Synthetic method of bicyclic pyridone derivative

Technical Field

The invention relates to the synthesis of the bicyclic pyridone derivatives a method. In order to easy preparation, and with structural diversity of the reaction center 5, 5-alkylthio -2, 4-pentadienoic acid ester as the raw material with parents nuclear reagent organic two primary amine substitution/condensation reaction, to obtain bicyclic pyridone derivatives. And the reported bicyclic pyridone derivative is compared to synthetic method, raw materials of this invention are easy, simple operation, synthetic mild reaction conditions with high efficiency.

Background Art

Bicyclic pyridone derivative is a potential biological activity with N-heterocyclic compounds, their use as potential analgesic and anti-inflammation drug has been wide attention of the people. 2003 years (WO2003053967A1) Bayer Company's patented and 2005 years Company's patented Amgen (WO2005/070932 A2) reports through TNF-α, IL-1β, IL -6 and/or IL-8 regulation and control, bicyclic pyridone derivatives are the effects of preventing and treating diseases. So far, four kinds of known a method for preparing bicyclic pyridone derivatives: 1) ketene condensation amine molecule inner ring condensation (Tetrahedron   2002, 58, 1309; Patent EP 296453); 2) cyano butene acid ester addition reaction with an organic diamine (Patent US   4186200 and WO   2005070932); 3) halogenated or sulfur methyl pyridone the addition reaction with diamine (J.Heterocycl. Chem. 1994, 31,393); 4) 6-fluoro-2-pyridinyl amino alcohol of the Mitsunobu reaction (Org. Lett. 2007, 9, 5175). However, restrictions on the molecular structure of the raw material, the above-mentioned method, can synthesize bicyclic pyridone derivatives have also been the molecular structure of the restriction, thus limiting the synthesis by the application of the bicyclic pyridone derivatives. This invention utilizes the easy preparation, and with structural diversity of the reaction center 5, 5-alkylthio -2, 4-pentadienoic acid ester 2 and organic two primary amine 3 substituted/condensation reaction, through the control 2 in R¹ substituents, synthetic the series of different structural macrobicyclic pyridone derivative 1.

Content of the invention

The purpose of this invention is to provide a kind of easy availability of raw materials, mild reaction conditions, wide adaptability, can be conveniently synthesizing bicyclic pyridone derivatives.

In order to realize the above purpose, the technical scheme of the present invention are as follows:

To palladium acetate Pd (OAc)₂ as catalyst, AgOAc in an oxidizing agent, such as silver acetate in an organic solvent in the presence of the second sulfur polycondensation derivatives A and acrylic ester (B) generating oxidation coupling reaction of 5, 5-alkylthio -2, 4-pentadienoic acid ester 2 (equation 1). Then in order to 2 (synthon) as raw material with an organic two primary amine 3 substitute/condensation reaction (reaction formula 2). After the reaction carried out according to the conventional method for separating and purifying the separation and characterization of the product, get macrobicyclic pyridone derivative 1.

Technical scheme is characterized in that:

1.5, 5-b alkylthio -2, 4-pentadienoic acid ester 2 is a synthon, its substituent is:

1) R¹ as acyl, cinnamoyl, ester-based, amide-based.

2) R² the carbon atom number 1-4 alkyl, allyl, benzyl, or R² … R² to represent a plurality of methylene (CH₂)_m (wherein m=2, 3, 4).

3) R³ the carbon atom number 1-4 alkyl; wherein to methyl and ethyl the best effect.

2. Organic two primary amine 3 to 1, 2-ethylenediamine, 1, 3-propane diamine and 1, 4-butanediamine.

3. The reaction solvent is one or more organic solvent is methanol, ethanol, isopropanol, tetrahydrofuran, 1, 4-dioxane and toluene; wherein protic solvent the reaction is carried out in methanol or ethanol to the best effect.

4. Synthon 2 and organic two primary amine 3 molar ratio of 1 the [...] the 1-1 [...] 10. Wherein the molar ratio of the 1 [...] 1.2 when the best reaction effect.

5. The reaction time is 1-24 hours. Wherein the reaction time is the best 12-24 hours.

6. The reaction temperature is the 20-120 [...]. Wherein the reaction temperature is the best the 70-100 [...].

The invention has the following advantages:

1) synthon 5, 5-alkylthio -2, 4-pentadienoic acid ester 2 diversity structure, can be used for synthesizing different types and structure of the bicyclic pyridone derivative 1.

2) synthon 2 is easy to prepare, preparing raw materials is cheap and easy to obtain.

3) bicyclic pyridone derivative 1 synthetic mild reaction conditions, simple steps, high yield of the product.

In short, this invention utilizes the 5, 5-alkylthio -2, 4-pentadienoic acid ester 2 diversity and the structure of the reaction center to efficiently synthesizing a plurality of different types and structure of the bicyclic pyridone derivative 1, raw material is cheap and easy to obtain, the operation is simple, high yield of target product.

Mode of execution

To palladium acetate Pd (OAc)₂ as catalyst, AgOAc in an oxidizing agent, such as silver acetate in an organic solvent in the presence of the second sulfur polycondensation derivatives A and acrylic ester (B) generating oxidation coupling reaction of 5, 5-alkylthio -2, 4-pentadienoic acid ester 2 (equation 1).

The specific process is as follows: the two sulfur polycondensation derivatives A (0.5mmol), acrylate B (1.0mmol), palladium acetate Pd (OAc)₂ (23 mg, 0 . 10mmol), AgOAc silver acetate (167 mg, 1 . 0mmol) and 2 ml solvent N, N-dimethyl formamide in a mixture of 50 the stirring [...] 8 hours. After cooling to room temperature 30 ml water, filtering, dichloromethane extraction aqueous phase (3 × 10 ml), the organic phase is separated. Organic phase dried with anhydrous magnesium sulfate, filtered. Removal of the volatile components under reduced pressure, then separation with silica gel column chromatography (eluant is petroleum ether (60-90 the [...] /ethyl ether, the v/v=9 [...] 1), to obtain the target product 2. The target product by nuclear magnetic resonance spectrum and high resolution mass spectrometry confirmed.

Through the following embodiment to further understand the invention, but the content of this invention is not limited to this.

Embodiment 1

In a 25 ml   Schlenk in the reaction bottle, adding 5, 5-alkylthio -2, 4-pentadienoic acid ester 2a (65 mg, 0 . 25mmol), organic two primary 1, 2-ethylenediamine (3a) (18 mg, 0 . 30mmol) and 2 ml ethanol solvent, stirring reflux reaction 14h. After the reaction, the mixture is cooled to the room temperature, removing the volatile components under reduced pressure, then with silica gel column chromatography separation, is petroleum ether eluant (the 60-90 [...])/ acetone, (the v/v=3 [...] 1), to obtain white solid target product 1a (35 mg, yield 79%). The target product by nuclear magnetic resonance spectrum and high resolution mass spectrometry confirmed.

Embodiment 2

The reaction steps of the embodiment 1, with the embodiment 1 is characterized in that different, the reaction time is 24h. Stop the reaction, the post-processed to obtain the target product 1a (32 mg, yield 72%). The reaction time is prolonged to note by decomposition product portion.

Embodiment 3

The reaction steps of the embodiment 1, with the embodiment 1 is characterized in that different, the reaction temperature is room temperature the 20 [...] , the reaction time is 24h. Stop the reaction, the post-processed to obtain the target product 1a (8 mg, yield 17%). Note the reaction temperature is too low the reaction slow.

Embodiment 4

The reaction steps of the embodiment 1, with the embodiment 1 is characterized in that different, the reaction solvent is tetrahydrofuran. Stop the reaction, the post-processed to obtain the target product 1a (12 mg, yield 26%). Using a non-protonic solvent to carry out reaction.

Embodiment 5

The reaction steps of the embodiment 1, with the embodiment 1 is characterized in that different, the reaction temperature of the 70 [...]. Stop the reaction, the post-processed to obtain the target product 1a (33 mg, yield 74%).

Embodiment 6

The reaction steps of the embodiment 1, with the embodiment 1 is characterized in that different, the reaction temperature of the 100 [...] , the reaction time is 9h. Stop the reaction, the post-processed to obtain the target product 1a (37 mg, yield 83%). Note raise the reaction temperature can shorten the reaction time.

Embodiment 7

The reaction steps of the embodiment 1, with the embodiment 1 is characterized in that different, the reaction solvent is toluene, the reaction temperature of the 120 [...] , reaction time 5h. Stop the reaction, the post-processed to obtain the target product 1a (12 mg, yield 26%). Note has a high boiling point of toluene can also be used as the reaction solvent, but is not the best reaction solvent, using a further detrimental to the reaction of the non-protic solvent.

Embodiment 8

The reaction steps of the embodiment 1, with the embodiment 1 is characterized in that the different, 1, 2-ethylenediamine (3a) for the adding amount of 15 mg (0.25mmol). Stop the reaction, the post-processed to obtain the target product 1a (30 mg, yield 67%). Note the use of only the organic equivalent oxophile, can't get the best yield of the target product.

Embodiment 9

The reaction steps of the embodiment 1, with the embodiment 1 is characterized in that the different, 1, 2-ethylenediamine (3a) adding amount is 30 mg (0.50mmol). Stop the reaction, the post-processed to obtain the target product 1a (35 mg, yield 79%).

Embodiment 10

The reaction steps of the embodiment 1, with the embodiment 1 is characterized in that the different, 1, 2-ethylenediamine (3a) adding amount is 150 mg (2.50mmol). Stop the reaction, the post-processed to obtain the target product 1a (36 mg, yield 81%). Note there is no need to use the greatly excessive organic two primary amine.

Embodiment 11

The reaction steps of the embodiment 1, with the embodiment 1 is characterized in that, in the reaction system by adding organic two primary amine is 1, 3-propane diamine (3b) (22 mg, 0 . 3mmol). Stop the reaction, the post-processed to obtain white solid target product 1b (28 mg, yield 58%). The target product by nuclear magnetic resonance spectrum and high resolution mass spectrometry confirmed.

Embodiment 12

The reaction steps of the embodiment 1, with the embodiment 1 is characterized in that the different, added in the reaction system 5, 5-alkylthio -2, 4-pentadienoic acid ester is 2b (80 mg, 0 . 25mmol). Stop the reaction, the post-processed to obtain white solid target product 1c (51 mg, yield 85%). The target product by nuclear magnetic resonance spectrum and high resolution mass spectrometry confirmed.

Embodiment 13

The reaction steps embodiment of operation 12, and the embodiment 12 is characterized in that, in the reaction system by adding organic two primary amine is 1, 3-propane diamine (3b) (22 mg, 0 . 3mmol). Stop the reaction, the post-processed to obtain white solid target product 1d (53 mg, yield 84%). The target product by nuclear magnetic resonance spectrum and high resolution mass spectrometry confirmed.

Embodiment 14

The reaction steps of the embodiment 1, with the embodiment 1 is characterized in that the different, added in the reaction system 5, 5-alkylthio -2, 4-pentadienoic acid ester is 2c (100 mg, 0 . 25mmol). Stop the reaction, the post-processed to obtain white solid target product 1e (69 mg, yield 87%). The target product by nuclear magnetic resonance spectrum and high resolution mass spectrometry confirmed.

Embodiment 15

The reaction steps of the embodiment 1, with the embodiment 1 is characterized in that the different, added in the reaction system 5, 5-alkylthio -2, 4-pentadienoic acid ester is 2d (75 mg, 0 . 25mmol), reaction time 24h. Stop the reaction, the post-processed to obtain white solid target product 1f (59 mg, yield is 88%). The target product by nuclear magnetic resonance spectrum and high resolution mass spectrometry confirmed.

Embodiment 16

The operation reaction steps with the embodiment 15, with the embodiment 15 is characterized in that, in the reaction system by adding organic two primary amine is 1, 3-propane diamine (3b) (22 mg, 0 . 3mmol). Stop the reaction, the post-processed to obtain white solid target product 1g (54 mg, yield 76%). The target product by nuclear magnetic resonance spectrum and high resolution mass spectrometry confirmed.

Embodiment 17

The reaction steps of the embodiment 1, with the embodiment 1 is characterized in that the different, added in the reaction system 5, 5-alkylthio -2, 4-pentadienoic acid ester is 2e (75 mg, 0 . 25mmol), reaction time 24h. Stop the reaction, the post-processed to obtain white solid target product 1h (55 mg, yield 82%). The target product by nuclear magnetic resonance spectrum and high resolution mass spectrometry confirmed.

Embodiment 18

The operation reaction steps with embodiment 17, embodiment with 17 is characterized in that, in the reaction system by adding organic two primary amine is 1, 3-propane diamine (3b) (22 mg, 0 . 3mmol). Stop the reaction, the post-processed to obtain white solid target product 1i (53 mg, yield 74%). The target product by nuclear magnetic resonance spectrum and high resolution mass spectrometry confirmed.

Embodiment 19

The reaction steps of the embodiment 1, with the embodiment 1 is characterized in that the different, added in the reaction system 5, 5-alkylthio -2, 4-pentadienoic acid ester is 2f (78 mg, 0 . 25mmol), reaction time 24h. Stop the reaction, the post-processed to obtain white solid target product 1j (43 mg, yield is 74%). The target product by nuclear magnetic resonance spectrum and high resolution mass spectrometry confirmed.

Embodiment 20

The reaction steps of the embodiment 1, with the embodiment 1 is characterized in that the different, added in the reaction system 5, 5-alkylthio -2, 4-pentadienoic acid ester is 2g (82 mg, 0 . 25mmol), reaction time 24h. Stop the reaction, the post-processed to obtain white solid target product 1k (44 mg, yield 71%). The target product by nuclear magnetic resonance spectrum and high resolution mass spectrometry confirmed.

Embodiment 21

The reaction steps of the embodiment 1, with the embodiment 1 is characterized in that the different, added in the reaction system 5, 5-alkylthio -2, 4-pentadienoic acid ester is 2h (87 mg, 0 . 25mmol), the reaction temperature of the 100 [...] , the reaction time is 24h. Stop the reaction, the post-processed to obtain the yellow solid target product 1l (42 mg, yield is 63%). The target product by nuclear magnetic resonance spectrum and high resolution mass spectrometry confirmed.

Embodiment 22

The operation reaction steps with embodiment 21, and the embodiment 21 is characterized in that, in the reaction system by adding organic two primary amine is 1, 3-propane diamine (3b) (22 mg, 0 . 3mmol). Stop the reaction, the post-processed to obtain the yellow solid target product 1m (41 mg, yield is 59%). The target product by nuclear magnetic resonance spectrum and high resolution mass spectrometry confirmed.

Embodiment 23

The reaction steps of the embodiment 1, with the embodiment 1 is characterized in that the different, added in the reaction system 5, 5-alkylthio -2, 4-pentadienoic acid ester is 2i (72 mg, 0 . 25mmol). Stop the reaction, the post-processed to obtain white solid target product 1n (31 mg, yield is 59%). The target product by nuclear magnetic resonance spectrum and high resolution mass spectrometry confirmed.

Embodiment 24

The reaction steps of the embodiment 1, with the embodiment 1 is characterized in that the different, added in the reaction system 5, 5-alkylthio -2, 4-pentadienoic acid ester is 2j (84 mg, 0 . 25mmol). Stop the reaction, the post-processed to obtain white solid target product 1o (35 mg, yield is 55%). The target product by nuclear magnetic resonance spectrum and high resolution mass spectrometry confirmed.

Embodiment 25

The reaction steps of the embodiment 1, with the embodiment 1 is characterized in that the different, added in the reaction system 5, 5-alkylthio -2, 4-pentadienoic acid ester is 2k (72 mg, 0 . 25mmol). Stop the reaction, the post-processed to obtain white solid target product 1a (36 mg, yield is 81%). The target product by nuclear magnetic resonance spectrum and high resolution mass spectrometry confirmed.

Embodiment 26

The reaction steps of the embodiment operate the same 25, and the embodiment 25 is characterized in that, in the reaction system by adding organic two primary amine is 1, 3-propane diamine (3b) (22 mg, 0 . 3mmol). Stop the reaction, the post-processed to obtain white solid target product 1b (32 mg, yield 67%). The target product by nuclear magnetic resonance spectrum and high resolution mass spectrometry confirmed.

Typical compound characterization data

Bicyclic pyridone derivatives 1a, 1c, 1d, 1f, 1g, 1h, 1i compounds are known, their nuclear magnetic resonance spectrum¹ H   NMR and¹³ CNMR, and HRMS high resolution mass spectrometry data is consistent with literature reports of the melting point (M.X.Zhao, M.X.Wang, Z.T.Huang, Tetrahedron   2002, 58, 1309; Z.T. Huang, Z.R.Liu, Heterocycles   1986, 24, 2247.)

Bicyclic pyridone derivatives (1b), white solid, melting point the 174-176 [...].¹ H   NMR (CDCl₃, 400MHz, 23 °C) δ 11.10 (s, 1H, NH), 7.62 (d, J=9.6Hz, 1H), 5.75 (d, J=9.6 Hz, 1H), 4.01 (m, 2H), 3.47 (m, 2H), 2.37 (s, 3H), 2.06 (m, 2H);¹³ C {¹ H} NMR (CDCl₃, 23     , 100MHz) δ 194.6, 162 . 1,154.1, 141.4, 103.4, 98.0, 39.2, 38.4, 26.6, 19.3. C₂₅ H₁₈ O₄ of theoretical value HRMS ([M⁺]): 192.0899; measured value: 192.0906.

Bicyclic pyridone derivatives (1e), white solid, melting point the 251-253 [...].¹ HNMR (DMSO-d₆, 400MHz, 23 °C) δ 9.09 (s, 1H, NH), 7.69 (d, J=8.3Hz, 2H), 7.43 (d, J=8.3 Hz, 1H), 7.33 (d, J=9.5Hz, 1H), 5.52 (d, J=9.5Hz, 1H), 4.05 (t, 2H), 3.82 (t, 2H);¹³ C {¹ H} NMR (DMSO-d₆, 23     , 100MHz) δ 189.7, 161 . 0,157.0, 142.9, 139 . 1,132.0, 130.5, 124 . 5,105.4, 96.5, 43.5, 43.4. C₂₅ H₁₈ O₄ of theoretical value HRMS ([M⁺]): 318.0004; measured value: 318.0002.

Bicyclic pyridone derivatives (1j), white solid, melting point the 238-240 [...].¹ H   NMR (DMSO-d₆, 400MHz, 23 °C) δ 9.08 (s, 1H, NH), 8.16 (d, J=9.6Hz, 1H), 7.94 (s, 1H), 7.18 (d, J=3.2Hz, 1H), 6.69 (t, 1H), 5.63 (d, J=9.6Hz, 1H), 4.04 (t, 2H), 3.80 (t, 2H);¹³ C {¹ H} NMR (DMSO-d₆, 23     , 100MHz) δ 175.3, 160 . 3,156.8, 152.6, 146 . 0,141.0, 116.7, 111 . 9,105.2, 95.7, 42.9, 42.7. C₂₅ H₁₈ O₄ of theoretical value HRMS ([M⁺]): 230.0691; measured value: 230.0694.

Bicyclic pyridone derivatives (1k), white solid, melting point the 208-210 [...].¹ H   NMR (DMSO-d₆, 400MHz, 23 °C) δ 9.00 (s, 1H, NH), 7.87 (t, 2H), 7.61 (d, J=3.5Hz, 1H), 7.20 (m, 1H), 5.60 (d, J=9.5Hz, 1H), 4.05 (t, 2H), 3.80 (t, 2H);¹³ C {¹ H} NMR (DMSO-d₆, 23     , 100MHz) δ 181.4, 161 . 0,157.1, 144.1, 142 . 1,132.2, 131.3, 128 . 5,105.6, 95.4, 43.6, 43.3. C₂₅ H₁₈ O₄ of theoretical value HRMS ([M⁺]): 246.0463; measured value: 246.0468.

Bicyclic pyridone derivatives (1l), yellow solid, melting point the 216-218 [...].¹ H   NMR (CDCl₃, 400MHz, 23 °C) δ 8.84 (s, 1H, NH), 7.82 (d, J=9.6Hz, 1H), 7.72 (d, J=15.5 Hz, 1H), 7.60 (m, 2H), 7.40 (m, 3H); 7.36 (d, J=15.5Hz, 1H), 5.84 (d, J= 9.6Hz, 1H), 4.25 (t, 2H), 3.98 (t, 2H);¹³ C {₁ H} NMR (CDCl₃, 23     , 100MHz) δ 184.7, 161 . 5,157.3, 142.1, 140 . 0,135.2, 130.2, 129 . 0,128.3, 120.9, 106.6, 98.5, 43.4, 42 . 8. C₁₆ H₁₄ N₂ O₂ of theoretical value HRMS ([M⁺]): 266.1055; measured value: 266.1065.

Bicyclic pyridone derivatives (1m), yellow solid, melting point the 175-177 [...].¹ HNMR (CDCl₃, 400MHz, 23 °C) δ 8.64 (s, 1H, NH), 7.72 (d, J=9.6Hz, 1H), 7.62 (d, J=15.5 Hz, 1H), 7.50 (m, 2H), 7.32 (m, 3H); 7.29 (d, J=15.5Hz, 1H), 5.74 (d, J= 9.6Hz, 1H), 4.05 (t, 2H), 3.78 (t, 2H), 2.01 (m, 2H);¹³ C {¹ H} NMR (CDCl₃, 23     , 100MHz) δ 181.7, 160 . 5,158.3, 141.1, 140 . 5,133.1, 130.2, 128 . 6,128.2, 120.1, 106.0, 99.1, 43.7, 41.9, 23.7. C₁₇ H₁₆ N₂ O₂ of theoretical value HRMS ([M⁺]): 280.1212; measured value: 280.1220.

Bicyclic pyridone derivatives (1n), yellow solid, melting point the 105-107 [...].¹ H   NMR (CDCl₃, 400MHz, 23 °C) δ 8.84 (s, 1H, NH), 7.62 (d, J=9.6Hz, 1H), 5.84 (d, J=9.6 Hz, 1H), 4.26 (m, 2H), 4.05 (t, 2H), 3.78 (t, 2H), 1.41 (t, 3H);¹³ C {¹ H} NMR (CDCl₃, 23     , 100MHz) δ 172.5, 161 . 5,159.3, 140.5, 126.1, 92.6, 58.3, 43.7, 41.9, 18.7. C₁₀ H₁₂ N₂ O₃ of theoretical value HRMS ([M⁺]): 208.0848; measured value: 208.0840.

Bicyclic pyridone derivatives (1o), yellow solid, melting point the 136-138 [...].¹ HNMR (CDCl₃, 400MHz, 23 °C) δ 9.21 (s, 1H, CONH), 8.80 (s, 1H, NH), 7.88 (d, J=9.6Hz, 1H), 7.64 (m, 2H), 7.49 (m, 3H), 5.92 (d, J=9.6Hz, 1H), 4.20 (t, 2H), 3.87 (t. 2H);¹³ C {¹ H} NMR (CDCl₃, 23     , 100MHz) δ 188.2, 161 . 5,156.2, 143.1, 139 . 3,132.6, 131.1, 123 . 4,105.8, 97.1, 43.2, 42.8. C₁₄ H₁₃ N₃ O₂ of theoretical value HRMS ([M⁺]): 255.1008; measured value: 255.1012.