
1) (R)-2-[2-hydroxyl-3-(4-luorobenzyl) is amino] tetrapropylisoindoline-1,3-diketone
In 1L three-necked bottle, add (S)-N-(2,3-epoxypropyl) phthalic diamide 100g, NSC 158269 74g and Virahol 600mL, back flow reaction 2.5h, after reaction terminating, placement is spent the night, suction filtration, solid isopropyl alcohol wash, methylene dichloride is pulled an oar, 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, CDCl
3) 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-propyl alcohol
In 2L three-necked bottle, add (R)-2-[2-hydroxyl-3-(4-luorobenzyl) is amino] tetrapropylisoindoline-1,3-diketone 127.2g, 80% hydrazine hydrate 760mL and methyl alcohol 250mL, 45 DEG C of reaction 5h, after reaction terminating, remove solvent under reduced pressure, residuum ethanol room temperature making beating, suction filtration, solvent in removing filtrate, obtain transparent oily liquid 63.0g, yield 82%, ESI-MS m/z:199.1 [M+H]
+; [221.1 M+Na]
+,
1h NMR (600MHz, CDCl
3) 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) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide
In 1L three-necked bottle, add the chloro-4-amino of (S)-1-amino-3-(4-luorobenzyl) amino-2-propyl alcohol 63.0g, EDCI 88.2g, HOBt 78.5g, 5--2-ethoxybenzoic acid 76.0g, triethylamine 45.5g and DMF 500mL,-25 DEG C of reaction 1h, after reaction terminating, pour in buck, separate out solid, suction filtration, washing, dry, Gossypol recrystallized from chloroform, obtain 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, CDCl
3) 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) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide hydrochloride
In 1L three-necked bottle, add (R)-N-[2-hydroxyl-3-(4-luorobenzyl) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide 106.2g, acetone 530mL, stirring at room temperature, after dissolution of solid, slowly ether solution of hydrogen chloride 380mL (1.78mol/L) is dripped in solution, stirring at room temperature reaction 1h, separate out solid, suction filtration, filter cake acetone is washed, and vacuum-drying obtains white solid 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) is amino] tetrapropylisoindoline-1,3-diketone
In 500mL three-necked bottle, add (S)-N-(2,3-epoxypropyl) phthalic diamide 78g, NSC 158269 55.5g and Virahol 430mL, back flow reaction 2.5h, after reaction terminating, placement is spent the night, suction filtration, solid isopropyl alcohol wash, methylene dichloride is pulled an oar, 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, CDCl
3) δ 7.84 – 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) is amino] tetrapropylisoindoline-1,3-diketone
In 1L three-necked bottle, add (R)-2-[2-hydroxyl-3-(4-luorobenzyl) is amino] tetrapropylisoindoline-1,3-diketone 90.7g, triethylamine 56g and DMF 700mL, at-10 ~ 0 DEG C, drip (Boc)
2o 66.7g, reacts 1h at this temperature, after reaction terminating, is poured into water, suction filtration, and 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, CDCl
3) 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-propyl alcohol
In 1L three-necked bottle, add (S)-N-tertbutyloxycarbonyl-2-[2-hydroxyl-3-(4-luorobenzyl) is amino] tetrapropylisoindoline-1,3-diketone 97.6g, 80% hydrazine hydrate 580mL and methyl alcohol 200mL, 45 DEG C of reaction 5h, after reaction terminating, solvent is divided exactly in decompression, residuum methylene dichloride room temperature making beating, suction filtration obtains filtrate, sloughs solvent and obtains pale yellow oily liquid body 54.0g, yield 79.5%, ESI-MS m/z:299.2 [M+H]
+; [321.2 M+Na]
+,
1hNMR (400MHz, CDCl
3) δ 7.21 – 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) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide
In 500mL three-necked bottle, add the chloro-4-amino of (S)-N-tertbutyloxycarbonyl-1-amino-3-(4-luorobenzyl) amino-2-propyl alcohol 54.0g, 5--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 buck, separate out solid, suction filtration, solid is washed, dry product 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, CDCl
3) 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) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide
In 1L three-necked bottle, add (S)-N-tertbutyloxycarbonyl-[2-hydroxyl-3-(4-luorobenzyl) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide 71.8g and methylene dichloride 280mL, trifluoroacetic acid 280mL is dripped at-15 ~-10 DEG C, 3h is reacted at this temperature, pour in buck, extraction into ethyl acetate, anhydrous sodium sulfate drying, slough solvent afforded crude material, Gossypol recrystallized from chloroform obtains 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, CDCl
3) 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) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide succinate
In 100mL three-necked bottle, add (R)-N-[2-hydroxyl-3-(4-luorobenzyl) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide 10g, ethyl acetate 50mL, 30 DEG C are stirred 30min, after dissolution of solid, slowly add succsinic acid 3.2g, stirring reaction 1h, separate out solid, suction filtration, filter cake ethyl acetate is washed, and vacuum-drying obtains 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) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide tartrate hydrochlorate
In 100mL three-necked bottle, add (R)-N-[2-hydroxyl-3-(4-luorobenzyl) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide 10g, acetone 55mL, 30 DEG C are stirred 30min, after dissolution of solid, slowly add tartrate 4g, stirring reaction 1h, separate out solid, suction filtration, filter cake acetone is washed, and vacuum-drying obtains 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) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide maleate
In 100mL three-necked bottle, add (R)-N-[2-hydroxyl-3-(4-luorobenzyl) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide 10g, ethyl acetate 60mL, 30 DEG C are stirred 40min, after dissolution of solid, slowly add toxilic acid 3.1g, stirring reaction 1.5h, separate out solid, suction filtration, filter cake ethyl acetate is washed, and vacuum-drying obtains 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) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide fumarate
In 100mL three-necked bottle, add (R)-N-[2-hydroxyl-3-(4-luorobenzyl) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide 9.8g, ethyl acetate 50mL, 30 DEG C are stirred 55min, after dissolution of solid, slowly add fumaric acid 3.0g, stirring reaction 2h, separate out solid, suction filtration, filter cake ethyl acetate is washed, and vacuum-drying obtains 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) is amino] tetrapropylisoindoline-1,3-diketone
In 1L three-necked bottle, add (R)-N-(2,3-epoxypropyl) phthalic diamide 100g, NSC 158269 74g and Virahol 600mL, back flow reaction 2h, after reaction terminating, placement is spent the night, next day suction filtration, solid isopropyl alcohol wash, methylene dichloride is pulled an oar, 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, CDCl
3) 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) is amino] tetrapropylisoindoline-1,3-diketone
In 1L three-necked bottle, add (S)-2-[2-hydroxyl-3-(4-luorobenzyl) is amino] tetrapropylisoindoline-1,3-diketone 121g, triethylamine 74.7g and DMF 600mL, at-15 DEG C, drip (Boc)
2o 88.7g, reacts 30min at this temperature, after reaction terminating, is poured into water, suction filtration, and 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, CDCl
3) 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-propyl alcohol
In 2L three-necked bottle, add (R)-N-tertbutyloxycarbonyl-2-[2-hydroxyl-3-(4-luorobenzyl) is amino] tetrapropylisoindoline-1,3-diketone 138.7g, 80% hydrazine hydrate 900mL and methyl alcohol 280mL, 45 DEG C of reaction 5h, after reaction terminating, remove solvent under reduced pressure, residuum methylene dichloride room temperature making beating, suction filtration obtains filtrate, sloughs solvent and obtains pale yellow oily liquid body 78.9g, yield 81.7%, ESI-MS m/z:299.2 [M+H]
+; [321.2 M+Na]
+,
1h NMR (400MHz, CDCl
3) δ 7.21 – 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) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide
In 500mL three-necked bottle, add the chloro-4-amino of (R)-N-tertbutyloxycarbonyl-1-amino-3-(4-luorobenzyl) amino-2-propyl alcohol 78.9g, 5--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 buck, separate out solid, suction filtration, solid is washed, dry product 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, CDCl
3) 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) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide
In 1L three-necked bottle, add (R)-N-tertbutyloxycarbonyl-[2-hydroxyl-3-(4-luorobenzyl) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide 92g and methylene dichloride 370mL, trifluoroacetic acid 370mL is dripped at-15 DEG C, 2h is reacted at this temperature, pour in buck, extraction into ethyl acetate, anhydrous sodium sulfate drying, slough 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, CDCl
3) 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) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide hydrochloride
In 1L three-necked bottle, add (S)-N-[2-hydroxyl-3-(4-luorobenzyl) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide 56.2g, acetone 300mL, stirring at room temperature, after dissolution of solid, slowly ether solution of hydrogen chloride 254mL (1.4mol/L) is dripped in solution, stirring at room temperature reaction 1h, separate out solid, add methyl tertiary butyl ether 254mL, stir 0.5h, suction filtration, filter cake acetone is washed, vacuum-drying obtains 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) is amino] tetrapropylisoindoline-1,3-diketone
In 500mL three-necked bottle, add (R, S)-N-(2,3-epoxypropyl) phthalic diamide 55g, NSC 158269 40.7g and methyl alcohol 220mL, back flow reaction 3h, after reaction terminating, placement is spent the night, suction filtration, solid methanol is washed, and methylene dichloride is pulled an oar, dry white solid powder 65.3g, 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, CDCl
3) 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) is amino] tetrapropylisoindoline-1,3-diketone
In 1L three-necked bottle, add (R, S)-2-[2-hydroxyl-3-(4-luorobenzyl) is amino] tetrapropylisoindoline-1,3-diketone 65.3g, Anhydrous potassium carbonate 44.9g and DMF 410mL, at-10 ~ 0 DEG C, drip (Boc)
2o 47.9g, room temperature reaction 1h, after reaction terminating, be poured into water, suction filtration, and 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, CDCl
3) 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-propyl alcohol
In 1L three-necked bottle, add (R, S)-N-tertbutyloxycarbonyl-2-[2-hydroxyl-3-(4-luorobenzyl) is amino] tetrapropylisoindoline-1,3-diketone 85.5g, 80% hydrazine hydrate 512mL and methyl alcohol 170mL, 45 DEG C of reaction 5h, after reaction terminating, solvent is divided exactly in decompression, and methylene dichloride room temperature is pulled an oar, suction filtration obtains filtrate, slough solvent and obtain pale yellow oily liquid body 47.3g, yield 79.5%, ESI-MS m/z:299.2 [M+H]
+; [321.2 M+Na]
+,
1h NMR (400MHz, CDCl
3) δ 7.20 – 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) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide
In 500mL three-necked bottle, add (R, S) the chloro-4-amino of-N-tertbutyloxycarbonyl-1-amino-3-(4-luorobenzyl) amino-2-propyl alcohol 47.3g, 5--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 buck, separate out solid, suction 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, CDCl
3) 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) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide
In 1L three-necked bottle, add (R, S)-N-tertbutyloxycarbonyl-[2-hydroxyl-3-(4-luorobenzyl) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide 62.9g and methylene dichloride 250mL, trifluoroacetic acid 250mL is dripped at-10 ~-5 DEG C, 3h is reacted at this temperature, pour in buck, extraction into ethyl acetate, anhydrous sodium sulfate drying, slough solvent afforded crude material 27.3g, Gossypol recrystallized from chloroform 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, CDCl
3) 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) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide hydrochloride
In 1L three-necked bottle, add (R, S)-N-[2-hydroxyl-3-(4-luorobenzyl) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide 33.9g, acetone 240mL, stirring at room temperature, after dissolution of solid, slowly ether solution of hydrogen chloride 153mL (1.4mol/L) is dripped in solution, stirring at room temperature reaction 1.5h, separate out solid, add methyl tertiary butyl ether 240mL, stir 0.5h, suction filtration, filter cake acetone is washed, vacuum-drying obtains 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) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide (raceme)
(R)-N-[2-hydroxyl-3-(4-luorobenzyl) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide (levo form)
(S)-N-[2-hydroxyl-3-(4-luorobenzyl) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide (dextrorotatory form)
There is provided unit: provided by medicine analytics teaching and research room of Shenyang Pharmaceutical University
Reagent and unit is provided:
Tropintran, He'nan Runhong Pharmaceutical Co., Ltd.'s lot number: 1206071
Sodium cellulose glycolate, Tianjin Bo Di Chemical Co., Ltd. lot number: XK-13-011-00003
Physiological saline, Dou Bang medicine company limited-liability company of Jilin Province lot number: 1303260307
Activity charcoal 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 coromegine (1mg/2mL) adds normal saline dilution to 0.1mg/mL.This liquid matching while using.1% sodium cellulose glycolate:
Take sodium cellulose glycolate 1g, measure 100mL distilled water and be placed in beaker, sodium cellulose glycolate is evenly sprinkling upon distilled water surface, leave standstill 24h.
5% charcoal end suspension:
Analytical balance takes activity charcoal powder 1g and joins in 20mL 1% sodium cellulose glycolate, mixes.Should stir before using can gavage evenly.
Prepared by mosapride solution:
Get commercially available medicine mosapride 1 (every sheet is containing mosapride 3.52mg), be placed in reagent bottle, measure in distilled water 22.7mL reagent bottle with 20mL syringe, can gavage after fully dissolving.
Prepared by test medicine solution:
Analytical balance takes test medicine and adds in distilled water, ultrasonic dissolution 5min, can gavage after fully dissolving.
Laboratory animal
KM mouse, SPF level, male, body weight 18 ~ 22g, Shenyang Pharmaceutical University's animal center provides, conformity certification: No.211002300005190, credit number: SCXK (the Liao Dynasty) 20100001.
Rearing conditions: temperature, 18 ~ 26 DEG C; Humidity, 40 ~ 70%.Feed is provided by Yuhong District, Shenyang City Qian Min animal-feed factory.
2) method and result
Get KM mouse 110, raise and train and be divided into 11 groups at random afterwards in three days, often organize 10, be respectively blank group, model group, mosapride group, the high, medium and low dosage group of racemic modification, the high, medium and low dosage group of levo form (I-1), the high, medium and low dosage group of dextrorotatory form (I-2).Each administration group gives the test medicine of corresponding dosage respectively by table 1 gavage, blank group and model group gavage give distilled water, administration volume is 0.2mL/10g, after 30min, except blank group, all the other are respectively organized all according to 1mg/kg abdominal injection 0.01% coromegine, continue timing 30min, the equal gavage of all animals gives 5% charcoal end suspension (0.3mL/ only), after 30min, mouse takes off cervical vertebra execution, abdominal cut, ligation stomach orifice of the stomach and pylorus end, rapid taking-up small intestine, do not add traction and be laid in (sheet glass scribbles physiological saline in advance) on sheet glass with a scale, measuring pyloric region respectively to the distance of ileocecus is total small intestinal length, pylorus is charcoal end advance distance to suspension forward position, charcoal end, calculate Intestinal propulsive rate, Intestinal propulsive rate=charcoal end suspension advance distance/total small intestinal length × 100%.
Table 1 respectively organizes dosage
Table 2: test medicine is to the promoter action of the gastrointestinal propulsive movement of gastrointestinal dysfunction mouse caused by coromegine
* P<0.05 administration group Vs blank group * * P<0.01 administration group Vs blank group
#P<0.05 is subject to reagent group Vs negative control by reagent group Vs negative control ##P<0.01
As can be seen from Table 2, model group compares propelling rate and significantly declines with blank, illustrates that coromegine causes Mouse Stomach intestinal dysfunction model modeling success; Raceme high dose group, dextrorotation height, middle dosage group propelling rate compared with model group significantly increase, to illustrate in raceme high dosage, dextrorotatory form high dosage and dextrorotatory form that dosage causes Mouse Stomach intestinal dysfunction model to abdominal injection coromegine and has and promote gastrointestinal motility effect, levo form is invalid.
Conclusion: under same dose, the activity of dextrorotatory form is greater than raceme, and dextrorotatory form and raceme cause Mouse Stomach intestinal dysfunction to abdominal injection coromegine and have therapeutic action, and levo form does not have the effect promoting gastrointestinal motility.
Embodiment 6: tablet
With containing compound (dextrorotatory form compound) 10g in claim 1, after adding auxiliary material 20g mixing according to the general pressed disc method of pharmaceutics, be pressed into 100, the heavy 300mg of every sheet.
Embodiment 7: capsule
With containing compound (dextrorotatory form compound) 10g in claim 1, after being mixed by auxiliary material 20g according to the requirement of pharmaceutics capsule, load Capsules, the heavy 300mg of each capsule.
Embodiment 8: injection
With containing compound (dextrorotatory form compound) 10g in claim 1, according to pharmaceutics ordinary method, carry out charcoal absorption, after 0.65 μM of filtering with microporous membrane, insert nitrogen pot and make hydro-acupuncture preparation, often only fill 2mL, filling 100 bottles altogether.
Claims (11)
1. there is compound and the pharmacy acceptable salt thereof of following structure:
1) (R)-N-[2-hydroxyl-3-(4-luorobenzyl) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide (I-1)
2) (S)-N-[2-hydroxyl-3-(4-luorobenzyl) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide (I-2)
2. synthesize (R) according to claim 1-N-[2-hydroxyl-3-(4-luorobenzyl) is amino] propyl group-5-chloro-4-amino-2-ethoxy benzamide (I-1), (S)-N-[2-hydroxyl-3-(4-luorobenzyl) is amino] chloro-4-amino of propyl group-5--2-ethoxy benzamide (I-2) or (R, S) intermediate of-N-[2-hydroxyl-3-(4-luorobenzyl) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide, they are selected from:
1) (R)-2-[2-hydroxyl-3-(4-luorobenzyl) is amino] tetrapropylisoindoline-1,3-diketone
2) (S)-2-[2-hydroxyl-3-(4-luorobenzyl) is amino] tetrapropylisoindoline-1,3-diketone
3) (R, S)-2-[2-hydroxyl-3-(4-luorobenzyl) is amino] tetrapropylisoindoline-1,3-diketone
4) (R)-1-amino-3-(4-luorobenzyl) amino-2-propyl alcohol
5) (S)-1-amino-3-(4-luorobenzyl) amino-2-propyl alcohol.
3. compound as claimed in claim 1 and pharmacy acceptable salt thereof, it is characterized in that, described pharmacy acceptable salt is obtained by reacting in a suitable solvent by compound according to claim 1 and corresponding acid, and described acid is selected from hydrochloric acid, phosphoric acid, acetic acid, tartrate, succsinic acid, fumaric acid or toxilic acid; Solvent is selected from ethyl acetate, methylene dichloride, acetone, methyl tertiary butyl ether, methyl alcohol, ethanol, Virahol and mixed solvent thereof, preferred acetone, ethanol, ethyl acetate, methyl tertiary butyl ether.
4. the preparation method of compound as claimed in claim 1 or (R, S)-N-[2-hydroxyl-3-(4-luorobenzyl) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide; It is characterized in that,
(1) be that raw material and NSC 158269 are carried out alkylation reaction and obtained 2-[2-hydroxyl-3-(4-luorobenzyl) amino] tetrapropylisoindoline-1,3-diketone with corresponding N-(2,3-epoxypropyl) phthalic imidine;
(2) 2-[2-hydroxyl-3-(4-luorobenzyl) is amino] tetrapropylisoindoline-1,3-diketone hydrazinolysis obtains corresponding 1-amino-3-(4-luorobenzyl) amino-2-propyl alcohol;
(3) 1-amino-3-(4-luorobenzyl) amino-2-propyl alcohol and the-2-ethoxybenzoic acid condensation of the chloro-4-amino of 5-and get final product; Or
(1 ＇) is that raw material and NSC 158269 are carried out alkylation reaction and obtained 2-[2-hydroxyl-3-(4-luorobenzyl) amino] tetrapropylisoindoline-1,3-diketone with corresponding N-(2,3-epoxypropyl) phthalic imidine;
(2 ＇) is again through protecting N-protected-2-[2-hydroxyl-3-(4-luorobenzyl) amino] tetrapropylisoindoline-1,3-diketone, hydrazinolysis obtain 1-amino-3-(4-luorobenzyl) amino-2-propyl alcohol of corresponding N-protected;
(3 ＇) then 4-amino-2-ethoxybenzoic acid chloro-to 5-condensation obtains corresponding acylate N-protected-[2-hydroxyl-3-(4-luorobenzyl) amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide, last deprotection and get final product;
Described N-(2,3-epoxypropyl) phthalic imidine is (R)-N-(2,3-epoxypropyl) phthalic imidine, (S)-N-(2,3-epoxypropyl) phthalic imidine or (R, S)-N-(2,3-epoxypropyl) phthalic imidine.
5. preparation method as claimed in claim 4, it is characterized in that, in step (1) or (1 ＇), by N-(2,3-epoxypropyl) phthalic diamide and NSC 158269 according to mol ratio 1:0.8 ~ 1:5, preferred proportion is 1:1 ~ 1:2, join in solvent, 20 ~ 100 DEG C, preferable temperature 60 ~ 100 DEG C reaction 5 ~ 7h, obtain 2-[2-hydroxyl-3-(4-luorobenzyl) is amino] tetrapropylisoindoline-1,3-diketone; Described solvent is the mixed solvent of methyl alcohol, ethanol, propyl alcohol, Virahol, acetonitrile or each solvent and water, and preferred solvent is methyl alcohol or Virahol.
6. preparation method as claimed in claim 4, it is characterized in that, in step (2) or (2 ＇), by 2-[2-hydroxyl-3-(4-luorobenzyl) is amino] tetrapropylisoindoline-1, 3-diketone or N-protected-2-[2-hydroxyl-3-(4-luorobenzyl) is amino] tetrapropylisoindoline-1, 3-diketone and hydrazine hydrate are according to mol ratio 1:1 ~ 1:8, preferred proportion is that 1:5 ~ 1:7 joins in solvent, 20 ~ 80 DEG C, preferable temperature is 40 ~ 60 DEG C of reaction 5 ~ 6h, obtain 1-amino-3-(4-luorobenzyl) amino-2-propyl alcohol or N-protected-1-amino-3-(4-luorobenzyl) amino-2-propyl alcohol, described solvent is methyl alcohol, ethanol, propyl alcohol, Virahol or acetonitrile, and preferred solvent is methyl alcohol or Virahol.
7. preparation method as claimed in claim 4, it is characterized in that, in step (3) or (3 ＇), N-protected-1-amino-3-(4-luorobenzyl) amino-2-propyl alcohol that 1-amino-3-(4-luorobenzyl) amino-2-propyl alcohol (2) obtained or (2 ') obtain and the chloro-4-amino of 5--2-ethoxybenzoic acid, EDCI, HOBt is according to mol ratio 1:(0.8-2): (1-3): (1-3), preferred proportion is 1:(0.8-1): (1-1.5): (1-1.5), and catalyzer joins in solvent,-25 ~ 80 DEG C, preferable temperature is-25 ~-10 DEG C of reaction 30min ~ 1h, obtain N-[2-hydroxyl-3-(4-luorobenzyl) is amino] propyl group-5-chloro-4-amino-2-ethoxy benzamide or N-protected-[2-hydroxyl-3-(4-luorobenzyl) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide, described solvent is DMF, methyl alcohol, ethanol or Virahol, and preferred solvent is DMF, catalyzer is one or more in anhydrous sodium carbonate, sodium bicarbonate, Anhydrous potassium carbonate, saleratus, sodium hydroxide, potassium hydroxide or triethylamine, and preferred catalyst is Anhydrous potassium carbonate or triethylamine.
8. preparation method as claimed in claim 4, it is characterized in that, in step (2 ＇), 2-[2-hydroxyl-3-(4-luorobenzyl) the is amino] tetrapropylisoindoline-1 that (1 ＇) is obtained, 3-diketone and protection reagent are according to mol ratio 1:1 ~ 1:5, preferred proportion is that 1:1 ~ 1:3 and catalyzer join in solvent,-20 ~ 50 DEG C, preferable temperature is-15 ~ 0 DEG C of reaction 30min ~ 1h, obtain N-protected-2-[2-hydroxyl-3-(4-luorobenzyl) is amino] tetrapropylisoindoline-1,3-diketone;
Described solvent is methyl alcohol, ethanol, propyl alcohol, Virahol, acetonitrile or DMF, and preferred solvent is DMF; Catalyzer is one or more in anhydrous sodium carbonate, sodium bicarbonate, Anhydrous potassium carbonate, saleratus, sodium hydroxide, potassium hydroxide or triethylamine, and preferred catalyst is Anhydrous potassium carbonate, triethylamine; Blocking group preferred tertiary butoxy carbonyl, p-toluenesulfonyl.
9. preparation method as claimed in claim 4, it is characterized in that, in step (3 ＇), by described N-protected-[2-hydroxyl-3-(4-luorobenzyl) amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide with acid according to mol ratio 1:1 ~ 1:6, preferred proportion is that 1:3 ~ 1:5 joins in solvent,-25 ~ 40 DEG C, preferable temperature is-25 ~ 0 DEG C of reaction 1 ~ 4h, pour in buck, extraction agent extracts, slough solvent, obtain N-[2-hydroxyl-3-(4-luorobenzyl) is amino] the chloro-4-amino of propyl group-5--2-ethoxy benzamide; Described solvent is methylene dichloride, chloroform, and preferred solvent is methylene dichloride; Described extraction agent is methylene dichloride, ethyl acetate, ethyl acetate, and described acid is hydrogenchloride, acetic acid, trifluoroacetic acid, preferred trifluoroacetic acid.
10. a medicinal compositions, comprises compound according to claim 1 and pharmacy acceptable salt thereof as active ingredient and pharmaceutically acceptable carrier.
11. compound according to claim 1 and pharmacy acceptable salt thereof or the application of pharmaceutical composition according to claim 10 in preparation treatment gastrointestinal motility disorder medicine.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0760368A1 (en) * | 1994-05-18 | 1997-03-05 | Nisshin Flour Milling Co., Ltd. | Novel pyrimidine derivative |
-
2015
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0760368A1 (en) * | 1994-05-18 | 1997-03-05 | Nisshin Flour Milling Co., Ltd. | Novel pyrimidine derivative |
Non-Patent Citations (3)
| Title |
|---|
| SELAHATTIN BOZKURT等: "Amino alcohol based chiral solvating agents: synthesis and applications in the NMR enantiodiscrimination of carboxylic acids", <TETRAHEDRON: ASYMMETRY> * |
| 孙晓红: "莫沙必利的代谢和药物动力学研究", 《中国优秀博士论文全文数据库》 * |
| 潘群等: "HPLC-MS/MS法测定人血浆中莫沙必利及其代谢物含量", 《药物分析杂志》 * |
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| WO2017185261A1 (en) * | 2016-04-27 | 2017-11-02 | 沈阳药科大学 | Mosapride active metabolites, preparation method therefor, and applications thereof |
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Effective date of registration: 20171012 Address after: 110016 Shenhe province Shenyang District Cultural Road, No. 103, No. Co-patentee after: Shenyang XinDa Taikang Pharmaceutical Technology Co., Ltd. Patentee after: Shenyang Pharmaceutical University Address before: 110016 Shenhe province Shenyang District Cultural Road, No. 103, No. Patentee before: Shenyang Pharmaceutical University |