CN110015996B - Method for synthesizing 2' -spiro-substituted ternary carbocyclic nucleoside - Google Patents

Abstract

The invention discloses a method for synthesizing a 2'-spirocyclic group-substituted three-membered carbocyclic nucleoside, and belongs to the technical field of organic chemistry. Using α-pyrimidine-substituted acrylate and α-chlorocycloalkanone as raw materials, a series of new spiro nucleosides were synthesized through cyclopropane cyclization initiated by Mike's reaction. The method of the invention adopts simple and easy-to-obtain raw materials, and avoids the disadvantages of numerous steps, low yield and poor universality in the previous method in the synthesis process. The yield of spirocyclic pyrimidine nucleosides synthesized by this method is as high as 84%, and the product structure is rich.

Description

A kind of method for synthesizing 2'-spirocyclyl-substituted three-membered carbocyclic nucleosides

technical field

The invention relates to a method for synthesizing spirocyclic nucleosides, in particular to a method for synthesizing 2'-spirocyclic group-substituted three-membered carbocyclic nucleosides by cyclopropane cyclization, and belongs to the technical field of organic chemistry.

Background technique

Most of the spiro nucleosides are conformationally restricted nucleosides, and their molecular conformation is relatively simple. Before the substrate is combined with the enzyme, the conformation of the active center of the enzyme will first change according to the conformation of the substrate, and then it will fit with the substrate to form an active complex. Conformation-restricted nucleosides have certain advantages over non-conformation-restricted nucleoside drugs. At present, the publicly reported methods for synthesizing spirocyclic nucleosides are cumbersome and poorly universal, mainly introducing a spiro ring at the 4' position of the sugar ring. A typical representative synthetic route is as follows:

1, the synthesis of spirocyclic pyrimidine nucleosides G and F, the reaction equation is as follows:

The method has long synthesis steps, expensive metal palladium catalysis is required for the condensation of C-N bonds, and the obtained product is a mixture of isomers of two configurations, which is difficult to separate.

2, the synthesis of spirocyclic pyrimidine nucleoside D, the reaction equation is as follows:

This method has long synthesis steps and poor substrate universality. First, o-bromoaniline is used for condensation, and finally, the n-Bu ₃ SnH method is used for free radical debromination, which increases unnecessary reactions.

Given that spiro nucleosides are an important part of conformationally restricted nucleosides, it is still necessary to find a simple and efficient method for the synthesis of spiro nucleosides.

SUMMARY OF THE INVENTION

In order to overcome the above-mentioned defects, the present invention provides a method for synthesizing 2'-spirocyclyl-substituted three-membered carbocyclic nucleosides. Using α-pyrimidine substituted acrylate and α-chlorocycloalkanone as raw materials, a series of new spirocyclic nucleoside compounds were synthesized by Mike reaction initiating cyclopropane cyclization under the action of inorganic base. This method provides a simple, cheap and efficient way for the synthesis of spirocyclic nucleoside compounds.

A method for synthesizing 2'-spirocyclyl-substituted three-membered carbocyclic nucleosides, comprising the following operations: using α-pyrimidine-substituted acrylate 1 and α-chlorocycloalkanone 2 as raw materials, and under the action of a base Under the following conditions, the spirocyclic pyrimidine nucleoside 3 is obtained by the reaction in an organic solvent. The reaction equation is as follows:

Wherein, R ¹ is selected from hydrogen, C1-C6 alkyl, alkoxy; R ² is selected from C1-C4 alkyl, benzyl, phenyl; R ³ is selected from benzoyl and tert-butoxycarbonyl; specifically , R ¹ is selected from methyl, ethyl, hydrogen, halogen, methoxy or trifluoromethyl; R ² is selected from methyl, ethyl, tert-butyl, phenyl or benzyl.

Further, in the above technical scheme, the molar ratio of the α-pyrimidine substituted acrylate 1, α-chlorocycloalkanone 2 and the base is 1:1.2-1.5:1.2-2.0, and the preferred molar ratio is 1:1.5: 1.5.

Further, in the above technical solution, the solvent is selected from acetonitrile, methanol, dichloromethane, tetrahydrofuran, toluene or dioxane.

Further, in the above technical scheme, the base is selected from: sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, DBU, sodium tert-butoxide or potassium tert-butoxide. Potassium carbonate, DBU, cesium carbonate or potassium tert-butoxide are preferred.

Further, in the above technical solution, the reaction temperature is selected from -30°C to 50°C.

Further, in the above technical solution, the entire reaction process does not require protection of inert gas.

Further, in the above technical scheme, the spirocyclic pyrimidine product 3 is further derivatized to obtain different types of derivative products 4 or 5. The reaction equation is as follows:

Wherein, the reducing agent is selected from sodium borohydride or lithium aluminum tetrahydrogen; the deprotection reaction is selected from ammonia/methanol or trifluoroacetic acid. Specifically, the reduction reaction solvent is selected from a mixed solvent of dichloromethane and methanol, and the volume ratio is preferably dichloromethane:methanol=2:1. Ammonia/methanol solution was used to remove R ³ for benzoyl protection, and trifluoroacetic acid was used to remove R ³ for tert-butoxycarbonyl protection.

Invention Beneficial Effects:

This method provides a simple, cheap and efficient way for the synthesis of spirocyclic nucleoside compounds. The raw materials used are simple and easy to obtain, and in the synthesis process, the disadvantages of many steps, low yield and poor universality in the previous method are avoided. The yield of spirocyclic pyrimidine nucleosides synthesized by this method is as high as 84%, and the product structure is rich.

Detailed ways

Example 1

^a Unless otherwise specified, the reaction steps are as follows: 1a (0.1 mmol), 2a (1.5 equiv), and base (1.5 equiv) were reacted in air for 5 hours. ^b Isolated yield ^c Potassium tert-butoxide (1.2 equiv) ^d Potassium tert-butoxide (2.0 equiv) ^e 1h ^f 0.5h.

During the screening of reaction conditions, the effect of bases on the reaction was first investigated (entries 1-6). Secondly, the solvent and temperature were investigated. By comparing the yields, it was finally determined that potassium tert-butoxide was the optimal base, acetonitrile was the optimal solvent, and -20°C was the optimal temperature.

Typical reaction conditions for operation:

In a reaction flask, α-pyrimidine substituted methyl acrylate 1a (0.1 mmol) and 1.5 eq (0.15 mmol) potassium tert-butoxide were dissolved in 1 mL of acetonitrile, and placed at -20 °C for 10 minutes with stirring and cooling, and then α-chloro Substituted cycloalkanone 2a (0.15mmol) was added to the reaction solution for reaction, and the reaction time was 0.5h. The reaction was completed as monitored by TLC, quenched by adding water, and extracted with ethyl acetate. The combined organic phases were dried, filtered and concentrated in vacuo to give a crude oil. Then the target compound 3aa was obtained by column chromatography with a yield of 83%.

3aa: White solid, m.p. 227.2-232.5℃; 33mg, 83% yield;

¹ H NMR (400 MHz, CDCl ₃ ): 7.90-7.88 (d, J=8.0 Hz, 2H), 7.62 (d, J=7.6 Hz, 1H), 7.48 (t, J=8.0 Hz, 2H), 7.06 ( d, J＝3.2Hz, 1H), 3.77(s, 3H), 2.44(m, 1H), 2.36-2.27(m, 1H), 2.27-2.17(m, 2H), 2.08(m, 2H), 2.01 -1.95(m, 4H), 1.89(s, 1H). ¹³ C NMR (100MHz, CDCl ₃ ): 212.1, 167.7, 139.4, 135.0, 131.5, 130.7, 129.1, 111.5, 77.3, 53.6, 50.4, 42.6, 38.9 ,28.5,26.2,20.2,12.7.HRMS(ESI-TOF):exact mass calcd for C ₂₁ H ₂₀ N ₂ NaO ₆ (M+Na) ⁺ requires m/z 419.1214,found m/z 419.1206.

Example 2

In a 10 mL vacuum tube, α-(3-benzoyl-5-methyl)uracil-substituted ethyl acrylate 1b and 1.5 eq (0.15 mmol) potassium tert-butoxide were dissolved in 1 mL of acetonitrile, and stirred at -20 °C After cooling for 10 minutes, α-chlorocycloalkanone 2a (0.15 mmol) was added to the reaction solution for reaction for 0.5 h. The reaction was completed as monitored by TLC, quenched by adding water, and extracted with ethyl acetate. The combined organic phases were dried, filtered and concentrated in vacuo to give a crude oil. Then the target compound 3ba was obtained by column chromatography with a yield of 85%.

Example 3

In a 10 mL vacuum tube, dissolve α-(3-benzoyl-5-methyl)uracil-substituted tert-butyl acrylate 1c and 1.5 eq (0.15 mmol) potassium tert-butoxide in 1 mL of acetonitrile and place at -20°C After stirring and cooling for 10 minutes, α-chlorocycloalkanone 2a (0.15 mmol) was added to the reaction solution for reaction for 0.5 h. The reaction was monitored by TLC for completion, quenched with water, and extracted with ethyl acetate. The combined organic phases were dried, filtered and concentrated in vacuo to give a crude oil. Then the target compound 3ca was obtained by column chromatography with a yield of 83%.

Example 4

In a 10 mL vacuum tube, dissolve α-(3-benzoyl-5-methyl)uracil-substituted benzyl acrylate 1d and 1.5 eq (0.15 mmol) potassium tert-butoxide in 1 mL of acetonitrile and place at -20°C After stirring and cooling for 10 minutes, α-chlorocycloalkanone 2a (0.15 mmol) was added to the reaction solution for reaction, and the reaction time was 0.5 h. The reaction was completed as monitored by TLC, quenched by adding water, and extracted with ethyl acetate. The combined organic phases were dried, filtered and concentrated in vacuo to give a crude oil. Then the target compound 3da was obtained by column chromatography with a yield of 83%.

Example 5

In a 10 mL vacuum tube, dissolve α-(3-tert-butoxycarbonyl-5-methyl)uracil substituted methyl acrylate 1f and 1.5 eq (0.15 mmol) potassium tert-butoxide in 1 mL of acetonitrile and place at -20°C After stirring and cooling for 10 minutes, α-chlorocycloalkanone 2a (0.15 mmol) was added to the reaction solution for reaction for 0.5 h. The reaction was completed as monitored by TLC, quenched by adding water, and extracted with ethyl acetate. The combined organic phases were dried, filtered and concentrated in vacuo to give a crude oil. Then the target compound 3fa was obtained by column chromatography with a yield of 79%.

3fa: White solid, m.p.180.0-185.4℃; 31mg, 79% yield;

¹ H NMR (600 MHz, CDCl ₃ ): 6.94-6.92 (m, 1H), 3.74 (s, 3H), 2.65-2.44 (m, 2H), 2.33-2.18 (m, 3H), 2.03 (d, J= 4.8Hz, 1H), 1.93-1.92(m, 3H), 1.89(d, J=5.4Hz, 1H), 1.68(s, 1H), 1.56(s, 9H). ¹³ C NMR (100MHz, CDCl ₃ ) :211.2,167.8,147.7,139.0,111.1,86.5,53.6,50.6,42.4,38.8,28.6,27.5,26.3,20.2,12.7.HRMS(ESI-TOF):exact mass calcd forC ₁₉ H ₂₄ N ₂ NaO ₇ ( M+Na) ⁺ requires m/z 415.1476, found m/z 415.1471.

Example 6

In a 10 mL vacuum tube, dissolve α-(3-benzoyl-5-ethyl)uracil substituted methyl acrylate 1i and 1.5 eq (0.15 mmol) of potassium tert-butoxide in 1 mL of acetonitrile and place at -20°C After stirring and cooling for 10 minutes, α-chlorocycloalkanone 2a (0.15 mmol) was added to the reaction solution for reaction for 0.5 h. The reaction was completed as monitored by TLC, quenched by adding water, and extracted with ethyl acetate. The combined organic phases were dried, filtered and concentrated in vacuo to give a crude oil. Then the target compound 3ia was obtained by column chromatography with a yield of 81%.

3ia Colorless oil, 33mg, 81% yield;

¹ H NMR (400 MHz, CDCl ₃ ): 7.88 (d, J=7.6 Hz, 2H), 7.61 (d, J=7.2 Hz, 1H), 7.47 (d, J=7.6 Hz, 2H), 6.98 (s, 1H), 3.77(s, 3H), 2.47-2.37(m, 3H), 2.35-2.18(m, 3H), 2.14-2.08(m, 2H), 1.96(d, J=5.2Hz, 1H), 1.90 -1.85 (m, 1H), 1.17 (t, J=7.2Hz, 3H). ¹³ C NMR (100 MHz, CDCl ₃ ): 212.1, 168.6, 167.7, 138.5, 135.0, 131.5, 130.6, 129.1, 117.1, 53.6, 50.5,42.6,38.9,28.5,26.2,20.3,20.1,12.5.HRMS(ESI-TOF):exact mass calcd for C ₂₂ H ₂₂ N ₂ NaO ₆ (M+Na) ⁺ requires m/z 433.1370,found m/ z 433.1365.

Example 7

In a 10 mL vacuum tube, α-(3-benzoyl-5-fluoro)uracil substituted methyl acrylate 1j and 1.5 eq (0.15 mmol) potassium tert-butoxide were dissolved in 1 mL of acetonitrile, and placed at -20°C for stirring and cooling After 10 minutes, α-chlorocycloalkanone 2a (0.15 mmol) was added to the reaction solution for reaction for 0.5 h. The reaction was completed as monitored by TLC, quenched by adding water, and extracted with ethyl acetate. The combined organic phases were dried, filtered and concentrated in vacuo to give a crude oil. Then the target compound 3ja was obtained by column chromatography with a yield of 68%.

Example 8

In a 10 mL vacuum tube, α-(3-benzoyl-5-methyl)uracil substituted methyl acrylate 1a and 1.5 eq (0.15 mmol) potassium tert-butoxide were dissolved in 1 mL of acetonitrile, and stirred at -20 °C After cooling for 10 minutes, α-chlorocyclohexanone 2b (0.15 mmol) was added to the reaction solution for reaction, and the reaction time was 12 h. The reaction was completed as monitored by TLC, quenched by adding water, and extracted with ethyl acetate. The combined organic phases were dried, filtered and concentrated in vacuo to give a crude oil. Then the target compound 3ab was obtained by column chromatography with a yield of 66%.

Example 9

In a 10 mL vacuum tube, α-(3-benzoyl-5-methyl)uracil substituted methyl acrylate 1a and 1.5 eq (0.15 mmol) potassium tert-butoxide were dissolved in 1 mL of acetonitrile, and stirred at -20 °C After cooling for 10 minutes, 0.15 mmol of α-chlorocycloheptanone 2c was added to the reaction solution for reaction, and the reaction time was 0.5 h. The reaction was complete by TLC and the reaction mixture was partitioned between ethyl acetate and water. The combined organic phases were dried, filtered and concentrated in vacuo to give a crude oil. Then the target compound 3ac was obtained by column chromatography with a yield of 72%.

3ac: White solid, m.p. 213.0-218.4℃; 31mg, 72% yield;

¹ H NMR (400 MHz, CDCl ₃ ): 7.87 (d, J=8.0 Hz, 2H), 7.62 (t, J=7.2 Hz, 1H), 7.48 (t, J=8.0 Hz, 2H), 7.04 (s, 1H), 3.76(s, 3H), 2.82(t, J＝12.0Hz, 1H), 2.34-2.29(m, 1H), 2.21-2.15(m, 3H), 2.00-1.73(m, 8H), 1.38 -1.25(m, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ): 207.6, 168.4, 167.6, 150.5, 139.7, 135.0, 131.5, 130.6, 129.1, 111.4, 53.7, 51.3, 46.1, 44.0, 30.6, 27.5, 27.1,26.4,25.6,12.6.HRMS(ESI-TOF):exact mass calcd for C ₂₃ H ₂₄ N ₂ NaO ₆ (M+Na) ⁺ requires m/z 447.1527,found m/z 447.1532.

Example 10

According to the reaction conditions and operations of implementing 2-9, only the reaction substrate was changed, and the reaction results were as follows:

Example 11

In a 10 mL vacuum tube, the cyclopropanation product 3aa (39.6 mg, 0.1 mmol) was added, and 1.5 mL of a mixed solvent of dichloromethane and methanol with a volume ratio of 2:1 was added, and the reaction solution was stirred and cooled in a low temperature reaction bath of -20 °C After 10 minutes, sodium borohydride (11.3 mg, 0.3 mmol) was weighed and slowly added to the reaction solution in batches, and the reaction solution was reacted at -20° C. for 30 minutes. TLC detected that the reaction was complete, 0.5 mL of saturated ammonium chloride solution was added to the reaction solution to quench the reaction, and then dichloromethane and water were added for extraction, and the product was separated and purified by column chromatography to finally obtain the ketone carbonyl reduction product 4aa ( 24 mg, 0.06 mmol).

4aa: White solid, m.p.175.5-180.1℃; 24mg, 60% yield;

¹ H NMR (400 MHz, CDCl ₃ ): 7.97-7.95 (m, 2H), 7.66-7.63 (m, 1H), 7.50 (t, J=8.0 Hz, 2H), 7.13 (s, 1H), 3.74 (s ,3H),3.54(d,J＝3.2Hz,1H),2.30(s,1H),2.13-2.02(m,1H),1.99-1.94(m,3H),1.90-1.70(m,6H), 1.34 (d, J=5.2 Hz, 1H). ¹³ C NMR (150 MHz, CDCl ₃ ): 169.2, 167.8, 153.5, 139.8, 135.3, 131.2, 130.5, 129.3, 112.8, 77.4, 53.3, 49.8, 47.0, 32.9, 27.9,26.6,20.9,12.6.HRMS(ESI-TOF):exact mass calcd for C ₂₁ H ₂₂ N ₂ NaO ₆ (M+Na) ⁺ requires m/z 421.1370,found m/z 421.1366.

Example 12

In a 10mL vacuum tube, accurately weigh 4aa (39.8mg, 0.1mmol) into the reaction tube, then plug it with a rubber stopper and seal it with parafilm, and perform nitrogen exchange to ensure that the reaction can be carried out in a nitrogen atmosphere. Use a syringe to absorb ammonia 1 mL of methanol solution (concentration of 1 mol/L) was added to the reaction tube, and the reaction solution was reacted at room temperature for 3 hours. TLC detected that the reaction was complete. The reaction solution was evaporated under reduced pressure and then passed through column chromatography. The product was isolated and purified to finally obtain product 5aa (24 mg, 0.08 mmol).

Representative compound characterization data are as follows:

5aa: White solid, m.p.233.0-238.4℃; 26mg, 87% yield;

¹ H NMR (400MHz, CDCl ₃ ): 9.36(s,1H), 7.00(s,1H), 4.23(s,1H), 3.71(s,3H), 3.52(d, J=3.2Hz,1H), 2.38(s, 1H), 2.11(s, 1H), 1.95-1.72(m, 8H), 1.69(d, J=5.3Hz, 1H), 1.27(d, J=5.2Hz, 1H). ¹³ CNMR( 150MHz, CDCl ₃ ): 169.4, 163.4, 154.3, 140.1, 112.7, 77.2, 53.3, 49.3, 47.0, 32.8, 27.9, 26.9, 20.9, 12.5.HRMS(ESI-TOF): exact mass calcd forC ₁₄ H ₁₈ N ₂ NaO ₅ (M+Na) ⁺ requires m/z 317.1108, found m/z 317.1107.

The above embodiments describe the basic principles, main features and advantages of the present invention. It should be understood by those skilled in the art that the present invention is not limited by the above-mentioned embodiments. The descriptions of the above-mentioned embodiments and the description only describe the principles of the present invention. Without departing from the scope of the principles of the present invention, there are various Variations and improvements all fall within the scope of the present invention.

Claims (5)

1. A method for synthesizing 2' -spiro substituted three-membered carbocyclic nucleoside 3 has the following reaction equation:

wherein R is¹Selected from hydrogen, C1-C6 alkyl, alkoxy; r²Selected from C1-C4 alkyl, benzyl, phenyl; r³Selected from benzoyl and tert-butoxycarbonyl;

the method is characterized by comprising the following steps of taking α -pyrimidine substituted acrylate 1 and α -chlorocycloalkanone 2 as raw materials, and reacting in acetonitrile or methanol under the action of potassium tert-butoxide to obtain the spiro pyrimidine nucleoside 3, wherein the reaction temperature is selected from-30 ℃ to-10 ℃.

2. The method of synthesizing a 2' -spirocyclic substituted tri-carbocyclic nucleoside 3 according to claim 1, wherein: r¹Selected from methyl, ethyl, hydrogen or methoxy; r²Selected from methyl, ethyl, tert-butyl, phenyl or benzyl.

3. The method according to claim 1, wherein the molar ratio of α -pyrimidine-substituted acrylate 1, α -chlorocycloalkanone 2 to base is 1:1.5: 1.5.

4. A method for synthesizing a 2' -spirocyclic group substituted ternary carbocyclic nucleoside 5, characterized in that: preparing a 2 '-spirocyclic-substituted-ternary carbocyclic nucleoside 3 according to the method of claim 1, followed by adding a reducing agent to the 2' -spirocyclic-substituted-ternary carbocyclic nucleoside 3 to react to obtain a compound 4, followed by deprotection to obtain a compound 5; the reaction equation is as follows:

wherein R is¹Selected from hydrogen, C1-C6 alkyl, alkoxy; r²Selected from C1-C4 alkyl, benzyl, phenyl; r³Selected from benzoyl and tert-butyloxycarbonyl.

5. The method of synthesizing a 2' -spirocyclic substituted tri-carbocyclic nucleoside 5 according to claim 4, wherein: the reducing agent is selected from sodium borohydride or lithium aluminum hydride; liquid ammonia/methanol or trifluoroacetic acid is selected for deprotection reaction.