CN101906069A - (S)-2-substituted-(3'-acetyl-2'-pyridone-1'-yl)acetic acid and its preparation method and application - Google Patents

Abstract

The invention discloses (S)-2-substituted-(3'-acetyl-2'-pyridon-1'-yl)acetic acid and its preparation method and application. The preparation method comprises: condensing L-amino acid methyl ester and diketene to prepare N-acetoacetyl-L-amino acid methyl ester; combining N-acetoacetyl-L-amino acid methyl ester with 2-acetaldehyde-5, 5-Dimethyl-1,3-dioxane reacts to generate N-[2-(5,5-dimethyl-1,3-dioxane-2-yl-)vinyl]-N-acetoacetyl Base-L-amino acid methyl ester, generate (S)-2-substituted-(3'-acetyl-2'-pyridone-1'-yl) methyl acetate, saponification, that is. The detoxification activity of the compounds of the present invention during iron poisoning in vivo was evaluated by using an animal model of high iron. Experimental results show that the compound of the present invention has an excellent iron repelling effect, and can be used as an antidote for iron poisoning clinically.

Description

(S)-2-substituted-(3'-acetyl-2'-pyridone-1'-yl)acetic acid and its preparation method and application

technical field

The present invention relates to N-substituted pyridone compounds, in particular to (S)-2-substituted-(3'-acetyl-2'-pyridone-1'-yl)acetic acid and its preparation method, and the present invention also relates to them The application as a heavy metal repellent belongs to the field of biomedicine.

Background technique

Excess iron or iron accumulation in human tissues can lead to organ dysfunction and cause serious conditions such as hemochromatosis, beta-thalassemia, neurodegenerative diseases, myelodysplastic syndrome, alcoholic liver disease and related kidney diseases . Furthermore, iron accumulation in the body leads to free radical mediated tissue/organ damage and eventually death. At present, iron chelation therapy is the only treatment method, and N-substituted pyridone compounds have various physiological activities, such as sterilization, analgesia, anti-tumor and treatment of Parkinson's disease. Since this type of pyridone compound has a strong coordination ability, especially 1,2-dimethyl-3-hydroxyl-4(1H)-pyridone and 1,2-diethyl-3-hydroxyl-4( 1H)-Pyridone compounds can coordinate with iron and other metal ions, and have a good effect on treating thalassemia. The inventors realized that the use of (S)-2-substituted-(3'-acetyl-2'-pyridinon-1'-yl)acetic acid as an iron repellant may promote iron excretion. Based on this idea, the inventors came up with the present invention.

Contents of the invention

One of the objects of the present invention is to provide a class of (S)-2-substituted-(3'-acetyl-2'-pyridone-1'-yl) acetic acid compounds;

The second object of the present invention is to provide a method for preparing the above-mentioned (S)-2-substituted-(3'-acetyl-2'-pyridone-1'-yl)acetic acid compound;

Above-mentioned purpose of the present invention is achieved through the following technical solutions:

A class of (S)-2-substituted-(3'-acetyl-2'-pyridone-1'-yl) acetic acid compounds, whose structural formula is shown in formula I, formula II or formula III:

Formula I Formula II Formula III

Wherein, R is selected from hydrogen, CH ₃ , CH(CH ₃ ) ₂ , CHCH(CH ₃ ) ₂ , CH(CH ₃ )C ₂ H ₅ , CH ₂ C ₆ H ₅ , CH ₂ C ₆ H ₄ -OH- _p , _CH2OH , CH( _CH3 ) _{OH , CH2CO2CH3 , CH2CH2CO2CH3 , 3 - indoleacetyl} , _{CH2CH2SCH3 , CH2CH2CH2NHC-} (NH)NH(NO ₂ ), CH ₂ CONH ₂ or CH ₂ CH ₂ CONH ₂ ;

A method for preparing the above-mentioned compound of formula I, comprising the following steps:

(1) Convert L-amino acid to L-amino acid methyl ester; wherein, said L-amino acid includes: L-glycine, L-alanine, L-valine, L-leucine, L-iso Leucine, L-Phenylalanine, L-Tyrosine, L-Serine, L-Threonine, L-Aspartic Acid, L-Glutamic Acid, L-Tryptophan, L-Methylthio amino acid, L-arginine, L-asparagine or L-glutamine;

(2) 1,1,3,3-Tetramethylpropane and 2,2-Dimethyl-1,3-propanediol undergo acetal transfer reaction to generate 2-(2',2'-dimethoxy -Ethyl)-5,5-dimethyl-1,3-dioxane;

(3) Hydrolyze 2-(2',2'-dimethoxy-ethyl)-5,5-dimethyl-1,3-dioxane to generate 2-acetaldehyde-5,5- Dimethyl-1,3-dioxane;

(4) condensing the L-amino acid methyl ester prepared in step (1) with diketene to prepare N-acetoacetyl-L-amino acid methyl ester;

(5) N-acetoacetyl-L-amino acid methyl ester is reacted with 2-acetaldehyde-5,5-dimethyl-1,3-dioxane to generate N-[2-(5,5 -Dimethyl-1,3-dioxane-2-yl-)vinyl]-N-acetoacetyl-L-amino acid methyl ester;

(6) In the presence of H ₂ SO ₄ and dioxane, N-[2-(5,5-dimethyl-1,3-dioxane-2 base-)vinyl]N-(1, 3-Dicarbonobutyl-L-amino acid methyl ester generates (S)-2-substituted-(3'-acetyl-2'-pyridone-1'-yl)methyl acetate;

(7) Saponification of (S)-2-substituted-(3'-acetyl-2'-pyridon-1'-yl)acetic acid methyl ester to obtain the compound described in formula I.

A method for preparing the above-mentioned compound of formula II, comprising the following steps:

(1) L-cysteine is converted into L-cysteine methyl ester;

(2) 1,1,3,3-Tetramethylpropane and 2,2-Dimethyl-1,3-propanediol undergo acetal transfer reaction to generate 2-(2',2'-dimethoxy -Ethyl)-5,5-dimethyl-1,3-dioxane;

(3) Hydrolyze 2-(2',2'-dimethoxy-ethyl)-5,5-dimethyl-1,3-dioxane to generate 2-acetaldehyde-5,5- Dimethyl-1,3-dioxane;

(4) condensing L-cysteine methyl ester with diketene to prepare N-acetoacetyl-L-cystine methyl ester;

(5) Reaction of N-acetoacetyl-L-cystine methyl ester with 2-acetaldehyde-5,5-dimethyl-1,3-dioxane to generate N', N-di- [2-(5,5-Dimethyl-1,3-dioxane-2-yl-)vinyl]-N-acetoacetyl-L-cystine dimethyl ester;

(6) N', N-bis-[2-(5,5-dimethyl-1,3-dioxane-2-yl-)vinyl]-N-acetoacetyl-L-cystine Dimethyl ester undergoes an intramolecular aldol reaction to generate (2S,2S')-3,3'-dithio-2,2-bis(3'-acetyl-2'-pyridon-1'-yl)- Dimethyl 3-propionate;

(7) Dimethyl (2S, 2S')-3,3'-dithio-2,2-bis(3'-acetyl-2'-pyridon-1'-yl)-3-propionate Saponification gives the compound of formula II.

A method for preparing the above-mentioned compound of formula III, comprising the following steps:

(1) L-lysine is converted into L-lysine methyl ester;

(2) 1,1,3,3-Tetramethylpropane and 2,2-Dimethyl-1,3-propanediol undergo acetal transfer reaction to generate 2-(2',2'-dimethoxy -Ethyl)-5,5-dimethyl-1,3-dioxane;

(3) Hydrolyze 2-(2',2'-dimethoxy-ethyl)-5,5-dimethyl-1,3-dioxane to generate 2-acetaldehyde-5,5- Dimethyl-1,3-dioxane;

(4) Condensing L-lysine methyl ester with diketene to prepare N, Nε-acetoacetyl-L-lysine methyl ester;

(5) N, Nε-acetoacetyl-L-lysine methyl ester reacts with 2-acetaldehyde-5,5-dimethyl-1,3-dioxane to generate N-[2- (5,5-Dimethyl-1,3-dioxane-2-yl-)vinyl]-N-acetoacetyl-L-lysine methyl ester;

(6) Intramolecularly generate N-[2-(5,5-dimethyl-1,3-dioxane-2-yl-)vinyl]-N-acetoacetyl-L-lysine methyl ester The aldol reaction generates (2S)-2,6-bis(3'-acetyl-2'-pyridone-1'-yl)-hexanoic acid methyl ester;

(7) Saponifying (2S)-2,6-bis(3'-acetyl-2'-pyridon-1'-yl)-hexanoic acid methyl ester to obtain the compound of formula III.

The detoxification activity of the compounds of the present invention during iron poisoning in vivo was evaluated by using an animal model of high iron. Experimental results show that the compound of the present invention has an excellent iron repelling effect and can be used as an antidote for iron poisoning clinically.

Another object of the present invention is to provide a pharmaceutical composition for repelling heavy metals, which consists of a therapeutically effective dose of the compound of the present invention and pharmaceutically acceptable excipients or adjuvants; that is: will effectively After a certain amount of the compound of the present invention is combined with a pharmaceutically acceptable carrier or diluent, it can be prepared into any suitable pharmaceutical composition according to the conventional preparation methods in the art. Usually the composition is suitable for oral administration and injection administration, and other administration methods are also suitable. The composition can be in the form of tablets, capsules, powders, granules, lozenges, suppositories, or liquid preparations such as oral liquids. According to different administration methods, the pharmaceutical composition of the present invention may contain 0.1%-99% by weight, preferably 10-60% by weight of the compound of the present invention.

Description of drawings

Fig. 1 is a synthetic route diagram of the compound of formula I of the present invention.

Fig. 2 is a synthetic route diagram of the compound of formula II of the present invention.

Fig. 3 is a synthetic route diagram of the compound of formula III of the present invention.

Detailed ways

In order to further illustrate the present invention, a series of examples are given below. These examples are entirely illustrative, and they are only used to specifically describe the present invention, and should not be construed as limiting the present invention.

Example 1 2-(2,2-dimethoxy-ethyl)-5,5-dimethyl-1,3-dioxane

Add 4.92g (30mmol) of 1,1,3,3-tetramethoxypropane, 0.78g (7.5mmol) of 2,2-dimethyl-1,3-propanediol into 25ml of dichloromethane, drop into 0.1ml (6N) hydrochloric acid, stirred at room temperature for 24 hours, added 0.78g (7.5mmol) 2,2-dimethyl-1,3-propanediol, continued to stir at room temperature for 24 hours, added 4.0g of anhydrous sodium carbonate, stirred for 2 hours, After filtration and concentration to remove the solvent, the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 15:1) to obtain 2.059 g of a colorless liquid with a yield of 67%.

Example 2 2-acetaldehyde-5,5-dimethyl-1,3-dioxane (1)

Add 2.04g (10.0mmol) of 2-(2,2-dimethoxy-ethyl)-5,5-dimethyl-1,3-dioxane into 50ml of acetonitrile, then add 98mg (0.43 mmol) DDQ and 5ml of water, stirred in a water bath at 50°C for 2 hours, TLC showed that the raw materials basically disappeared, took it out to cool to room temperature, added 200ml of water, extracted with dichloromethane (50ml×6), and dried the extract over anhydrous sodium sulfate , filtered, and the solvent was removed by rotary evaporation, and the residue was subjected to silica gel column chromatography (petroleum ether (30-60°C): ether = 4:1) to obtain 1.27 g of a colorless liquid, with a yield of 80%. ESI-MS (m/e): 159.3[M+H] ⁺ , 181.4[M+Na] ⁺

Embodiment 3 General method for the preparation of 18 kinds of L-amino acid methyl ester hydrochloride 2a-r

Add 3.75ml (50mmol) of thionyl chloride dropwise to 50ml of anhydrous methanol under ice bath. After the dropwise addition is completed within 30min, add 42mmol of L-amino acid in batches, stir at room temperature for 24h, TLC (CHCl ₃ :MeOH=2:3) Monitor until the raw material disappears to terminate the reaction. The unreacted thionyl chloride _SOCl and HCl were pumped away, and the white solid was repeatedly ground with ether, and recrystallized with methanol-ether to obtain L-amino acid methyl ester hydrochloride as a white solid (proline methyl ester hydrochloride Salt is a colorless viscous oil). According to this general method, HCl·Phe-OMe, HCl·Ala-OMe, HCl·Gly-OMe, HCl·Arg-OMe, HCl·Asp-(OMe) ₂ , HCl·Leu-OMe, HCl·Met-OMe were synthesized , HCl Ser-OMe, HCl Tyr-OMe, HCl Thr-OMe, HCl Ile-OMe, HCl Trp-OMe, HCl Val-OMe, HCl Pro-OMe, HCl His-OMe, HCl ·Glu-(OMe) ₂ , HCl·Arg(NO ₂ )-OMe, HCl·Asn-OMe, HCl·Gln-OMe, the yield is 85-99%, the physical constants such as melting point and optical rotation are consistent with the reported data .

Example 4 General method for the preparation of N-acetoacetyl-L-amino acid methyl ester 3a-r

Add 30mmol of L-amino acid methyl ester hydrochloride into 50ml of methanol, add 5ml (35.6mmol) of triethylamine, stir to dissolve, then transfer to an ice bath, and drop diketene 2.646g (31.5 mmol), add in about 10 minutes, the solution turns orange yellow, continue to stir for 15 minutes, then move to room temperature for 1 hour, rotate to remove methanol, after cooling slightly, colorless needle crystals will appear in the bottle, add a small amount of acetic acid Ethyl ester, filter, wash the filter cake with a small amount of ethyl acetate for several times until no color reaction occurs between the filter cake and 2% FeCl ₃ ethanol solution, concentrate the filtrate, a small amount of crystals will appear again, repeat the previous operation, and rotate to dryness , dissolve the residue with chloroform or acetone, add 1.2 to 1.5 times of crude product silica gel dry mixing sample, separate by vacuum column chromatography, adopt petroleum ether-ethyl acetate system gradient elution, in petroleum ether: ethyl acetate When eluted with ester=3:1, the product L-amino acid methyl ester acetoacetylation product is obtained.

Example 5 Preparation of N-acetoacetyl-L-glycine methyl ester (3a)

According to the general method of preparation, 3a was obtained as light yellow oil with a yield of 89.7%. ESI-MS (m/e): 346[2M+H] ⁺ , 369[2M+Na] ⁺ .

The preparation of embodiment 6N-acetoacetyl-L-alanine methyl ester (3b)

According to the general method of preparation, 3b was obtained as light yellow oil with a yield of 90.74%; ESI-MS (m/e): 188.0 [M+H] ⁺ .

The preparation of embodiment 7N-acetoacetyl-L-valine methyl ester (3c)

According to the general method of preparation, 3c was obtained as light yellow oil with a yield of 88.7%; ESI-MS (m/e): 216[M+H]+, 238[M+Na] ⁺ .

The preparation of embodiment 8N-acetoacetyl-L-leucine methyl ester (3d)

According to the general preparation method, 3d was obtained as a light yellow oil with a yield of 90.8%; ESI-MS (m/e): 230[M+H] ⁺ .

The preparation of embodiment 9N-acetoacetyl group-L-isoleucine methyl ester (3e)

According to the general method of preparation, 3e was obtained as light yellow oil with a yield of 79.9%; ESI-MS (m/e): 230[M+H] ⁺ .

The preparation of embodiment 10N-acetoacetyl-L-phenylalanine methyl ester (3f)

According to the general method of preparation, 3f was obtained as light yellow oil with a yield of 90.7%; ESI-MS (m/e): 287[M+Na] ⁺ .

The preparation of embodiment 11N-acetoacetyl-L-tyrosine methyl ester (3g)

According to the general preparation method, 3 g was obtained as a light yellow oil with a yield of 84.3%; ESI-MS (m/e): 302[M+Na] ⁺ .

The preparation of embodiment 12N-acetoacetyl-L-serine methyl ester (3h)

According to the general preparation method, 3h was obtained as colorless crystals with a yield of 81.2%; ESI-MS (m/e): 204[M+H] ⁺ .

Preparation of Example 13 N-acetoacetyl-L-threonine methyl ester (3i)

According to the general method of preparation, 3i was obtained as a light yellow oil, and crystals were precipitated after long standing, with a yield of 82.7%; ESI-MS (m/e): 216[MH] ⁺ .

Preparation of Example 14 N-acetoacetyl-L-aspartic acid dimethyl ester (3j)

According to the general preparation method, 3j was obtained as a light yellow oil with a yield of 65.22%; ESI-MS (m/e): 246[M+H] ⁺ .

The preparation of embodiment 15N-acetoacetyl-L-glutamic acid dimethyl ester (3k)

According to the general method of preparation, 3k was obtained as light yellow oil with a yield of 82.74%; ESI-MS (m/e): 541[2M+Na] ⁺ .

The preparation of embodiment 16N-acetoacetyl group-L-tryptophan methyl ester (3l)

According to the general method of preparation, 3l was obtained as light yellow oil with a yield of 92.35%; ESI-MS (m/e): 303[M+H] ⁺ .

The preparation of embodiment 17N-acetoacetyl-L-methionine methyl ester (3m)

According to the general preparation method, 3m was obtained as a light yellow oil with a yield of 80.8%; ESI-MS (m/e): 287[M+K] ⁺ .

The preparation of embodiment 18N-acetoacetyl-L-arginine methyl ester (3n)

According to the general preparation method, 3n was obtained as a reddish-brown oily compound with a yield of 56%; ESI-MS (m/e): 274[M+H] ⁺ .

The preparation of embodiment 19N-acetoacetyl group-L-asparagine methyl ester (3o)

According to the general method of preparation, 3o was obtained as light yellow oil with a yield of 65%, ESI-MS (m/e): 231[M+H] ⁺ .

The preparation of embodiment 20N-acetoacetyl group-L-glutamine methyl ester (3p)

According to the general method of preparation, 3o was obtained as light yellow oil with a yield of 83%, ESI-MS (m/e): 245[M+H] ⁺ .

The preparation of embodiment 21N'-N-diacetoacetyl-L-cystine dimethyl ester (3q)

According to the general method of preparation, 3q was obtained as light yellow oil with a yield of 80.2%; ESI-MS (m/e): 437[M+H] ⁺ .

Embodiment 22N, the preparation of Nε-acetoacetyl-L-lysine methyl ester (3r)

According to the general method of preparation, the ratio of lysine methyl ester to diketene was 1:2.1, and 3r was obtained as light yellow oil with a yield of 90.29%; ESI-MS (m/e): 329[M+H] ⁺ .

Example 23 N-[2-(5,5-dimethyl-1,3-dioxane-2-yl-)vinyl]-N-(1,3-dicarbonylbutyl-L-amino acid methyl ester 4a -r preparation

In a 100ml round bottom flask, add 4.469mmol of N-acetoacetyl-L-glycine methyl ester, 2-acetaldehyde-5,5-dimethyl-1,3-dioxane 938mg (5.936mmol), Freshly steam 30ml of toluene, 8.0g of anhydrous magnesium sulfate, connect the reflux condenser, dry the tube, stir and react in an oil bath at 100°C for 72 hours, stop heating, take out and cool, filter, rinse with a small amount of ethyl acetate, concentrate, The solvent was evaporated, the sample was mixed with 1.2-1.5 times of the residue on silica gel, and subjected to column chromatography under reduced pressure with gradient elution (ethyl acetate-petroleum ether system) to obtain a light yellow oil.

Example 24 Preparation of N-[2-(5,5-dimethyl-1,3-dioxane-2-yl-)vinyl]-N-acetoacetyl-L-glycine methyl ester (4a)

According to the general preparation method, 4a was obtained as light yellow oil with a yield of 36.9%. FAB-MS (m/e): 314 [M+H] ⁺ .

Example 25 Preparation of N-[2-(5,5-dimethyl-1,3-dioxane-2-yl-)vinyl]-N-acetoacetyl-L-alanine methyl ester (4b)

According to the general preparation method, 4b was obtained as light yellow oil with a yield of 37.6%; FAB-MS (m/e): 328[M] ⁺ .

Example 26 Preparation of N-[2-(5,5-dimethyl-1,3-dioxane-2-yl-)vinyl]-N-acetoacetyl-L-valine methyl ester (4c)

According to the general preparation method, 4c was obtained as a light yellow oil with a yield of 40.2%; ESI-MS (m/e): 357 [M+H] ⁺ .

Example 27 Preparation of N-[2-(5,5-dimethyl-1,3-dioxane-2-yl-)vinyl]-N-acetoacetyl-L-leucine methyl ester (4d)

According to the general method of preparation, 4d was obtained as light yellow oil with a yield of 24.3%; ESI-MS (m/e): 371 [M+H] ⁺ .

Example 28 N-[2-(5,5-dimethyl-1,3 dioxane-2 base-)vinyl]-N-acetoacetyl-L-isoleucine methyl ester (4e) preparation

According to the general method of preparation, 4e was obtained as light yellow oil with a yield of 37.4%; ESI-MS (m/e): 371[M+H] ⁺ .

Example 29 N-[2-(5,5-dimethyl-1,3 dioxane-2 base-)vinyl]-N-acetoacetyl-L-phenylalanine methyl ester (4f) preparation

According to the general preparation method, 4f was obtained as a light yellow oil with a yield of 33.8%; FAB-MS (m/e): 401[M] ⁺ .

Example 30 Preparation of N-[2-(5,5-dimethyl-1,3-dioxane-2-yl-)vinyl]-N-acetoacetyl-L-tyrosine methyl ester (4g)

According to the general method of preparation, 4 g was obtained as a light yellow oil, with a yield of 33.1%; FAB-MS (m/e): 420[M] ⁺ .

Example 31 Preparation of N-[2-(5,5-dimethyl-1,3-dioxane-2-yl-)vinyl]-N-acetoacetyl-L-serine methyl ester (4h)

According to the general method of preparation, 4h was obtained as light yellow oil with a yield of 19.4%; ESI-MS (m/e): 366[M+Na] ⁺ .

Example 32 Preparation of N-[2-(5,5-dimethyl-1,3-dioxane-2-yl-)vinyl]-N-acetoacetyl-L-threonine methyl ester (4i)

According to the general method of preparation, 4i was obtained as light yellow oil with a yield of 42..8%; ESI-MS (m/e): 380[M+Na] ⁺ .

Example 33 N-[2-(5,5-dimethyl-1,3-dioxane-2-yl-)vinyl]-N-acetoacetyl-L-aspartic acid dimethyl ester (4j) preparation of

According to the general preparation method, 4j was obtained as light yellow oil with a yield of 29.4%; FAB-MS (m/e): 385[M] ⁺ .

Example 34 N-[2-(5,5-dimethyl-1,3 dioxane-2 base-)vinyl]-N-acetoacetyl-L-glutamic acid dimethyl ester (4k) preparation

According to the general preparation method, 4k was obtained as light yellow oil with a yield of 40.7%; FAB-MS (m/e): 423[M+H+Na] ⁺ .

Example 35 Preparation of N-[2-(5,5-dimethyl-1,3-dioxane-2-yl-)vinyl]-N-acetoacetyl-L-tryptophan methyl ester (4l)

According to the general preparation method, 4l was obtained as light yellow oil with a yield of 36.4%; FAB-MS (m/e): 443[M+H] ⁺ .

Example 36 N-[2-(5,5-dimethyl-1,3 dioxane-2 base-)vinyl]-N-acetoacetyl-L-methionine methyl ester (4m) preparation

According to the general preparation method, 4m was obtained as light yellow oil with a yield of 52.8%; FAB-MS (m/e): 388[M+H] ⁺ .

Example 37 N-[2-(5,5-Dimethyl-1,3-dioxane-2-yl-)vinyl]-N-acetoacetyl- ^NG- (NO ₂ )-L-arginine Preparation of benzyl acid ester (4n)

According to the general preparation method, 4n was obtained as a light yellow oil with a yield of 16.8%; ESI-MS (m/e): 534[M+H] ⁺ .

Example 38 Preparation of N-[2-(5,5-dimethyl-1,3-dioxane-2-yl-)vinyl]-N-acetoacetyl-L-asparagine methyl ester (4o)

According to the general method of preparation, 4o was obtained as light yellow oil with a yield of 33%, ESI-MS (m/e): 371[M+H] ⁺ .

Example 39 Preparation of N-[2-(5,5-dimethyl-1,3-dioxane-2-yl-)vinyl]-N-acetoacetyl-L-glutamine methyl ester (4p)

According to the general preparation method, 4p was obtained as light yellow oil with a yield of 43%, ESI-MS (m/e): 385[M+H] ⁺ .

Example 40N', N-di-[2-(5,5-dimethyl-1,3-dioxane-2-yl-)vinyl]-N-acetoacetyl-L-cystine dimethyl Preparation of ester (4q)

According to the general method of preparation, 4q was obtained as light yellow oil with a yield of 16.4%; ESI-MS (m/e): 718[M+H] ⁺ .

Example 41 Preparation of N-[2-(5,5-dimethyl-1,3-dioxane-2-yl-)vinyl]-N-acetoacetyl-L-lysine methyl ester (4r)

According to the general preparation method, 4r was obtained as light yellow oil with a yield of 16%, ESI-MS (m/e): 623[M+H] ⁺ .

Example 42 General method for preparing (S)-2-substituted-(3'-acetyl-2'-pyridone-1'-yl)acetic acid methyl ester (5a-r)

Add 2.58mmol N-[2-(5,5-dimethyl-1,3-dioxane-2-yl-)vinyl]-N-acetoacetyl-L-amino acid methyl ester into 8ml 1,4 Add 4ml of 0.4M H ₂ SO ₄ to a round bottom flask of dioxane, protect it with argon, and react at 60°C for 16 hours. TLC shows that the raw material disappears _. Neutralize to neutral, add 30ml of water, and extract with ethyl acetate (15ml x 3). The extract is dried, concentrated, and subjected to silica gel column chromatography to obtain a light yellow oil.

Preparation of Example 43 (3'-acetyl-2'-pyridone-1'-yl) methyl acetate (5a)

According to the general preparation method, 5a was obtained as colorless crystals with a yield of 47.3%; ESI-MS (m/e): 210[M+H] ⁺ .

Example 44 Preparation of (2S)-2-(3'-acetyl-2'-pyridone-1'-yl)propionic acid methyl ester (5b)

According to the general preparation method, 5b was obtained as light yellow oil with a yield of 50.4%; FAB-MS (m/e): 224[M] ⁺ .

Example 45 Preparation of (2S)-2-(3'-acetyl-2'-pyridone-1'-yl)-3-methyl-butyric acid methyl ester (5c)

According to the general method of preparation, 5c was obtained as light yellow oil with a yield of 64.8%; ESI-MS (m/e): 252[M+H] ⁺ .

Example 46 Preparation of (2S)-2-(3'-acetyl-2'-pyridone-1'-yl)-4-methyl-pentanoic acid methyl ester (5d)

According to the general method of preparation, 5d was obtained as light yellow oil with a yield of 64%, ESI-MS (m/e): 266[M+H] ⁺ .

Example 47 Preparation of (2S)-2-(3'-acetyl-2'-pyridone-1'-yl)-3-methyl-pentanoic acid methyl ester (5e)

According to the general method of preparation, 5e was obtained as light yellow oil with a yield of 55.9%, ESI-MS (m/e): 266[M+H] ⁺ .

Example 48 Preparation of (2S)-2-(3'-acetyl-2'-pyridone-1'-yl)-3-phenyl-propionic acid methyl ester (5f)

According to the general preparation method, 5f was obtained as colorless crystals with a yield of 57.3%, FAB-MS (m/e): 300[M] ⁺ .

Example 49 Preparation of (2S)-2-(3'-acetyl-2'-pyridone-1'-yl)-3-(4"-hydroxyl-phenyl)-propionic acid methyl ester (5g)

According to the general method of preparation, 5 g was obtained as light yellow oil, the yield was 65.9%, ESI-MS (m/e): 316[M+H] ⁺ .

Example 50 Preparation of (2S)-2-(3'-acetyl-2'-pyridone-1'-yl)-3-hydroxyl-propionic acid methyl ester (5h)

According to the general preparation method, 5h was obtained as light yellow oil with a yield of 36%, ESI-MS (m/e): 240[M+H] ⁺ .

Example 51 Preparation of (2S)-2-(3'-acetyl-2'-pyridone-1'-yl)-3-hydroxy-butyric acid methyl ester (5i)

According to the general preparation method, 5i was obtained as light yellow oil with a yield of 57%, ESI-MS (m/e): 254[M+H] ⁺ .

Example 52 Preparation of (2S)-2-(3'-acetyl-2'-pyridone-1'-yl)-3-methoxycarbonyl-propionic acid methyl ester (5j)

According to the general method of preparation, 5j was obtained as light yellow oil with a yield of 35%, ESI-MS (m/e): 282[M+H] ⁺ .

Example 53 Preparation of (2S)-2-(3'-acetyl-2'-pyridone-1'-yl)-4-methoxycarbonyl-butyric acid methyl ester (5k)

According to the general preparation method, 5k was obtained as light yellow oil with a yield of 35%, ESI-MS (m/e): 296[M+H] ⁺ .

Example 54 Preparation of (2S)-2-(3'-acetyl-2'-pyridone-1'-yl)-3-(indol-3'-yl)-propionic acid methyl ester (5l)

According to the general method of preparation, 5l was obtained as a light yellow oil with a yield of 49%, ESI-MS (m/e): 339[M+H] ⁺ .

Example 55 Preparation of (2S)-2-(3'-acetyl-2'-pyridone-1'-yl)-4-methylmercapto-butyric acid methyl ester (5m)

According to the general method of preparation, 5m was obtained as a light yellow oil with a yield of 47.9%, FAB-MS (m/e): 284[M] ⁺ .

Example 56 Preparation of (2S)-2-(3'-acetyl-2'-pyridone-1'-yl)-5-nitroguanidino-valeric acid methyl ester (5n)

According to the general preparation method, 5n was obtained as a light yellow oil with a yield of 36.9%, ESI-MS (m/e): 430[M+H] ⁺ .

Example 57 Preparation of (2S)-2-(3'-acetyl-2'-pyridone-1'-yl)-3-aminocarbonylpropionic acid methyl ester (5o)

According to the general method of preparation, 5o was obtained as light yellow oil with a yield of 33%, ESI-MS (m/e): 267[M+H] ⁺ .

Example 58 Preparation of (2S)-2-(3'-acetyl-2'-pyridone-1'-yl)-3-aminocarbonylbutanoic acid methyl ester (5p)

According to the general preparation method, 5p was obtained as light yellow oil with a yield of 33%, ESI-MS (m/e): 281[M+H] ⁺ .

Example 59 (2S, 2S')-3,3'-dithio-2,2-bis(3'-acetyl-2'-pyridon-1'-yl)-3-propionic acid dimethyl ester ( 5q) Preparation

According to the general preparation method, 5q was obtained as light yellow oil with a yield of 34%, ESI-MS (m/e): 509[M+H] ⁺ .

Example 60 Preparation of (2S)-2,6-bis(3'-acetyl-2'-pyridone-1'-yl)-hexanoic acid methyl ester (5r)

According to the general preparation method, 5r was obtained as light yellow oil with a yield of 26%, ESI-MS (m/e): 401[M+H] ⁺ .

Example 61 General method for the preparation of (S)-2-substituted-(3'-acetyl-2'-pyridon-1'-yl)acetic acid 6a-r

Dissolve 1mmol (S)-2-substituted-(3'-acetyl-2'-pyridon-1'-yl)methyl acetate in 5ml of methanol, add 2N NaOH under ice-bath conditions until the pH value is 13. After reacting for 3 hours, TLC showed that the raw material disappeared completely, and the pH value was adjusted to 7 with 2N HCl, and the methanol in the reaction solution was removed with a rotary evaporator. Then adjust the pH value to 3 with 2N HCl, extract with ethyl acetate (15ml x 3), combine the ester layer, wash the ester layer (15ml) with saturated NaCl solution, dry the ester layer with anhydrous sodium sulfate, concentrate, and use a silica gel column layer Analysis gave the title compound as a colorless solid.

Preparation of Example 62 (S)-2-substituted-(3'-acetyl-2'-pyridone-1'-yl)acetic acid (6a)

According to the general preparation method, 6a was obtained as a colorless solid with a yield of 62%, ESI-MS (m/e): 196[M] ⁺ .

Example 63 Preparation of (2S)-2-(3'-acetyl-2'-pyridone-1'-yl)propionic acid (6b)

According to the preparation method, 6b was obtained as a colorless solid with a yield of 45%, ESI-MS (m/e): 211[M] ⁺ .

Example 64 Preparation of (2S)-2-(3'-acetyl-2'-pyridone-1'-yl)-3-methyl-butyric acid (6c)

According to the general preparation method, 6c was obtained as a light yellow solid with a yield of 70%, ESI-MS (m/e): 238[M+H] ⁺ .

Example 65 Preparation of (2S)-2-(3'-acetyl-2'-pyridone-1'-yl)-4-methyl-pentanoic acid (6d)

According to the general preparation method, 6d was obtained as a light yellow solid with a yield of 76%, ESI-MS (m/e): 252[M+H] ⁺ .

Example 66 Preparation of (2S)-2-(3'-acetyl-2'-pyridone-1'-yl)-3-methyl-pentanoic acid methyl ester (6e)

According to the general preparation method, 6e was obtained as a light yellow solid with a yield of 71%, ESI-MS (m/e): 252[M+H] ⁺ .

Example 67 Preparation of (2S)-2-(3'-acetyl-2'-pyridone-1'-yl)-3-phenyl-propionic acid (6f)

According to the general preparation method, 6f was obtained as a colorless solid with a yield of 68.5%, ESI-MS (m/e): 286.3 [M+H] ⁺ .

Example 68 Preparation of (2S)-2-(3'-acetyl-2'-pyridone-1'-yl)-3-(4"-hydroxyl-phenyl)-propionic acid methyl ester (6g)

According to the general preparation method, 6 g was obtained as a light yellow solid with a yield of 75%, ESI-MS (m/e): 302 [M+H] ⁺ .

Example 69 Preparation of (2S)-2-(3'-acetyl-2'-pyridone-1'-yl)-3-hydroxyl-propionic acid methyl ester (6h)

According to the general preparation method, 6h was obtained as a light yellow solid with a yield of 51%, ESI-MS (m/e): 226[M+H] ⁺ .

Example 70 Preparation of (2S)-2-(3'-acetyl-2'-pyridone-1'-yl)-3-hydroxy-butyric acid methyl ester (6i)

According to the general preparation method, 6i was obtained as a light yellow solid with a yield of 65.2%, ESI-MS (m/e): 240[M+H] ⁺ .

Example 71 Preparation of (2S)-2-(3'-acetyl-2'-pyridone-1'-yl)-3-methoxycarbonyl-propionic acid methyl ester (6j)

According to the general preparation method, 6j was obtained as a light yellow solid with a yield of 55%, ESI-MS (m/e): 254[M+H] ⁺ .

Example 72 Preparation of (2S)-2-(3'-acetyl-2'-pyridone-1'-yl)-4-methoxycarbonyl-butyric acid methyl ester (6k)

According to the general preparation method, 6k was obtained as a yellow oil with a yield of 52%, ESI-MS (m/e): 268[M+H] ⁺ .

Example 73 Preparation of (2S)-2-(3'-acetyl-2'-pyridone-1'-yl)-3-(indol-3'-yl)-propionic acid methyl ester (6l)

According to the general preparation method, 6l was obtained as a yellow oil with a yield of 74%, ESI-MS (m/e): 325[M+H] ⁺ .

Example 74 Preparation of (2S)-2-(3'-acetyl-2'-pyridone-1'-yl)-4-methylmercapto-butyric acid methyl ester (6m)

According to the general preparation method, 6m was obtained as a light yellow solid with a yield of 60%, ESI-MS (m/e): 270[M+H] ⁺ .

Example 75 Preparation of (2S)-2-(3'-acetyl-2'-pyridone-1'-yl)-5-nitroguanidino-valeric acid methyl ester (6n')

According to the general method of preparation, 6n' was obtained as a yellow oil with a yield of 52%, ESI-MS (m/e): 340[M+H] ⁺ ..

Example 76 Preparation of (2S)-2-(3'-acetyl-2'-pyridone-1'-yl)-5-guanidino-pentanoic acid (6n)

Add (294mg, 1.0mmol) (2S)-2-(3'-acetyl-2'-pyridone-1'-yl)-5-nitroguanidino-valeric acid methyl ester, ethanol to 25ml eggplant bottle (8ml), water (2ml), Pd/C (1.0g, 5%) and formic acid (30μl), pass into H ₂ gas, react for 4 hours, TLC shows no (2S)-2-(3'-acetyl -2'-pyridon-1'-yl)-5-nitroguanidino-pentanoic acid methyl ester remained. After filtering, the filtrate was evaporated to dryness, and the residue was repeatedly washed with ether until 280 mg of 6n colorless powder was obtained, with a yield of 95%, ESI-MS (m/e): 295[M+H] ⁺ .

Example 77 Preparation of (2S)-2-(3'-acetyl-2'-pyridone-1'-yl)-3-aminocarbonyl-propionic acid (6o)

According to the general preparation method, 6o was obtained as a yellow solid with a yield of 52%, ESI-MS (m/e): 253[M+H] ⁺ .

Example 78 Preparation of (2S)-2-(3'-acetyl-2'-pyridone-1'-yl)-4-aminocarbonyl-propionic acid (6p)

According to the general preparation method, 6p was obtained as a light yellow solid with a yield of 53%, ESI-MS (m/e): 267[M+H] ⁺ .

Example 79 (2S, 2S')-3,3'-dithio-2,2'-(3'-acetyl-2'-pyridon-1'-yl)-3-propionic acid (6q) preparation

According to the general preparation method, 6q was obtained as a light yellow solid with a yield of 50%, ESI-MS (m/e): 481[M+H] ⁺ .

Example 80 Preparation of (2S)-2,6-bis(3'-acetyl-2'-pyridone-1'-yl)-hexanoic acid (6r)

According to the general preparation method, 6r was obtained as a yellow oil with a yield of 60%, ESI-MS (m/e): 387[M+H] ⁺ .

Experimental example 1 The evaluation experiment of the iron flooding activity of the compound of the present invention

1) Test samples: Compounds 6a-r prepared in Examples; prepared to desired concentration with PBS containing 1% DMSO.

2) Experimental animals: ICR male mice, weighing 18-22 g.

表示。3) Animal model preparation and experimental method: The experimental animals were divided into groups of 12, and the experimental group was injected intraperitoneally with 0.2ml of 2mgkg-1 of ferrodextranum physiological saline solution every day, twice a day for five consecutive days. The treatment group was injected intraperitoneally with 50% DMSO solution of (S)-2-substituted-(3'-acetyl-2'-pyridone-1'-yl)acetic acid 6a-r every day, and the positive control group was injected with 0.3mmolkg intraperitoneally every day. -1 DMSO (50%, 0.2ml) solution, and the negative control group was intraperitoneally injected with DMSO (50%, 0.2ml) solution every day. Urine was collected for 5 hours and stool samples were collected for 24 hours after two hours of daily dosing. After 5 consecutive days of administration, 24 days after the last administration, the body weight was weighed, the blood was collected from the eyeballs, the mice were killed by dislocation of the cervical spine, and the liver, kidney, brain, spleen, heart, and left femur were collected. All biological samples were nitrified on an electric heating plate with HNO3:HClO4 (3:1) until a white solid appeared, dissolved in double distilled water and transferred to a volumetric flask to constant volume, and the content of iron was determined by an atomic absorption spectrophotometer. Excel software was used to process the data, and the significance test of the differences among the groups was performed by analysis of variance and t test. by

express.

4) The experimental results are shown in Table 1.

The evaluation experiment result of the iron flooding activity of the compound of the present invention in table 1

a) The data is X±SD μg iron/g tissue, n=12; H.M.=healthy mouse, N.C.=blank control, P.C.=positive control; b) compared with positive control, p<0.01; c) compared with positive control, p<0.01; d) compared with the positive control, p<0.05; e) compared with the positive control, p<0.05; f) compared with the positive control, p<0.05; g) compared with the positive control, p<0.05.

Experimental results show that the compound of the present invention has an excellent iron repelling effect, and can be used as an antidote for iron poisoning clinically.

Claims (9)

1. (S)-2-substituted-(3'-acetyl-2'-pyridone-1'-yl) acetic acid compound, its structural formula is shown in formula I, formula II or formula III:

Formula I Formula II Formula II Wherein, R is selected from hydrogen, CH ₃ , CH(CH ₃ ) ₂ , CHCH(CH ₃ ) ₂ , CH(CH ₃ )C ₂ H ₅ , CH ₂ C ₆ H ₅ , CH ₂ C ₆ H ₄ -OH- _p , _CH2OH , CH( _CH3 ) _{OH , CH2CO2CH3 , CH2CH2CO2CH3 , 3 - indoleacetyl} , _{CH2CH2SCH3 , CH2CH2CH2NHC-} (NH)NH _{( NO2} ), _{CH2CONH2 or CH2CH2CONH2 .} 2. A method for preparing the compound of formula I described in claim 1, comprising the following steps: (1) converting L-amino acid into L-amino acid methyl ester; (2) 1,1,3,3-Tetramethylpropane and 2,2-Dimethyl-1,3-propanediol undergo acetal transfer reaction to generate 2-(2',2'-dimethoxy -Ethyl)-5,5-dimethyl-1,3-dioxane; (3) Hydrolyze 2-(2',2'-dimethoxy-ethyl)-5,5-dimethyl-1,3-dioxane to generate 2-acetaldehyde-5,5- Dimethyl-1,3-dioxane; (4) condensing the L-amino acid methyl ester prepared in step (1) with diketene to prepare N-acetoacetyl-L-amino acid methyl ester; (5) N-acetoacetyl-L-amino acid methyl ester is reacted with 2-acetaldehyde-5,5-dimethyl-1,3-dioxane to generate N-[2-(5,5 -Dimethyl-1,3-dioxane-2-yl-)vinyl]-N-acetoacetyl-L-amino acid methyl ester; (6) In the presence of H ₂ SO ₄ and dioxane, N-[2-(5,5-dimethyl-1,3-dioxane-2 base-)vinyl]N-(1, 3-Dicarbonobutyl-L-amino acid methyl ester generates (S)-2-substituted-(3'-acetyl-2'-pyridone-1'-yl)methyl acetate; (7) Saponification of (S)-2-substituted-(3'-acetyl-2'-pyridon-1'-yl)acetic acid methyl ester to obtain. 3. according to the described method of claim 2, it is characterized in that: wherein, described L-amino acid comprises: L-glycine, L-alanine, L-valine, L-leucine, L-iso Leucine, L-Phenylalanine, L-Tyrosine, L-Serine, L-Threonine, L-Aspartic Acid, L-Glutamic Acid, L-Tryptophan, L-Methylthio amino acid, L-arginine, L-asparagine or L-glutamine. 4. a method for preparing the formula II compound described in claim 1, comprising the following steps: (1) L-cysteine is converted into L-cysteine methyl ester; (2) 1,1,3,3-Tetramethylpropane and 2,2-Dimethyl-1,3-propanediol undergo acetal transfer reaction to generate 2-(2',2'-dimethoxy -Ethyl)-5,5-dimethyl-1,3-dioxane; (3) Hydrolyze 2-(2',2'-dimethoxy-ethyl)-5,5-dimethyl-1,3-dioxane to generate 2-acetaldehyde-5,5- Dimethyl-1,3-dioxane; (4) condensing L-cysteine methyl ester with diketene to prepare N-acetoacetyl-L-cystine methyl ester; (5) Reaction of N-acetoacetyl-L-cystine methyl ester with 2-acetaldehyde-5,5-dimethyl-1,3-dioxane to generate N', N-di- [2-(5,5-Dimethyl-1,3-dioxane-2-yl-)vinyl]-N-acetoacetyl-L-cystine dimethyl ester; (6) N', N-bis-[2-(5,5-dimethyl-1,3-dioxane-2-yl-)vinyl]-N-acetoacetyl-L-cystine Dimethyl ester undergoes an intramolecular aldol reaction to generate (2S,2S')-3,3'-dithio-2,2-bis(3'-acetyl-2'-pyridon-1'-yl)- Dimethyl 3-propionate; (7) Dimethyl (2S, 2S')-3,3'-dithio-2,2-bis(3'-acetyl-2'-pyridon-1'-yl)-3-propionate Saponification, that is. 5. A method for preparing the compound of formula III according to claim 1, comprising the following steps: (1) L-lysine is converted into L-lysine methyl ester; (2) 1,1,3,3-Tetramethylpropane and 2,2-Dimethyl-1,3-propanediol undergo acetal transfer reaction to generate 2-(2',2'-dimethoxy -Ethyl)-5,5-dimethyl-1,3-dioxane; (3) Hydrolyze 2-(2',2'-dimethoxy-ethyl)-5,5-dimethyl-1,3-dioxane to generate 2-acetaldehyde-5,5- Dimethyl-1,3-dioxane; (4) Condensing L-lysine methyl ester with diketene to prepare N, Nε-acetoacetyl-L-lysine methyl ester; (5) N, Nε-acetoacetyl-L-lysine methyl ester reacts with 2-acetaldehyde-5,5-dimethyl-1,3-dioxane to generate N-[2- (5,5-Dimethyl-1,3-dioxane-2-yl-)vinyl]-N-acetoacetyl-L-lysine methyl ester; (6) Intramolecularly generate N-[2-(5,5-dimethyl-1,3-dioxane-2-yl-)vinyl]-N-acetoacetyl-L-lysine methyl ester The aldol reaction generates (2S)-2,6-bis(3'-acetyl-2'-pyridone-1'-yl)-hexanoic acid methyl ester; (7) Saponification of (2S)-2,6-bis(3'-acetyl-2'-pyridon-1'-yl)-hexanoic acid methyl ester to obtain. 6. A pharmaceutical composition for driving out heavy metals, consisting of (S)-2-substituted-(3'-acetyl-2'-pyridone-1'-yl) acetic acid compound according to claim 1 and a pharmaceutically acceptable carrier or adjuvant. 7. The pharmaceutical composition for repelling heavy metals according to claim 6, wherein the heavy metal is iron. 8. The (S)-2-substituted-(3'-acetyl-2'-pyridone-1'-yl) acetic acid compound as claimed in claim 1 is used in the preparation of heavy metal-expelling medicines. 9. Use according to claim 8, characterized in that said heavy metal is iron.

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