Method for achieving methoxymethylation under photocatalytic conditions

Abstract

The present invention discloses a method for achieving methoxymethylation under photocatalytic conditions, comprising: mixing a raw material (I), an alkaline substance, a photocatalyst, and methanol, reacting the mixture in an air atmosphere at 20 to 45° C. under visible light irradiation for 12 to 48 hours, and then post-treating the reaction solution to obtain a methoxymethylation product (II). The method of the present invention avoids the use of a transition metal catalyst and the addition of an additional strong oxidant, has mild reaction conditions, is simple to operate, uses cheap and readily available reaction raw materials, is clean and pollution-free, and has a fast reaction rate, thereby having significant green and sustainable characteristics.

Description

Technical Field

[0001] The invention relates to a method for realizing methoxymethylation under photocatalytic conditions. Background Art

[0002] Methoxymethylation is common in organic synthesis. Methanol is a common organic solvent and a frequently used C1 source in organic synthesis (Angew. Chem. Int. Ed., 2017, 56, 6384-6394). The methoxymethyl group is an important structural unit in drug molecules and natural products. Methoxymethyl moieties are present in many best-selling pharmaceutical compounds and can effectively modulate the physical and biological properties of compounds. Cefpodoxime proxetil, a third-generation oral cephalosporin, has become one of the most popular new cephalosporin drugs due to its broad antimicrobial spectrum, strong antimicrobial activity, and low toxicity (Coal & Chemical Industry, 2019, 42, 126-131). The key intermediate in the synthesis of cefpodoxime proxetil is 7-amino-3-methoxymethyl-cephalosporanic acid.

[0003]

[0004] Traditional methoxymethylation reactions are primarily carried out using various transition metal catalysts (Angew. Chem. Int. Ed. 2014, 53, 761-765). These catalysts pose serious environmental risks and often require the addition of oxidants and high temperatures (Org. Lett., 2020, 22, 5390-5395). Furthermore, traditional methoxymethylation reactions take a long time. Summary of the Invention

[0005] In view of the shortcomings of the prior art, the present invention provides a method for achieving methoxymethylation under photocatalytic conditions.

[0006] The technical solutions of the present invention are as follows:

[0007] A method for achieving methoxymethylation under photocatalytic conditions, comprising:

[0008] The raw material (I), alkaline substance, photocatalyst and methanol are mixed and reacted in an air atmosphere at 20-45°C (preferably 40°C) under visible light irradiation for 12-48 hours (preferably 24 hours), and the reaction solution is then post-treated to obtain a methoxymethylation product (II);

[0009] Preferably, the molar ratio of raw material (I), alkaline substance and photocatalyst is 1:2:0.05;

[0010] Preferably, the volume molar ratio of methanol to raw material (I) is 10 to 20:1, mL / mmol;

[0011] The alkaline substance is selected from at least one of Na2CO3, K2CO3, K3PO4, NaHCO3, KHCO3, t-BuONa, t-BuOK, and CsCO3, preferably K2CO3; under the same conditions as in Example 1, replacing K2CO3 with K3PO4, the yield is 47%, the yield of t-BuONa is 48%, the yield of t-BuOK is 42%, and the yield of CsCO3 is 50%. Na2CO3, NaHCO3, and KHCO3 do not react;

[0012] The photocatalyst is selected from one of the following:

[0013]

[0014] The preferred photocatalyst is PC6. Under the same conditions as in Example 1, the yield of PC1 instead of PC6 is 32%, the yield of PC2 is 30%, the yield of PC3 is 19%, the yield of PC4 is 28%, the yield of PC5 is 20%, the yield of PC7 is 28%, and PC8, PC9, and PC10 do not react.

[0015] The light source of visible light can be blue LED, preferably 15W blue LED;

[0016] The specific post-treatment method is as follows: after the reaction is completed, the reaction solution is concentrated under reduced pressure, loaded onto a silica column for chromatography, and the elution reagent is petroleum ether. The eluate containing the target compound is collected and concentrated to dryness under reduced pressure to obtain product (II);

[0017] The reaction formula is as follows:

[0018]

[0019] In formula (I) or (II),

[0020] R is H, C1-C5 alkyl, C1-C5 alkoxy or halogen.

[0021] The beneficial effects of the present invention are:

[0022] The method described in the present invention avoids the use of transition metal catalysts and the additional addition of strong oxidants, has mild reaction conditions, simple operation, cheap and easily available reaction raw materials, is clean and pollution-free, and has a fast reaction rate, and has significant green and sustainable characteristics. DETAILED DESCRIPTION

[0023] The present invention is further described below by means of specific examples, but the protection scope of the present invention is not limited thereto.

[0024] Example 1: Synthesis of 3-methoxy-2-methyl-1-phenylpropan-1-one

[0025] The reaction formula is as follows:

[0026]

[0027] 26.8 mg (0.2 mmol) of phenylpropiophenone, 55.2 mg (0.4 mmol) of potassium carbonate, and 11 mg (0.01 mmol) of copper-based photosensitizer PC6 were added to a glass tube, and 3 ml of methanol was added. The mixture was reacted at 40°C under 15 W LED blue light for 24 h. After the reaction was completed, the mixture was monitored by TLC (developing solvent: petroleum ether: ethyl acetate = 20:1, volume ratio), and the mixture was concentrated in vacuo to 2 ml. The mixture was applied to a silica column for chromatography. The elution reagent was petroleum ether, the elution rate was 2 ml / min, and the elution volume was 100 ml (5 column volumes). 75 ml of the eluate with an Rf value of 0.8 was collected and concentrated to dryness under reduced pressure to obtain 25 mg of the product as a colorless oily liquid with a yield of 70%.

[0028] 1 H NMR(400MHz, CDCl3)δ8.02-7.94(m,2H),7.59-7.53(m,1H),7.51-7.43(m,2H), 3.83-3.72(m,2H),3.47(qd,J=5.3,1.7Hz,1H),3.32(s,3H),1.22-1.18(m,3H). 13 C NMR (101MHz, CDCl3) δ202.77,136.64,133.04,128.62,128.39,74.97,59.11,41.25,14.86.

[0029] Example 2: Synthesis of 3-methoxy-2-methyl-1-(p-tolyl)propan-1-one

[0030] The reaction formula is as follows:

[0031]

[0032] The raw material 29.6 mg (0.2 mmol) 1-(p-tolyl)propan-1-one, 55.2 mg (0.4 mmol) potassium carbonate, 11 mg (0.01 mmol) copper-based photosensitizer PC6 were added to a glass tube, and then 3 ml of methanol was added. The reaction was carried out at 40 ° C. under 15 W LED blue light irradiation for 24 h. After the reaction was completed, it was monitored by TLC (developing solvent: petroleum ether: ethyl acetate = 20:1, volume ratio). The mixture was concentrated in vacuo to 2 ml and applied to a silica column for chromatography. The elution reagent was petroleum ether, the elution rate was 2 ml / min, and the elution volume was 100 ml (5 column volumes). 75 ml of the eluate with an Rf value of 0.8 was collected and concentrated to dryness under reduced pressure to obtain 31.1 mg of the product as a colorless oily liquid with a yield of 81%.

[0033] 1 H NMR (400MHz, CDCl3) δ7.92-7.82(m,2H),7.29-7.24(m,2H),3.80-3.71(m,2H),3.48-3.41(m,1H),3.32(s,3H),2.41(s,3H),1.22-1.16(m,3H). 13 C NMR (101MHz, CDCl3) δ202.33,143.84,134.11,129.31,128.52,75.03,59.08,41.08,21.62,14.93.

[0034] Example 3: Synthesis of 1-(4-bromophenyl)-3-methoxy-2-methylpropan-1-one

[0035] The reaction formula is as follows:

[0036]

[0037] The raw material 42.2 mg (0.2 mmol) 1-(4-bromophenyl)propan-1-one, 55.2 mg (0.4 mmol) potassium carbonate, 11 mg (0.01 mmol) copper-based photosensitizer PC6 were added to a glass tube, and then 3 ml of methanol was added. The reaction was carried out at 40 ° C. under 15 W LED blue light irradiation for 24 h. After the reaction was completed, it was monitored by TLC (developing solvent: petroleum ether: ethyl acetate = 20:1, volume ratio). The mixture was concentrated in vacuo to 2 ml and applied to a silica column for chromatography. The elution reagent was petroleum ether, the elution rate was 2 ml / min, and the elution volume was 100 ml (5 column volumes). 75 ml of the eluate with an Rf value of 0.8 was collected and concentrated to dryness under reduced pressure to obtain 27.1 mg of the product as a colorless oily liquid with a yield of 53%.

[0038] 1 H NMR (400MHz, CDCl3) δ7.87-7.81(m,2H),7.63-7.58(m,2H),3.75-3.69(m,2H),3.49-3.42(m,1H),3.31(s,3H),1.20-1.16(m,3H). 13 C NMR (101MHz, CDCl3) δ201.85,135.45,131.91,129.95,74.95,59.12,41.27,14.69.

[0039] Example 4: Synthesis of 1-(4-chlorophenyl)-3-methoxy-2-methylpropan-1-one

[0040] The reaction formula is as follows:

[0041]

[0042] 33.6 mg (0.2 mmol) of 1-(4-chlorophenyl)propan-1-one, 55.2 mg (0.4 mmol) of potassium carbonate, and 11 mg (0.01 mmol) of copper-based photosensitizer PC6 were added to a glass tube, and 3 ml of methanol was added. The mixture was reacted at 40°C under 15 W LED blue light for 24 h. After completion of the reaction, the mixture was monitored by TLC (developing solvent: petroleum ether: ethyl acetate = 20:1, volume ratio), and the mixture was concentrated in vacuo to 2 ml. The mixture was applied to a silica column for chromatography, with petroleum ether as the eluting reagent, an elution rate of 2 ml / min, and an elution volume of 100 ml (5 column volumes). 75 ml of the eluate with an Rf value of 0.8 was collected and concentrated to dryness under reduced pressure to obtain 25.4 mg of the product as a colorless oily liquid with a yield of 59%.

[0043] 1 H NMR (400MHz, CDCl3) δ7.86-7.81(m,2H),7.63-7.59(m,2H),3.75-3.69(m,2H),3.48-3.43(m,1H),3.31(s,3H),1.20-1.17(m,3H). 13 C NMR (101MHz, CDCl3) δ201.84,135.45,131.91,129.95,128.20,74.95,59.12,41.27,14.69.

[0044] Example 5: Synthesis of 1-(4-ethylphenyl)-3-methoxy-2-methylpropan-1-one

[0045] The reaction formula is as follows:

[0046]

[0047] 32.4 mg (0.2 mmol) of 1-(4-ethylphenyl)propan-1-one, 55.2 mg (0.4 mmol) of potassium carbonate, and 11 mg (0.01 mmol) of copper-based photosensitizer PC6 were added to a glass tube, and 3 ml of methanol was added. The mixture was reacted at 40°C under 15 W LED blue light for 24 h. After completion of the reaction, the mixture was monitored by TLC (developing solvent: petroleum ether: ethyl acetate = 20:1, volume ratio), and vacuum concentrated to 2 ml. The mixture was applied to a silica column for chromatography. The elution reagent was petroleum ether, the elution rate was 2 ml / min, and the elution volume was 100 ml (5 column volumes). 75 ml of the eluate with an Rf value of 0.8 was collected and concentrated to dryness under reduced pressure to obtain 29.2 mg of the product as a colorless oily liquid with a yield of 71%.

[0048] 1 H NMR (400MHz, CDCl3) δ7.97-7.87(m,2H),7.32-7.27(m,2H),3.80-3.72(m,2H),3.48-3. 41(m,1H),3.32(s,3H),2.71(q,J=7.6Hz,2H),1.26(t,J=7.6Hz,3H),1.22-1.18(m,3H). 13 C NMR (101MHz, CDCl3) δ202.35,150.00,134.32,128.63,128.13,75.04,59.09,41.10,28.93,15.19,14.94.

[0049] Example 6: Synthesis of 1-(4-ethylphenyl)-3-methoxy-2-methylpropan-1-one

[0050] The reaction formula is as follows:

[0051]

[0052] 32.8 mg (0.2 mmol) of 1-(4-methoxyphenyl)propan-1-one, 55.2 mg (0.4 mmol) of potassium carbonate, and 11 mg (0.01 mmol) of copper-based photosensitizer PC6 were added to a glass tube, and 3 ml of methanol was added. The mixture was reacted at 40°C under 15 W LED blue light for 24 h. After completion of the reaction, the mixture was monitored by TLC (developing solvent: petroleum ether: ethyl acetate = 20:1, volume ratio), and the mixture was concentrated in vacuo to 2 ml. The mixture was applied to a silica column for chromatography, with petroleum ether as the eluting reagent, an elution rate of 2 ml / min, and an elution volume of 100 ml (5 column volumes). 75 ml of the eluate with an Rf value of 0.8 was collected and concentrated to dryness under reduced pressure to obtain 31.2 mg of the product as a colorless oily liquid with a yield of 75%.

[0053] 1H NMR (400MHz, CDCl3) δ8.15-7.73(m,2H),7.11-6.79(m,2H),3.87(s,3H),3.80-3.70(m,2H),3.47-3.41(m,1H),3.32(s,3H),1.22-1.17(m,3H). 13 C NMR (101MHz, CDCl3) δ201.20,163.50,130.68,129.63,113.77,75.11,59.07,55.46,40.81,15.00.

[0054] Example 7: Synthesis of 3-methoxy-1-(3-methoxyphenyl)-2-methylpropan-1-one

[0055] The reaction formula is as follows:

[0056]

[0057] 32.8 mg (0.2 mmol) of 1-(3-methoxyphenyl)propan-1-one, 55.2 mg (0.4 mmol) of potassium carbonate, and 11 mg (0.01 mmol) of copper-based photosensitizer PC6 were added to a glass tube, and 3 ml of methanol was added. The mixture was reacted at 40°C under 15 W LED blue light for 24 h. After completion of the reaction, the mixture was monitored by TLC (developing solvent: petroleum ether: ethyl acetate = 20:1, volume ratio), and the mixture was concentrated in vacuo to 2 ml. The mixture was applied to a silica column for chromatography, with petroleum ether as the eluting reagent, an elution rate of 2 ml / min, and an elution volume of 100 ml (5 column volumes). 75 ml of the eluate with an Rf value of 0.8 was collected and concentrated to dryness under reduced pressure to obtain 25.3 mg of the product as a colorless oily liquid with a yield of 61%.

[0058] 1 H NMR (400MHz, CDCl3) δ7.61-7.49(m,2H),7.39(t,J=7.9Hz,1H),7.13(ddd,J=8.2,2.7,1.0H z,1H),3.87(s,3H),3.82-3.73(m,2H),3.50-3.43(m,1H),3.34(s,3H),1.25-1.18(m,3H). 13 C NMR (101MHz, CDCl3) δ202.55,159.87,138.03,129.57,120.96,119.58,112.61,74.98,59.10,55.42,41.40,14.91.

[0059] Example 8: Synthesis of 3-methoxy-2-methyl-1-(m-tolyl)propan-1-one

[0060] The reaction formula is as follows:

[0061]

[0062] The raw material 29.6 mg (0.2 mmol) 1-(m-tolyl)propan-1-one, 55.2 mg (0.4 mmol) potassium carbonate, 11 mg (0.01 mmol) copper-based photosensitizer PC6 were added to a glass tube, and then 3 ml of methanol was added. The reaction was carried out at 40 ° C. under 15 W LED blue light irradiation for 24 h. After the reaction was completed, it was monitored by TLC (developing solvent: petroleum ether: ethyl acetate = 20:1, volume ratio). The mixture was concentrated in vacuo to 2 ml and applied to a silica column for chromatography. The elution reagent was petroleum ether, the elution rate was 2 ml / min, and the elution volume was 100 ml (5 column volumes). 75 ml of the eluate with an Rf value of 0.8 was collected and concentrated to dryness under reduced pressure to obtain 31.1 mg of the product as a colorless oily liquid with a yield of 81%.

[0063] 1 H NMR (400MHz, CDCl3) δ7.84-7.75(m,2H),7.42-7.34(m,2H),3.84-3.74(m, 2H),3.52-3.43(m,1H),3.34(s,3H),2.46-2.41(m,3H),1.24-1.19(m,3H). 13 C NMR (101MHz, CDCl3) δ202.99,138.41,136.68,133.81,128.89,128.49,125.59,75.00,59.11,41.26,21.39,14.91.

[0064] Example 9: Synthesis of 1-(3-fluorophenyl)-3-methoxy-2-methylpropan-1-one

[0065] The reaction formula is as follows:

[0066]

[0067] The raw material 30.4 mg (0.2 mmol) 1-(3-fluorophenyl)propan-1-one, 55.2 mg (0.4 mmol) potassium carbonate, 11 mg (0.01 mmol) copper-based photosensitizer PC6 were added to a glass tube, and then 3 ml of methanol was added. The reaction was carried out at 40 ° C. under 15 W LED blue light irradiation for 24 h. After the reaction was completed, it was monitored by TLC (developing solvent: petroleum ether: ethyl acetate = 20:1, volume ratio). The mixture was concentrated in vacuo to 2 ml and applied to a silica column for chromatography. The elution reagent was petroleum ether, the elution rate was 2 ml / min, and the elution volume was 100 ml (5 column volumes). 75 ml of the eluate with an Rf value of 0.8 was collected and concentrated to dryness under reduced pressure to obtain 23.5 mg of the product as a colorless oily liquid with a yield of 60%.

[0068] 1H NMR (400MHz, CDCl3) δ7.79-7.61 (m, 2H), 7.45 (td, J = 8.0, 5.5Hz, 1H), 7.29-7.2 6(m,1H),3.76-3.67(m,2H),3.49-3.42(m,1H),3.32(s,3H),1.22-1.18(m,3H). 13 C NMR (101MHz, CDCl3) δ201.63,201.61,164.14,161.68,138.89,138.83,130.28,130 .21,124.11,124.08,120.13,119.92,115.28,115.05,74.89,59.13,41.52,14.70.

[0069] Example 10: Synthesis of 1-(4-fluorophenyl)-3-methoxy-2-methylpropan-1-one

[0070] The reaction formula is as follows:

[0071]

[0072] 30.4 mg (0.2 mmol) of 1-(4-fluorophenyl)propan-1-one, 55.2 mg (0.4 mmol) of potassium carbonate, and 11 mg (0.01 mmol) of copper-based photosensitizer PC6 were added to a glass tube, and 3 ml of methanol was added. The reaction was carried out at 40°C under 15 W LED blue light for 24 h. After the reaction was completed, the mixture was concentrated in vacuo to 2 ml and applied to a silica column for chromatography. The elution reagent was petroleum ether, the elution rate was 2 ml / min, and the elution volume was 100 ml (5 column volumes). 75 ml of the eluate with an Rf value of 0.8 was collected and concentrated to dryness under reduced pressure to obtain 25.4 mg of the product as a colorless oily liquid with a yield of 65%.

[0073] 1 H NMR (400MHz, CDCl3) δ8.06-7.93(m,2H),7.22-7.09(m,2H),3.78-3.68(m,2H),3.49-3.41(m,1H),3.32(s,3H),1.21-1.17(m,3H). 13 C NMR (101MHz, CDCl3) δ201.25,167.01,164.48,133.12,133.09,131.10,131.00,115.80,115.58,75.00,59.12,41.20,14.78.

Claims

1. A method for achieving methoxymethylation under photocatalytic conditions, characterized in that: The method comprises: The raw material (I), alkaline substance, photocatalyst and methanol are mixed and reacted in an air atmosphere at 20-45°C under visible light irradiation for 12-48 hours, and the reaction solution is then post-treated to obtain a methoxymethylation product (II); The alkaline substance is K2CO3; The visible light source uses blue LED; Photocatalyst is PC6: The reaction formula is as follows: In formula (I) or (II), R is H, C1-C5 alkyl, C1-C5 alkoxy or halogen.

2. The method for achieving methoxymethylation under photocatalytic conditions according to claim 1, wherein The molar ratio of the raw material (I), the alkaline substance and the photocatalyst is 1:2:0.

05.

3. The method for achieving methoxymethylation under photocatalytic conditions according to claim 1, characterized in that The volume molar ratio of methanol to the raw material (I) is 10-20:1, mL / mmol.

4. The method for achieving methoxymethylation under photocatalytic conditions according to claim 1, wherein The post-treatment method is as follows: after the reaction is completed, the reaction solution is concentrated under reduced pressure, loaded onto a silica column for chromatography, and the elution reagent is petroleum ether. The eluate containing the target compound is collected and concentrated to dryness under reduced pressure to obtain product (II).

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