Method for realizing methoxyl methylation under photocatalysis condition

Abstract

The invention discloses a method for realizing methoxyl methylation under a photocatalysis condition, which comprises the following steps: mixing a raw material (I), an alkaline substance, a photocatalyst and methanol, reacting for 12-48 hours under the conditions of air atmosphere, 20-45 DEG C and visible light irradiation, and post-treating the reaction liquid to obtain a methoxyl methylation product (II), according to the method disclosed by the invention, the use of a transition metal catalyst and the additional addition of a strong oxidant are avoided, the reaction condition is mild, the operation is simple, the reaction raw materials are cheap and easy to obtain, clean and pollution-free, the reaction rate is high, and obvious green and sustainable characteristics are realized; # imgabs0 #

Description

Technical Field

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

[0002] Methoxymethylation is very common in organic synthesis. Methanol is a common organic solvent and a commonly used C1 source in organic synthesis (Angew. Chem. Int. Ed., 2017, 56, 6384-6394.). Methoxymethyl is an important structural unit in drug molecules and natural products. Methoxymethyl fragments exist in many best-selling drug compounds and can effectively regulate the physical and biological properties of compounds. Cefpodoxime axetil, as a third-generation cephalosporin oral drug, has become one of the most popular new cephalosporin drugs because of its broad antibacterial spectrum, strong antibacterial activity and low toxicity (Coal and Chemical Industry, 2019, 42, 126-131). The key intermediate for the synthesis of cefpodoxime axetil is 7-amino-3-methoxymethyl-cephalosporanic acid.

[0003]

[0004] Traditional methoxymethylation reactions are mainly achieved through various transition metal catalysts (Angew. Chem. Int. Ed. 2014, 53, 761-765). Such catalysts cause serious environmental pollution, usually require the addition of oxidants and are accompanied by high temperatures (Org. Lett., 2020, 22, 5390-5395), and traditional methoxymethylation reactions take too long. Summary of the invention

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

[0006] The technical solution of the present invention is as follows:

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

[0008] The raw material (I), alkaline substance, photocatalyst and methanol are mixed, reacted in air atmosphere at 20 to 45° C. (preferably 40° C.) and under visible light irradiation for 12 to 48 hours (preferably 24 hours), and then the reaction solution is 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%, the yield of CsCO3 is 50%, and 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, replacing the photocatalyst PC6, the yield of using PC1 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 on a silica column for chromatography, 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 readily available reaction raw materials, is clean and pollution-free, 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 embodiments, 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 phenylacetone, 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 then 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, it was monitored by TLC (developing agent was petroleum ether: ethyl acetate = 20:1, volume ratio), and vacuum concentrated to 2 ml. The sample was loaded onto a silica column for chromatography. The eluting 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 for 24 h. After the reaction was completed, it was monitored by TLC (developing agent was petroleum ether: ethyl acetate = 20:1, volume ratio), and vacuum concentrated to 2 ml. The sample was loaded onto a silica column for chromatography. The eluting 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 for 24 h. After the reaction was completed, it was monitored by TLC (developing agent was petroleum ether: ethyl acetate = 20:1, volume ratio), and vacuum concentrated to 2 ml. The silica column was loaded for chromatography. The eluting 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 then 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 concentrated in vacuo to 2 ml and applied to a silica column for chromatography. The eluting agent 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 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] The raw material 32.4 mg (0.2 mmol) 1-(4-ethylphenyl) 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 and 15 W LED blue light for 24 h. After the reaction was completed, it was monitored by TLC (developing agent was petroleum ether: ethyl acetate = 20:1, volume ratio), and vacuum concentrated to 2 ml. The silica column was loaded for chromatography. The eluting 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] The raw material 32.8mg (0.2mmol) 1-(4-methoxyphenyl)propan-1-one, 55.2mg (0.4mmol) potassium carbonate, 11mg (0.01mmol) copper-based photosensitizer PC6 were added to a glass tube, and then 3ml of methanol was added. The reaction was carried out at 40°C and 15W LED blue light for 24h. After the reaction was completed, it was monitored by TLC (developing agent was petroleum ether: ethyl acetate = 20:1, volume ratio), and vacuum concentrated to 2ml. The silica column was loaded for chromatography, the eluting reagent was petroleum ether, the elution rate was 2ml / min, the elution volume was 100ml (5 column volumes), and 75ml of the eluate with an Rf value of 0.8 was collected and concentrated to dryness under reduced pressure to obtain 31.2mg 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 then 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 concentrated in vacuo to 2 ml and applied to a silica column for chromatography. The eluting agent 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 25.3 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 for 24 h. After the reaction was completed, it was monitored by TLC (developing agent was petroleum ether: ethyl acetate = 20:1, volume ratio), and vacuum concentrated to 2 ml. The sample was loaded onto a silica column for chromatography. The eluting 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 for 24 h. After the reaction was completed, it was monitored by TLC (developing agent was petroleum ether: ethyl acetate = 20:1, volume ratio), and vacuum concentrated to 2 ml. The silica column was loaded for chromatography. The eluting 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] The raw material 30.4 mg (0.2 mmol) 1-(4-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 for 24 h. After the reaction was completed, it was monitored by TLC (developing agent was petroleum ether: ethyl acetate = 20:1, volume ratio), and vacuum concentrated to 2 ml. The silica column was loaded for chromatography. The eluting 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 for 12 to 48 hours in an air atmosphere at 20 to 45° C. and under visible light irradiation, and then the reaction solution is post-treated to obtain a methoxymethylation product (II); The alkaline substance is selected from at least one of Na2CO3, K2CO3, K3PO4, NaHCO3, KHCO3, t-BuONa, t-BuOK, and CsCO3; The photocatalyst is selected from one of the following: 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 as claimed in claim 1, characterized in that: The alkaline substance is K2CO3.

3. The method for achieving methoxymethylation under photocatalytic conditions as claimed in claim 1, characterized in that: The photocatalyst is PC6.

4. The method for achieving methoxymethylation under photocatalytic conditions as claimed in claim 1, characterized in that: The molar ratio of the raw material (I), the alkaline substance and the photocatalyst is 1:2:0.

05.

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

6. The method for achieving methoxymethylation under photocatalytic conditions as claimed in claim 1, characterized in that: The visible light source uses blue LED.

7. The method for achieving methoxymethylation under photocatalytic conditions as claimed in claim 1, characterized in that: 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, 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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