CN100358908C - NMDA receptor antagonist intermediate, synthesis method and use - Google Patents

Abstract

The present invention relates to an intermediate, synthesis method and use of a receptor antagonist with the following structural formula: wherein, R is NO ₂ , halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 Haloalkyl groups or C1-C4 alkanoyl amido groups. The receptor antagonist intermediate can be synthesized in one step starting from (S)-1-(4-R substituted phenyl)ethylamine, and then reacted with hydrochloric acid to obtain the NMDA receptor antagonist. It is also possible to start from the purchased 2,3-diaminotoluene, synthesize (S)-1-(4-R substituted phenyl)ethylamine through a 4-step reaction, and then react with hydrochloric acid to obtain an NMDA receptor antagonist, especially It is the synthesis of NMDA receptor antagonist NVP-AAM077.

Description

NMDA receptor antagonist intermediate, synthesis method and use

technical field

This patent relates to an intermediate, synthesis method and application of a receptor antagonist, specifically a kind of NMDA receptor antagonist (1-(R substituted phenyl)-ethylamino)-(2,3-dicarbonyl -1,2,3,4-tetrahydroquinoxaline-5-)-methyl)-phosphoric acid intermediate synthesis method.

Background technique

NMDA receptor is a voltage-dependent ligand-gated ion channel. The opening of the channel requires the combination of glutamate and glycine, and is regulated by polyamines, Mg2+, H, Zn, etc. Molecular cloning studies have found that NMDA receptors contain three gene families: NR1, NR2 and NR3. Recombinant receptor experiments confirmed that NMDA receptors are composed of different subunits, NR1 subunit is an essential component, and different NR2 subunits are assembled with it to form NMDA receptor subtypes with different channel characteristics. The NR2B subunit is expressed early in development and is responsible for the establishment of normal neuronal patterns and maintenance of normal viability in animals. With age, the expression and synaptic content of NR2A subunits gradually increased. Switching of NR2B to NR2A subunits reduces synaptic plasticity observed in aged animals. It is known that NMDA receptors are related to many complex physiological and pathological mechanisms, such as synaptic plasticity, long-term potentiation (LTP), learning and memory, excitatory neurotoxicity, neurodegenerative diseases and so on. The arrangement and number of subunits of NMDA receptors are still unclear. Due to the important function of NMDA receptors in the nervous system, many research groups have been researching specific antagonists for different subtypes of receptors, with a view to applying them in the clinical treatment of diseases. At present, some competitive antagonists that can specifically act on NR2B containing NMDA receptors have been developed, such as ifenprodil, Ro25-6981, etc., as well as some non-specific competitive antagonists such as APV, and some NMDA receptor channels Blockers such as MK801, however, have not been able to develop NMDA receptor antagonists targeting the NR2A subtype. Previous studies have shown that NMDA receptors contained in NR ₂ A play an important role in synaptic plasticity, so it is particularly important to develop specific antagonists for this subtype. Recently, Yves P. Auberson developed a new compound called NVP-AAM077, which is considered to be an NR2A subtype-specific antagonist. At present, some laboratories have used this compound to study the relationship between NMDA receptor subtype function and synaptic plasticity. Research, the results obtained about NR2A subtype mediating LTP induction and NR2B subtype mediating LTD induction have attracted great attention from the academic community, but there is little relevant research on the total synthesis and pharmacodynamic function of NVP-AAM077 reports.

Contents of the invention

The object of the present invention is to provide a kind of receptor antagonist intermediate, further say a kind of NMDA receptor antagonist (1-(R substituted phenyl)-ethylamino)-(2,3-dicarbonyl-1,2 , 3,4-Tetrahydrooxaline-5-)-methyl)-phosphoric acid intermediate.

The purpose of the present invention is also to provide a synthesis method of the above-mentioned receptor antagonist intermediate.

Another object of the present invention is to provide a kind of purposes of above-mentioned receptor antagonist intermediate, can be used for preparing NMDA receptor antagonist NVP-AAM077 and analog thereof, namely NMDA receptor antagonist (1-(R substituted phenyl base)-ethylamino)-(2,3-dicarbonyl-1,2,3,4-tetrahydroquinoxaline-5-)-methyl)-phosphoric acid, especially the NMDA receptor antagonist can be prepared conveniently (1-(Bromophenyl)-ethylamino)-(2,3-dicarbonyl-1,2,3,4-tetrahydroquinoxaline-5-)-methyl)-phosphoric acid, also by far The latest synthetic route.

A receptor antagonist intermediate of the present invention has the following structural formula:

Wherein, R is NO ₂ , halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 alkanoylamide. Said halogen is, for example, F, Cl, Br or I.

Receptor antagonist intermediate of the present invention especially refers to the compound of following structural formula:

The synthetic reaction 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, first compound 5, (S)-1-(4-R substituted phenyl) ethylamine and monovalent metal carbonate or bicarbonate React at reflux temperature for 1-5 hours, then react with diethyl phosphite and boron trifluoride ethyl ether at room temperature for 0.5-2 hours to obtain. Wherein the molar ratio of compound 5, (S)-1-(4-R substituted phenyl)ethylamine, monovalent metal carbonate or bicarbonate, diethyl phosphite and boron trifluoride ether is 1:1 ~1.2:1.5~5:1~1.1:1~1.5.

Described monovalent metal carbonate or bicarbonate is lithium carbonate, potassium carbonate, sodium carbonate, lithium bicarbonate, sodium bicarbonate or potassium bicarbonate.

The (S)-1-(4-R substituted phenyl)ethylamine can be obtained from the market, or synthesized from reference methods, and can also be synthesized by the following method:

1), under reflux conditions, react compound 1 and oxalic acid in hydrochloric acid solution for 4-10 hours to obtain compound 2, wherein the molar ratio of compound 1 and oxalic acid is 1: 1 ~ 1.2, the recommended hydrochloric acid is 1 ~ 4N, further recommended as 4N, react for 6 hours.

2) First, react compound 2 with thionyl chloride under reflux conditions for 1-5 hours, and then react with sodium methoxide in an organic solvent for 0.5-2 hours to obtain compound 3. Wherein the molar ratio of compound 2, thionyl chloride and sodium methoxide is 1:50-100:1.5-2. It is recommended to use N,N-dimethylformamide as a catalyst and carry out the reaction under the protection of an inert gas, such as nitrogen.

3) In an organic solvent, compound 3, bromobutyrolactam and α, α-isobutylidene dinitrile are heated to reflux for 40 minutes under the irradiation of a 100-1000 watt sun lamp to obtain compound 4. Wherein the molar ratio of compound 3, bromobutyrolactam and α,α-isobutyl dinitrile is 1:1.01～1.1:0.1～0.2. A 500W solar lamp is recommended.

4) In an organic solvent, compound 4 was reacted with sodium periodate at 100-200□ for 20-60 minutes to obtain compound 5. Wherein the molar ratio of compound 4 and sodium periodate is 1:1-1.2. The recommended reaction temperature is 120□.

The above typical reaction formula can be expressed as follows:

The above-mentioned receptor antagonist intermediate of the present invention can be used for preparing NMDA receptor antagonist NVP-AAM077 and analog thereof, namely NMDA receptor antagonist (1-(R substituted phenyl)-ethylamino)-(2 , 3-dicarbonyl-1,2,3,4-tetrahydroquinoxaline-5-)-methyl)-phosphoric acid.

The reaction formula is as follows;

In the formula: R is NO ₂ , halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 alkanoylamino. The halogen is F, Cl, Br or I. For example R=o-NO 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. Among them, Ac is acetyl, o-ortho, m-inter, o-para.

Wherein (1-(4-bromophenyl)-ethylamino)-(2,3-dicarbonyl-1,2,3,4-tetrahydrooxaline-5-)-methyl)-phosphate NVP-AAM077 The structural formula is as follows:

The receptor antagonist intermediate of the present invention can be used to prepare NMDA receptor antagonist (1-(R substituted phenyl)-ethylamino)-(2,3-dicarbonyl-1,2,3,4-tetrahydro Quinoxaline-5-)-methyl)-phosphate, especially for the preparation of NMDA receptor antagonist (1-(R-substituted phenyl)-ethylamino)-(2,3-dicarbonyl-1,2,3, 4-tetrahydroquinoxaline-5-)-methyl)-phosphoric acid. The preparation method is to react the compound 6 with hydrochloric acid for 12-20 hours under the condition of reflux to obtain the receptor antagonist. The molar ratio of the receptor antagonist intermediate to hydrochloric acid is 1:50-100. It is recommended to react for 16 hours and purify by recrystallization with ethanol. The organic solvent can be tetrahydrofuran, methanol, 1,2-dichloroethane, dichloromethane, ethanol, N,N-dimethylformamide or benzene, etc.

The method of the present invention specifically starts from easily available (S)-1-(4-R substituted phenyl) ethylamines to synthesize receptor antagonist intermediates, and (S)-1-(4-R substituted phenyl Base) ethylamine can be synthesized by 2,3-diaminotoluene, so it is a simple, short and economical synthetic method. The NMDA receptor antagonist (1-(R substituted phenyl)-ethylamino)-(2,3-dicarbonyl-1,2,3,4-tetrahydroquinoxaline can be synthesized in one step from the receptor antagonist intermediate -5-)-methyl)-phosphoric acid, especially for the preparation of the NMDA receptor antagonist (1-(bromophenyl)-ethylamino)-(2,3-dicarbonyl-1,2,3,4-tetra Hydroquinoxaline-5-)-methyl)-phosphoric acid.

Detailed ways

The following examples will help to understand the present invention, but can not limit the content of the present invention. The following examples show that the present invention can start from (S)-1-(4-R substituted phenyl)ethylamine and react with hydrochloric acid to synthesize receptor antagonist intermediates in one step, and can also synthesize receptor antagonist intermediates from 2,3-diaminotoluene The (S)-1-(4-R substituted phenyl)ethylamine was synthesized through 4-step reaction, and then reacted with hydrochloric acid to obtain NMDA receptor antagonist. In other words, NMDA receptor antagonist NVP-AAM077 can be obtained from commercially available 2,3-diaminotoluene 1. Typical embodiments are described below.

Example 1

Compound 1 (8g, 67mmol) and oxalic acid (10g, 68mmol) were dissolved in hydrochloric acid solution (4N, 450ml), and then heated to reflux for 6 hours. After the reaction, cool naturally, adjust the PH value to be neutral, then filter, dissolve the brown solid with ether, wash with water, wash with saturated sodium chloride, dry over anhydrous sodium sulfate, filter, concentrate to obtain a brown solid, and dry the solid Weighed 11.6 g, 99% yield.

¹ H NMR (300 MHz, CDCl ₃ ): δ 11.90 (1H, s), 11.21 (1H, S), 6.98-6.94 (3H, m), 2.33 (3H, s) ppm.

Example 2

Compound 2 (11.6g, 65.9mmol) was dissolved in freshly distilled thionyl chloride (250ml), N,N-dimethylformamide (DMF, 0.5ml) was added, and then heated to reflux for 3 hours. After the reaction was completed, it was allowed to cool naturally, and then the reactant was poured into ice water (1000ml), stirred continuously, then filtered, and dried to obtain a brownish-yellow solid. Under nitrogen protection, freshly distilled tetrahydrofuran (THF, 100ml) and sodium methoxide/methanol solution (25%, 30ml) were successively added to the brownish-yellow solid, and stirred at room temperature for 1 hour. Finish the reaction, add ethyl acetate (300ml) to the reactant, wash with water (200ml) three times, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate, column chromatography, use n-hexane as eluent, obtain Product 14.2 g, yield 98%.

¹ H 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.

Example 3

To the mixture of compound 3 (9g, 4.4mmol) and bromobutyrolactam (NBS, 7.83g, 4.4mmol), α, α-isobutylonitrile (a, a-azoisobutyronitrile, 715mg, 0.44mmol) Add 1,2-dichloroethane (200ml) to the mixture, and heat to reflux for 40 minutes under the irradiation of a 500-watt sun lamp. Cool naturally to room temperature, add silica gel (18 g, 60-230 μ), remove the solvent under reduced pressure, put the solid mixture on a silica gel column, rinse with n-hexane: ethyl acetate = 70: 1, and obtain 8.38 g of the product. The rate is 91%.

¹ HNMR (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.

Example 4

At room temperature, compound 4 (2.293g, 8.1mmol)) was mixed with sodium periodate (1.7g, 8.1mmol)), N,N-dimethylformamide (200ml) was added, heated to an internal temperature of 120°C, maintain this temperature for 30 minutes, let it cool to room temperature naturally after the reaction, add water to the reaction system, extract with ethyl acetate, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, filter, concentrate, column Chromatography, eluting with petroleum ether: ethyl acetate = 20:1, afforded 1.38 g of the product with a yield of 78%.

¹ H 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=8.1 Hz), 7.62-7.56 (1H, m), 4.22 (3H, S), 4.16 (3H, s) ppm.

Example 5

(S)-1-(4-bromophenyl)ethylamine (1.445g, 7.266mmol) was added dropwise to 80ml of benzene of compound 5 (1.584g, 7.266mmol) and anhydrous potassium carbonate (2g, 14.5mmol). In the solution, after the dropwise addition was completed, the temperature was raised to reflux for 2 hours, and then filtered. Add diethyl phosphite (1.1g, 7.99mmol) to the filtrate, slowly add boron trifluoride diethyl ether (1.55g, 10.89mmol) under stirring at room temperature, and continue stirring for 1 hour after the addition, then add water and 5% hydrogen Washed with sodium oxide, dried with anhydrous sodium sulfate, filtered, concentrated, column chromatography, rinsed with dichloromethane:methanol=50:1, then recrystallized with ethyl acetate and petroleum ether to obtain 3.4g of the product, yield 88 %.

¹ H 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 (0.77 H, J=8.7Hz), 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), 3.66-3.61 (2.23H, br), 3.48-3.46 (0.67H, m), 2.70 (1.86H, br), 1.36-1.25 (6.24H, m), 0.95-0.87 (3H, m) ppm.IR(KBr): □max: 2982, 1615, 1588, 1523, 1479cm ^-1 ESI(M+H): 538.2. Elemental analysis C ₂₃ H ₂₉ BrN ₃ O ₅ P: calculated value C 51.31, H 5.43, N 7.81 found C 51.64, H 5.57, N 7.47.

When the R group in (S)-1-(R-bromophenyl)ethylamine is changed, compound 6 with different substituents is obtained, and the analysis results are as follows:

R=H,

ESI (M+H): 459; Yield 91%;

Elemental analysis Calculated value: C 60.12, H 6.58, N 9.15

  Measured values: C 60.10, H 6.55, N 9.18

R=p-NO ₂ , yield 82%;

ESI(M+H): 504;

Elemental analysis Calculated value: C 54.76, H 5.79, N 11.11

  Measured values: C 54.82, H 5.77, N 11.05

R=o-CH ₃ , yield 85%;

ESI(M+H): 473;

Elemental analysis Calculated value: C 60.80, H 6.81, N 8.87

  Measured values: C 60.76, H 6.83, N 8.93

R=m-OCH ₃ , yield 87%

ESI(M+H): 489;

Elemental analysis Calculated value: C 58.89, H 6.59, N 8.58

  Measured values: C 58.85, H 6.60, N 8.61

R=p-CF ₃ , yield 85%

ESI(M+H): 527;

Elemental analysis Calculated value: C 54.56, H 5.54, N 7.97

  Measured values: C 54.61, H 5.58, N 8.01

R=p-NHAc, yield 84%;

ESI(M+H): 516;

Elemental analysis Calculated value: C 58.13, H 6.44, N 10.85

  Found values: C 58.21, H 6.47, N 10.80.

Example 6

Compound 6 (50 mg, 0.093 mmol) was added to a solution of hydrochloric acid (4N, 20 ml), heated to reflux for 16 hours, and the reaction was monitored by phosphospectrum until compound 6 was completely hydrolyzed, dissolved in ethanol, and propylene oxide was added dropwise until The pH value was 5-6, and a solid was precipitated, filtered, dried, and recrystallized with ethanol and water to obtain 42 mg of the product, with a yield of 99%.

¹ H 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. An NMDA receptor antagonist intermediate having the structural formula:

   

   wherein R is NO₂Halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl or C1-C4 alkylamide.
2. The NMDA receptor antagonist intermediate of claim 1, characterized by the structural formula:

   
3. the method of claim 1, wherein the intermediate is synthesized by steps 1) to 5) as follows: :

   1) under the reflux condition, reacting the compound 1 with oxalic acid for 4-10 hours in a hydrochloric acid solution to obtain a compound 2; wherein the molar ratio of the compound 1 to the oxalic acid is 1: 1-1.2;

   2) firstly, reacting a compound 2 with thionyl chloride for 1-5 hours under a reflux condition, and then reacting with sodium methoxide for 0.5-2 hours in an organic solvent to obtain a compound 3; wherein the molar ratio of the compound 2, thionyl chloride and sodium methoxide is 1: 50-100: 1.5-2;

   3) in an organic solvent, heating and refluxing a compound 3, bromosuccinimide and alpha, alpha-isobutyl dinitrile for 40 minutes under the irradiation of a 100-watt 1000-watt solar lamp to obtain a compound 4; wherein the molar ratio of the compound 3, the bromosuccinimide to the alpha, alpha-isobutyl dinitrile is 1: 1.01-1.1: 0.1-0.2;

   4) reacting the compound 4 with sodium periodate in an organic solvent at 100-200 ℃ for 20-60 minutes to obtain a compound 5; wherein the molar ratio of the compound 4 to the sodium periodate is 1: 1-1.2;

   5) reacting compound 5, (S) -1- (4-R substituted phenyl) ethylamine with a monovalent metal carbonate or bicarbonate in an organic solvent at a reflux temperature for 1-5 hours, and then reacting with diethyl phosphite and boron trifluoride diethyl etherate at room temperature for 0.5-2 hours to obtain an NMDA receptor antagonist intermediate as claimed in claim 1; wherein the mol ratio of the compound 5, (S) -1- (4-R substituted phenyl) ethylamine, monovalent metal carbonate or bicarbonate, diethyl phosphite and boron trifluoride diethyl etherate is 1: 1-1.2: 1.5-5: 1-1.1: 1-1.5; r is as defined in claim 1;

   the structural formula of the compound is as follows:

   
4. the method of claim 3, wherein said monovalent metal carbonate or bicarbonate of step 5) is lithium carbonate, potassium carbonate, sodium carbonate, lithium bicarbonate, sodium bicarbonate, or potassium bicarbonate.
5. Use of an NMDA receptor antagonist intermediate as claimed in claim 1 for the preparation of a receptor antagonist of (1- (R-substituted phenyl) -ethylamino) - (2, 3-dicarbonyl-1, 2, 3, 4-tetrahydroquinoxalin-5-) -methyl) -phosphoric acid of the formula:

   

   wherein,

   r is as defined in claim 1.
6. Use according to claim 5, characterized in that the receptor antagonist has the following structural formula:

   
7. use of an NMDA receptor antagonist intermediate according to claim 5, characterized in that the receptor antagonist of (1- (R-substituted phenyl) -ethylamino) - (2, 3-dicarbonyl-1, 2, 3, 4-tetrahydroquinoxalin-5-) -methyl) -phosphoric acid according to claim 5 is synthesized by: reacting the receptor antagonist intermediate of claim 1 with hydrochloric acid under reflux conditions for 12-20 hours, wherein the molar ratio of the receptor antagonist intermediate to hydrochloric acid is 1: 50-100.
8. The use according to claim 7, wherein the hydrochloric acid is 1 to 4 mol/L.