CN100358908C - NMDA receptor antagonist intermediate, its synthesis and use - Google Patents
NMDA receptor antagonist intermediate, its synthesis and use Download PDFInfo
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- CN100358908C CN100358908C CNB2006100247796A CN200610024779A CN100358908C CN 100358908 C CN100358908 C CN 100358908C CN B2006100247796 A CNB2006100247796 A CN B2006100247796A CN 200610024779 A CN200610024779 A CN 200610024779A CN 100358908 C CN100358908 C CN 100358908C
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Abstract
The present invention relates to an intermediate body of a receptor antagonist having a structural formula as the right formula, a synthesis method and a purpose, wherein R is NO2, halogen, C1 to C4 alkyl radicals, C1 to C4 alkoxyl radicals, C1 to C4 halogenating alkyl radicals or C1 to C4 alkyl amido radicals. The intermediate body of the receptor antagonist can be synthesized by (S)-1-(4-R substituted phenyl radicals) ethylamine for one step and can be reacted with hydrochloric acid to prepare an NMDA receptor antagonist. The bought 2, 3-diaminotoluene is synthesized into the (S)-1-(4-R substituted phenyl radicals) ethylamine in four steps, and the (S)-1-(4-R substituted phenyl radicals) ethylamine is reacted with hydrochloric acid to prepare the NMDA receptor antagonist, particularly the synthesis of the NMDA receptor antagonist NVP-AAM077.
Description
Technical field
This patent relates to a kind of intermediate, preparation method and use of receptor antagonist, specifically a kind of nmda receptor antagonist (1-(R substituted-phenyl)-ethylamino)-(2,3-dicarbapentaborane-1,2,3,4-tetrahydroquinoxaline-5-)-methyl)-the intermediate synthetic method of phosphoric acid.
Background technology
Nmda receptor is the ligand-gated ion channel that a voltage relies on, and the opening of passage requires the combination of L-glutamic acid and glycine, and is subjected to polyamines, Mg2+, H, the regulation and control of Zn etc.The nmda receptor of discovering of molecular cloning contains NR1, three gene families of NR2 and NR3.Recombinant receptor experiment confirm nmda receptor is made up of different subunits, and NR1 subunit is essential component, and different NR2 subunits assembles with it and formed the nmda receptor hypotype with different channel characteristics.NR2B subunit is expressed in early days in growth, is responsible for the foundation of normal neurone pattern and keeps the normal viability of animal.And with advancing age, the expression amount of NR2A subunit and cynapse content increase gradually.In geriatric animals, observe NR2B and reduced synaptic plasticity to the conversion of NR2A subunit.Known nmda receptor is relevant with many complex physical and pathomechanism, as the plasticity-of cynapse, long time-histories enhancement (LTP), learning and memory, excititoxic, nervus retrogression sex change disease etc.Arrange and form number about the subunit of nmda receptor at present and it be unclear that.Because the critical function of nmda receptor in neural system, many all the time research groups all can have specific antagonist at the different subtype acceptor in research, in the hope of being applied to clinical treating disease.At present, developed the competitive antagonist that NR2B contains nmda receptor of acting on that some can be special, as ifenprodil, Ro25-6981 or the like, and some non-specific competitive antagonist such as APV, also have some nmda receptor channel blocker such as MK801, but fail to develop nmda receptor antagonist always at the NR2A hypotype.And former studies shows, NR
2The nmda receptor that A contains plays an important role in synaptic plasticity, and therefore exploitation just seems particularly important at the specific antagonist of this hypotype.Recently, Yves P.Auberson has developed a kind of new compound NVP-AAM077, think the antagonist of NR2A subtype sepcific, at present there have been some laboratories to use this compound to carry out the research of nmda receptor hypotype function and synaptic plasticity relation, resulting relevant NR2A hypotype inducing of LTP of mediation and the inductive result of NR2B hypotype mediation LTD has caused the great attention of academia, but but rarely have relevant report about the complete synthesis and pharmacodynamic feature research of NVP-AAM077.
Summary of the invention
The purpose of this invention is to provide a kind of receptor antagonist intermediate, is the intermediate of a kind of nmda receptor antagonist (1-(R substituted-phenyl)-ethylamino)-(2,3-dicarbapentaborane-1,2,3,4-tetrahydrochysene caye quinoline-5-)-methyl)-phosphoric acid furtherly.
Purpose of the present invention also provides a kind of synthetic method of above-mentioned receptor antagonist intermediate.
Another object of the present invention provides a kind of purposes of above-mentioned receptor antagonist intermediate, can be used to prepare nmda receptor antagonist NVP-AAM077 and analogue thereof, it is nmda receptor antagonist (1-(R substituted-phenyl)-ethylamino)-(2,3-dicarbapentaborane-1,2,3, the 4-tetrahydroquinoxaline-5-)-methyl)-phosphoric acid, especially can prepare nmda receptor antagonist (1-(bromo is for phenyl)-ethylamino)-(2 easily, 3-dicarbapentaborane-1,2,3, the 4-tetrahydroquinoxaline-5-)-methyl)-phosphoric acid, also be up-to-date up to now synthetic route.
A kind of receptor antagonist intermediate of the present invention has following structural formula:
Wherein, R is NO
2, halogen, the alkyl of C1～C4, the alkoxyl group of C1～C4, the haloalkyl of C1～C4, the alkyl amide of C1～C4.Described halogen is F, Cl, Br or I for example.
Receptor antagonist intermediate of the present invention refers to the compound of following structural formula especially:
The building-up reactions formula of receptor antagonist intermediate of the present invention is as follows:
The synthetic method of receptor antagonist intermediate of the present invention is in organic solvent, earlier compound 5, (S)-1-(4-R substituted-phenyl) ethamine and monovalence metal carbonate or supercarbonate were reacted under reflux temperature 1～5 hour, at room temperature react acquisition in 0.5～2 hour with diethyl phosphite, boron trifluoride diethyl etherate then.Wherein the mol ratio of compound 5, (S)-1-(4-R substituted-phenyl) ethamine, monovalence metal carbonate or supercarbonate, diethyl phosphite and boron trifluoride diethyl etherate is 1: 1～1.2: 1.5～5: 1～1.1: 1～1.5.
Described monovalence metal carbonate or supercarbonate are Quilonum Retard, salt of wormwood, yellow soda ash, lithium bicarbonate, sodium bicarbonate or saleratus.
Described (S)-1-(4-R substituted-phenyl) ethamine can be obtained by market, or synthetic from the reference method, also can be synthetic by following method:
1), under refluxad, compound 1 and oxalic acid react under hydrochloric acid soln and obtained compound 2 in 4-10 hour, and wherein the mol ratio of compound 1 and oxalic acid is 1: 1～1.2, and suggestion hydrochloric acid is 1～4N, further is recommended as 4N, reacts 6 hours.
2), at first under refluxad, compound 2 and thionyl chloride reaction 1-5 hour then in organic solvent, obtained compound 3 in 0.5～2 hour with the sodium methylate reaction.Wherein compound 2, and the mol ratio of thionyl chloride and sodium methylate is 1: 50～100: 1.5～2.Recommending to use N, N-dimethylformamide is that catalyzer carries out with being reflected under the protection of inert gas, under nitrogen protection.
3), in organic solvent, compound 3, bromo fourth lactim and α, α-isobutyl-dintrile is under 100-1000 watt sun lamp irradiation, and reflux obtained compound 4 in 40 minutes.Wherein compound 3, bromo fourth lactim and α, the mol ratio of α-isobutyl-dintrile is 1: 1.01～1.1: 0.1～0.2.Recommend sun lamp with 500 watts.
4), in organic solvent, compound 4 reacts under 100～200 with sodium periodate and obtained compound 5 in 20～60 minutes.Wherein the mol ratio of compound 4 and sodium periodate is 1: 1～1.2.The recommendation response temperature is 120.
Above-mentioned typical reaction formula can be expressed as follows:
Above-mentioned receptor antagonist intermediate of the present invention can be used to prepare nmda receptor antagonist NVP-AAM077 and analogue thereof, be nmda receptor antagonist (1-(R substituted-phenyl)-ethylamino)-(2,3-dicarbapentaborane-1,2,3, the 4-tetrahydroquinoxaline-5-)-methyl)-phosphoric acid.
Reaction formula is as follows;
In the formula: R is NO
2, halogen, the alkyl of C1～C4, the alkoxyl group of C1～C4, the haloalkyl of C1～C4, the alkyl amido of C1～C4.Described halogen is F, Cl, Br or I.R=o-NO for example
2, m-NO
2, p-NO
2, o-Cl, m-Cl, p-Cl, o-CH
3, m-CH
3, p-CH3, o-OCH
3, m-OCH
3, p-OCH
3, o-CF
3, m-CF
3, p-CF
3, O-NHAc, m-NHAc, p-NHAc, o-Br, m-Br and p-Br.Wherein, Ac is an ethanoyl, o-neighbour, and between m-, the o-contraposition.
The structural formula of wherein (1-(4-bromophenyl)-ethylamino)-(2,3-dicarbapentaborane-1,2,3,4-tetrahydrochysene caye quinoline-5-)-methyl)-phosphoric acid NVP-AAM077 is as follows:
Receptor antagonist intermediate of the present invention can be used to prepare nmda receptor antagonist (1-(R substituted-phenyl)-ethylamino)-(2,3-dicarbapentaborane-1,2,3, the 4-tetrahydroquinoxaline-5-)-methyl)-phosphoric acid, especially prepare nmda receptor antagonist (1-(R substituted-phenyl)-ethylamino)-(2,3-dicarbapentaborane-1,2,3, the 4-tetrahydroquinoxaline-5-)-methyl)-phosphoric acid.The method of preparation is under refluxad, and compound 6 and hydrochloric acid reaction obtained receptor antagonist in 12～20 hours.Wherein the mol ratio of receptor antagonist intermediate and hydrochloric acid is 1: 50～100.Recommendation response 16 hours is purified with ethyl alcohol recrystallization.Described organic solvent can be tetrahydrofuran (THF), methyl alcohol, 1,2-ethylene dichloride, methylene dichloride, ethanol, N, dinethylformamide or benzene etc.
Method of the present invention is specifically from (S)-1-(4-R substituted-phenyl) ethamine synthesis of receptor antagonist intermediate of easy acquisition, and (S)-1-(4-R substituted-phenyl) ethamine can be by 2,3-two amido toluene are synthetic to be obtained, so be that a kind of method is easy, synthetic route short, economic synthetic method.Can one-step synthesis nmda receptor antagonist (1-(R substituted-phenyl)-ethylamino)-(2 from the receptor antagonist intermediate, 3-dicarbapentaborane-1,2,3, the 4-tetrahydroquinoxaline-5-)-methyl)-phosphoric acid, especially prepare nmda receptor antagonist (1-(bromo phenyl)-ethylamino)-(2,3-dicarbapentaborane-1,2,3, the 4-tetrahydroquinoxaline-5-)-methyl)-phosphoric acid.
Embodiment
The present invention will be helped to understand by following embodiment, but content of the present invention can not be limited.Following embodiment shows, the present invention can be set out and hydrochloric acid reaction one-step synthesis receptor antagonist intermediate by (S)-1-(4-R substituted-phenyl) ethamine, also can be from 2,3-two amido toluene set out and have synthesized (S)-1-(4-R substituted-phenyl) ethamine by the reaction of 4 steps, obtain nmda receptor antagonist with hydrochloric acid reaction again.In other words, can from buy 2,3-diaminotoluene 1 sets out, and obtains nmda receptor antagonist NVP-AAM077.Typical embodiment is described below.
Embodiment 1
With compound 1 (8g, 67mmol) and oxalic acid (10g, 68mmol) be dissolved in hydrochloric acid soln (4N, 450ml) in, reflux is 6 hours then.After reaction finishes, naturally cooling, it be neutral transferring pH value, filters then, the solid ether dissolution of brown washes with water, the saturated sodium-chloride washing, anhydrous sodium sulfate drying filters, and concentrated brown solid is dried solid and is weighed as 11.6g, and productive rate is 99%.
1HNMR(300MHz，CDCl
3)：δ11.90(1H，s)，11.21(1H，S)，6.98-6.94(3H，m)，2.33(3H，s)ppm。
Embodiment 2
(11.6g 65.9mmol) is dissolved in the thionyl chloride (250ml) of new steaming compound 2, adds N, and (DMF, 0.5ml), reflux is 3 hours then for the N-dimethylformamide.Reaction finishes its naturally cooling of relief, then reactant is poured in the frozen water (1000ml), constantly stir, and subsequent filtration, drying obtains tawny solid.Under nitrogen protection, add successively in the tawny solid the new tetrahydrofuran (THF) that steams (THF, 100ml), the solution of sodium methylate/methyl alcohol (25%, 30ml), stirring at room 1 hour.Finish reaction, in reactant, add ethyl acetate (300ml), water (200ml) washing three times, the saturated common salt water washing, anhydrous sodium sulfate drying filters, and concentrates, and column chromatography is made leacheate with normal hexane, obtains product 14.2 grams, and productive rate is 98%.
1H?NMR(300MHz，CDCl
3)：δ7.58(1H，dd，J＝2.1Hz，J＝7.8Hz)，7.37-7.31(2H，m)，4.13(3H，s)，4.12(3H，s)，2.62(3H，s)ppm。
Embodiment 3
Toward compound 3 (9g, 4.4mmol) and bromo fourth lactim (NBS, 7.83g, 4.4mmol), α, α-isobutyl-dintrile (a, a-azoisobutyronitrile, 715mg, 0.44mmol) mixture in add 1,2-ethylene dichloride (200ml), under 500 watts sun lamp irradiation, reflux 40 minutes.Naturally cool to room temperature, add silica gel (18 grams, 60-230 μ), removal of solvent under reduced pressure is placed on solid mixture on the silicagel column, uses normal hexane: ethyl acetate=drip washing in 70: 1 obtains product 8.38g, yield 91%.
1HNMR(300MHz，CDCl
3)：δ7.66(1Hm?dd，J＝1.5Hz，J＝8.4Hz)，7.50(1H，dd，J＝1.2Hz，J＝6.9Hz)，7.39-7.34(1H，m)，4.96(2H，s)，4.12(3H，s)，4.07(3H，s)ppm。
Embodiment 4
At room temperature, compound 4 (2.293g, 8.1mmol)) and sodium periodate (1.7g, 8.1mmol)) is mixed, add N, N-dimethylformamide (200ml), temperature is 120 in being heated to, kept this thermotonus 30 minutes, reaction finishes relief, and it naturally cools to room temperature, adds entry in reaction system, use ethyl acetate extraction, saturated sodium-chloride is washed, anhydrous sodium sulfate drying, filter, concentrate column chromatography, use sherwood oil: ethyl acetate=drip washing in 20: 1 obtains product 1.38g, yield 78%.
1H?NMR(300MHz，CDCl
3)：δ11.19(1H，s)，8.01(1H，dd，J＝1.5Hz，J＝7.8Hz)，8.03(1H，dd，J＝1.5Hz，J＝8.1Hz)，7.62-7.56(1H，m)，4.22(3H，S)，4.16(3H，s)ppm。
Embodiment 5
With (S)-1-(4-bromophenyl) ethamine (1.445g, 7.266mmol) be added drop-wise to compound 5 (1.584g, 7.266mmol) and Anhydrous potassium carbonate (2g in 80 milliliters of benzole solns 14.5mmol), dropwised temperature rising reflux 2 hours, filtered.(1.1g 7.99mmol), slowly adds boron trifluoride diethyl etherate (1.55g under stirring at room to add diethyl phosphite in the filtrate, 10.89mmol), add the back and continue to stir 1 hour, anhydrous sodium sulfate drying is used in water and the washing of 5% sodium hydroxide, filter, concentrate, column chromatography is used methylene dichloride: methyl alcohol=drip washing in 50: 1, then get product 3.4g with ethyl acetate and sherwood oil recrystallization, yield 88%.
1H NMR (300MHz, CDCl
3): 7.77-7.71 (1.76H, m), 7.53-7.50 (1.04H, m), 7.39-7.28 (1.19H, d, J=8.1Hz), 7.31-7.28 (0.77H, J=8.7Hz), and 7.10-7.01 (1.84H, m), 4.23-4.17 (5.96H, m), 4.15 (2.04h, s), 3.98 (1.13H, s), 3.88-3.80 (1.63H, m), and 3.66-3.61 (2.23H, br), 3.48-3.46 (0.67H, m), 2.70 (1.86H, br), and 1.36-1.25 (6.24H, m), 0.95-0.87 (3H, m) ppm.IR (KBr): max:2982,1615,1588,1523,1479cm
-1ESI (M+H): 538.2. ultimate analysis C
23H
29BrN
3O
5P: calculated value C 51.31, H 5.43, N 7.81 found C 51.64, H 5.57, and N 7.47.
R group in change (S)-1-(R-bromophenyl) ethamine, the compound 6 of acquisition different substituents, analytical results is as follows:
R＝H，
ESI (M+H): 459; Productive rate 91%;
Ultimate analysis calculated value: C 60.12, H 6.58, and N 9.15
Measured value: C 60.10, H 6.55, and N 9.18
R=p-NO
2, productive rate 82%;
ESI(M+H)：504；
Ultimate analysis calculated value: C 54.76, H 5.79, and N 11.11
Measured value: C 54.82, H 5.77, and N 11.05
R=o-CH
3, productive rate 85%;
ESI(M+H)：473；
Ultimate analysis calculated value: C 60.80, H 6.81, and N 8.87
Measured value: C 60.76, H 6.83, and N 8.93
R=m-OCH
3, productive rate 87%
ESI(M+H)：489；
Ultimate analysis calculated value: C 58.89, H 6.59, and N 8.58
Measured value: C 58.85, H 6.60, and N 8.61
R=p-CF
3, productive rate 85%
ESI(M+H)：527；
Ultimate analysis calculated value: C 54.56, H 5.54, and N 7.97
Measured value: C 54.61, H 5.58, and N 8.01
R=p-NHAc, productive rate 84%;
ESI(M+H)：516；
Ultimate analysis calculated value: C 58.13, H 6.44, and N 10.85
Measured value: C 58.21, H 6.47, and N 10.80.
Embodiment 6
With compound 6 (50mg, (4N is in solution 20ml) 0.093mmol) to join hydrochloric acid, reflux 16 hours is composed monitoring reaction with phosphorus, till compound 6 whole hydrolysis, add dissolve with ethanol, dripping propylene oxide, is 5～6 up to pH value, separates out solid, filter, drying gets product 42mg with second alcohol and water recrystallization, yield 99%.
1H?NMR(300MHz，CDCl
3)：7.29(0.96H，br)，7.08-6.66(6.04H，m)，4.016(0.64H，d，J＝18Hz)，3.61-3.53(1.06H，br)，3.32-3.26(0.5H，m)，1.28(1.70H，br)，1.18(1.35H，br).ESI(M+H)：454。
Claims (8)
1, a kind of nmda receptor antagonist intermediate, it has following structural formula:
Wherein, R is NO
2, halogen, C1～C4 alkyl, C1～C4 alkoxyl group, C1～C4 haloalkyl or C1～C4 alkyl amide.
2, the described a kind of nmda receptor antagonist intermediate of claim 1 is characterized in that having following structural formula:
3, the synthetic method of a kind of nmda receptor antagonist intermediate as claimed in claim 1 is characterized in that adopting following 1)～5) step is synthetic::
1), under refluxad, compound 1 and oxalic acid react under hydrochloric acid soln and obtained compound 2 in 4-10 hour; Wherein the mol ratio of compound 1 and oxalic acid is 1: 1～1.2;
2), at first under refluxad, compound 2 and thionyl chloride reaction 1-5 hour then in organic solvent, obtained compound 3 in 0.5～2 hour with the sodium methylate reaction; Wherein compound 2, and the mol ratio of thionyl chloride and sodium methylate is 1: 50～100: 1.5～2;
3), in organic solvent, compound 3, bromo fourth lactim and α, α-isobutyl-dintrile is under 100-1000 watt sun lamp irradiation, and reflux obtained compound 4 in 40 minutes; Wherein compound 3, bromo fourth lactim and α, the mol ratio of α-isobutyl-dintrile is 1: 1.01～1.1: 0.1～0.2;
4), in organic solvent, compound 4 reacts down at 100～200 ℃ with sodium periodate and obtained compound 5 in 20～60 minutes; Wherein the mol ratio of compound 4 and sodium periodate is 1: 1～1.2;
5), in organic solvent, elder generation reacted compound 5, (S)-1-(4-R substituted-phenyl) ethamine and monovalence metal carbonate or supercarbonate 1～5 hour under reflux temperature, at room temperature react with diethyl phosphite, boron trifluoride diethyl etherate then to obtain nmda receptor antagonist intermediate as claimed in claim 1 in 0.5～2 hour; Wherein, the mol ratio of compound 5, (S)-1-(4-R substituted-phenyl) ethamine, monovalence metal carbonate or supercarbonate, diethyl phosphite and boron trifluoride diethyl etherate is 1: 1～1.2: 1.5～5: 1～1.1: 1～1.5; R according to claim 1;
Described structural formula of compound is as follows:
4, the synthetic method of a kind of nmda receptor antagonist intermediate as claimed in claim 3 is characterized in that monovalence metal carbonate described in the described step 5) or supercarbonate are Quilonum Retard, salt of wormwood, yellow soda ash, lithium bicarbonate, sodium bicarbonate or saleratus.
5, the purposes of a kind of nmda receptor antagonist intermediate as claimed in claim 1 is characterized in that being used to be prepared as follows (1-(R substituted-phenyl)-ethylamino)-(2 of structural formula, 3-dicarbapentaborane-1,2,3,4-tetrahydroquinoxaline-5-)-methyl)-receptor antagonist of phosphoric acid:
Wherein,
R according to claim 1.
6, purposes as claimed in claim 5 is characterized in that the structural formula of described receptor antagonist is as follows:
7, the purposes of a kind of nmda receptor antagonist intermediate as claimed in claim 5, it is characterized in that synthetic by the following method (1-(R substituted-phenyl)-ethylamino)-(2 as claimed in claim 5,3-dicarbapentaborane-1,2,3,4-tetrahydroquinoxaline-5-)-methyl)-receptor antagonist of phosphoric acid: under refluxad, receptor antagonist intermediate as claimed in claim 1 and hydrochloric acid reaction obtained in 12～20 hours, and wherein the mol ratio of receptor antagonist intermediate and hydrochloric acid is 1: 50～100.
8, purposes as claimed in claim 7 is characterized in that described hydrochloric acid is 1～4mol/L.
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Non-Patent Citations (3)
| Title |
|---|
| 5-Phosphonomethylquinoxalinediones as competitive NMDAreceptor antagonists with a preference for the human 1A/2A,rather than 1A/2B receptor composition.. Auberson, Yves P., Allgeier, Hans, Bischoff, Serge,Lingenhoehl, Kurt, Moretti,Robert, Schmutz, Markus.Bioorganic & Medicinal Chemistry Letters,Vol.12 No.7. 2002 * |
| Substitution for PCP, disruption of prepulse inhibition andhyperactivity induced by N-methyl-D-aspartate receptorantagonists: preferential involvement of the NR2B rather thanNR2A subunit. Chaperon, F., Mueller, W., Auberson, Y. P., Tricklebank, M.D., Neijt, H. C.Behavioural Pharmacology,Vol.14 No.5&6. 2003 * |
| Synthesis and Pharmacology of N1-SubstitutedPiperazine-2,3-dicarboxylic Acid Derivatives Acting as NMDAReceptor Antagonists.. Morley, Richard M., Tse, Heong-Wai, Feng, Bihua, Miller,Jacqueline C., Monaghan,Daniel T., Jane, David E.Journal of Medicinal Chemistry,Vol.48 No.7. 2005 * |
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